Pharmacy and Drug Development

Abstract

One of the leading causes of mortality and morbidity, cancer has complicated pathogenesis.  Traditional cancer treatments include chemotherapy, radiation, targeted, and immunotherapy.  However, limitations, including lack of specificity, cytotoxicity, and multidrug resistance, are significant obstacles to effective cancer therapy. The field of cancer detection and treatment has undergone a revolution with the development of nanotechnology. Due to their unique benefits, such as biocompatibility, less toxicity, excellent stability, higher permeability and retention impact, and precision targeting, nanoparticles (1-100 nm) may be utilized to treat cancer. There are numerous significant categories into which nanoparticles fall. The unique nanoparticle medication delivery technology uses features of the tumor and tumor surroundings.  Nanoparticles not only circumvent multidrug resistance but also address the shortcomings of traditional cancer therapy. Moreover, nanoparticles are aggressively researched as novel multidrug resistance pathways are uncovered and analyzed. Nano formulations' many therapeutic implications have opened up fresh possibilities in the fight against cancer. Most research, however, is restricted to in vivo and in vitro experiments, and the number of Nanomedicines authorized throughout time has remained relatively high. This study covers many nanoparticle kinds, and targeting strategies, and tasked Nano therapeutics with oncological applications in cancer treatment. We also summarize the pros, disadvantages, and present state of clinical translation.

Introduction

Uncontrolled, random cell growth and invasiveness are features of a collection of illnesses referred to as cancer. This uncontrolled growth can form lumps or tumors and may spread to other tissues and organs. Extensive research has been conducted over the course of several years to identify several cancer risk factors. There exists a substantial correlation between the origin of many malignancies and certain environmental factors that are acquired throughout time, such as pollution and radiation. A sedentary lifestyle, smoking, alcohol use, stress, and other unhealthy behaviors all have a substantial impact on cancer risk assessment.  [1]

It has been challenging to determine the extent to which tumor suppressor gene expression patterns, DNA repair genes, and mutations in proto-oncogenes have contributed to cancer, even though these external variables are widely acknowledged as primary drivers of the disease. Just 5–10%–of cancer instances are related to genetic inheritance. [2]

About 23% of all fatalities in the United States are attributed to cancer, which is regarded as the second leading cause of mortality after heart disease. The likelihood of developing breast or prostate cancer is 29% and 28%, respectively, making them the most prevalent malignancies in both men and women. [3]

Surgery, chemotherapy, radiation therapy, tumor-specific therapy, targeted therapy, immunotherapy, and hormone therapy are traditional therapeutic modalities used to treat cancer [4]. Surgery may relieve pain and increase patient survival when used as the primary treatment strategy for solid tumors. Another treatment for tumors is chemotherapy, which kills malignant cells, and radiation. However, having the capacity for cytostasis and cytotoxicity, chemotherapy and radiation treatment are often associated with acute side effects and a significant risk of recurrences. The primary goal in treating various malignancies is tumor-specific therapy, which has not been covered by the previously discussed tumor therapeutic techniques [5]. The most frequent adverse reactions caused include neuropathies, bone marrow suppression, gastrointestinal and skin conditions, hair loss, and fatigue. The anthracyclines and bleomycin induced cardiotoxicity and pulmonary toxicity are additional drug-specific adverse effects [6].

As a result, cancer immunotherapy is becoming a standard treatment for cancer patients. Several immunotherapeutic antibodies and cell therapies are in development [7]. In particular, PD-1 inhibitors have been approved for treating melanoma, non-small cell lung cancer, renal cancer, Hodgkin’s lymphoma, bladder cancer, and head and neck cancer. Immune checkpoint blockades have also been developed using antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1). However, cancer immunotherapy comes with its side effects, such as autoimmune disease. Moreover, immunotherapy is less successful against solid tumors than lymphoma because these malignancies develop an immune-suppressive tumor microenvironment (TME) and an aberrant extracellular matrix (ECM) that is difficult for immune cells to penetrate [8].

In light of these facts, the need for developing novel approaches to pursuing targeted cancer therapy has grown in recent years. Recently, attempts have been made to use nanoparticles to overcome the shortcomings of current medicinal techniques. By showing excellent pharmacokinetics, accurate targeting, fewer side effects, and decreased drug resistance, nanoparticle-based drug delivery systems have shown advantages in treating and managing cancer. [9]

Many nontherapeutic medications have been developed and extensively sold in the wake of nanotechnology breakthroughs, and many more have reached the clinical stage since 2010. By enabling medication combination treatment and inhibiting drug resistance mechanisms, nano therapeutic medicines have advanced drug delivery methods and anti-tumor multidrug resistance (MDR). In the 1960s, ETH Zurich launched the first attempt to use nanotechnology in medicine [10]. This combination has shown to be a more effective amalgamation for creating numerous diagnostic tools and improved treatments. This study primarily focuses on fundamental ideas behind the use of nanotherapeutics, existing problems, and future directions [11].

Technically speaking, nanoparticles (NPs) are described as particles with one dimension less than 100 nm and distinctive features often absent from bulk samples of the same material. The overall shape of the nanoparticles may be categorized as 0D, 1D, 2D, or 3D [12]. The surface layer, the shell layer, and the core, essentially the NP's center component and often referred to as the NP itself, make up the elemental composition of nanoparticles, which is highly complicated.  These materials have become very important in various disciplinary sectors due to their unique qualities, such as high surface: volume ratio, dissimilarity, sub-micron size, and increased targeting system [13]. The ability of nanomaterials to carry vast quantities of agents, many medications, or probes onto the surface or inside of a cell without interfering with its function is due to their smaller size than that of a cell. Due to their small size, these particles may quickly infiltrate tissues and pass via tiny vessels. These particles increase the drug's therapeutic index and blood circulation half-life with fewer adverse effects and no platelet activation.  Nanoparticles may also make water-insoluble medications more bioavailable and shield therapeutic molecules from physiological barriers. Such tiny particles provide enough surface area and methods for quick drug release [14].

Deep tissue penetration of NPs is also discovered to boost the increased permeability and retention (EPR) impact. For instance, NPs coated with the hydrophilic polymer polyethylene glycol (PEG) reduce opsonization and evade immune system clearance. By adjusting the particle polymer properties, maximizing the release rate of medications or active moieties is also feasible. Together, the unique characteristics of NPs control their therapeutic impact in the prevention and treatment of cancer. [15]

Preparation and Characterization of Medical Functional Nanoparticles

According to their component materials and functions, nanoparticles typically employed in medicine may be categorized into three types: metal, non-metal, and composite. Factors including size and form influence their physical and chemical characteristics. Choosing an appropriate preparation procedure is crucial in light of the functional needs of nanoparticles in various application areas. Bottom-up approaches and top-down approaches may be used to categorize all nanoparticle preparation techniques.

The top-down method entails a solid material starting to break down into nanoparticles. In contrast, the bottom-up approach involves basic units (atoms, molecules, and even smaller particles can be used as the basis for assembling the required nanostructures) stacked on top of each other to form nanoparticles [16].

This technique called the constructive approach, entails constructing the material from more superficial elements such as atoms, clusters, and NPs. Sol-gel synthesis, chemical vapor deposition (CVD), plasma or famous spraying synthesis, laser pyrolysis, and biosynthesis are frequently employed techniques.

Metal nanoparticles are the most regularly utilized of the three nanoparticles often employed in medicine. Metals and metal oxides are examples of materials with metal nanoparticles. The sol gel (Sol-Gel) method, introduced by Japanese scientist Sugimoto et al. in the 1990s and is often used to generate monodisperse metal oxide particles in a liquid phase, is the most widely used method for producing metal nanoparticles. The sol-gel preparation technique uses a bottom-up approach. The primary idea behind this technique for making metal nanoparticles is to create an evenly distributed metal ion sol using physical and chemical methods and then create a gel using a redox reaction. The gel-produced metal nanoparticles have a controlled ability to nucleate, develop, and deposit. The size of the generated metal nanoparticles may be adjusted as long as the monodispersed metal colloid utilized in the experiment, the concentration relationship of the metal ions, and the oxidizing/reducing agent are all under control. Co-precipitation, hydrothermal, and photochemical methods often utilize bottom-up techniques for producing metal nanoparticles (Fig. 1). The co-deposition process involves simultaneous nucleation, growth, and aggregation in a liquid environment. Many tiny, insoluble particles are produced when a solution is oversaturated. By adjusting the vapor pressure delivered to the substance in the solution, the hydrothermal technique is carried out in a liquid environment to regulate the shape of the resultant nanoparticles [17].

The destructive process sometimes called the top-down approach, reduces bulk material or substance to synthesize NPs. A giant molecule is broken into smaller pieces and then transformed into NPs. Mechanical milling, nanolithography, chemical etching, laser ablation, sputtering, electro-explosion, and thermal breakdown are some methods used.Surprisingly, altering the reaction conditions and other synthesis factors may change the morphological properties of NPs, such as size, shape, and charge. Moreover, the development method also influences the chemical characteristics of NPs. So, it is crucial to comprehend the growth process to produce the necessary NPs. [18]

Furthermore, top-down techniques like electrical wire explosion and ball milling may be used to create metal nanoparticles. The theory of electrical wire explosion holds that during the electric outbreak, metal atoms are rapidly cooled in the electrolyte and evaporated, forming oxide nanoparticles. Finer and more uniform nanoparticles may be controlled by adjusting the electrolyte's composition and current strength. Ball milling is a technique for producing nanoparticles on a massive scale quickly and with adjustable size by choosing the right grinding time and associated equipment process parameters. This preparation technique may be used to create nanoparticles other than metal nanoparticles. Non-metallic nanoparticles are the second most prevalent kind. Polymer nanoparticles, biomolecule-derived NPs, carbon-based NPs, and silica nanoparticles are examples of non-metallic nanoparticles often employed in medicine. The most typical of them are silica nanoparticles. The silica surface includes many hydroxyl groups,

Consequently, functional expansion may be achieved by mixing nanoparticles made of various materials into composite nanoparticles using different production techniques. To create near-infrared responsive nanohybrids, Wei et al.  produced gold nanorods (AuNRs) and then engaged in surface-initiated atom transfer radical polymerization (SI-ATRP) of N-isopropylacryla-mide (NIPAAM) on Au NRs [20]. This metal and polymer composite nanoparticle can release drugs in response to photothermal and near-infrared light. This nanoparticle has superior biocompatibility than individual Au nanoparticles thanks to its encasing hydrogel shell. Using the enhanced Stöber approach, Prakash created composite NPs with an Au core and a SiO2 shell. The inert surface of core-shell nanoparticles helps to increase the material stability and drug-carrying capabilities of the initial single metal NPs while lowering the toxicity of metal particles. Along with the traditional preparation methods for nanoparticles mentioned above, new demands for ecological and environmental protection have been made due to the advancement of nanotechnology science [21]. As a result, new environmentally friendly nanoparticle synthesis methods have emerged. Hajar et al. effectively synthesized ZnS nanoparticles with a particle size ranging from 1 to 40 nm using Stevia rebaudiana as a biological reducing agent for the first time. This method produces ZnS nanoparticles with high biocompatibility. P. fractal (a plant in the family Leguminosae) extract was utilized by Miri et al. to the swift synthesis of CeO2 NPs with a particle size of around 30 nm following the principles of green chemistry. The biocompatibility of these nanoparticles is excellent [22].

Mechanisms of Cellular Targeting

Developing or engineering a medication or gene delivery system with a tremendous capacity to target tumor cells while preserving normal healthy cells is vital for successful cancer treatment.  It increases therapeutic effectiveness, protecting healthy cells from cytotoxicity. It is possible to do this by strategically delivering NPs to the tumor microenvironment (TME) and indirectly targeting cancer cells. These nanoformulations can cross several physical and biological barriers.  These barriers are intricate systems comprising several membranes and layers, including epithelium, endothelium, and cellular membranes (mechanical, physicochemical, and enzymatic obstacles). To avoid non-specific targeting, these realities restrict the size, biocompatibility, and surface chemistry of NPs. Therefore, internalizing an NP drug molecule in the cytosol does not guarantee it has reached its subcellular target. To allow cellular or nuclear targeting, specific engineering and optimization are required.

Research has been conducted to find NP-based medication targeting design, and more are coming. These nanocarriers should typically have a few fundamental properties, including the ability to: 1) stay stable in the bloodstream until they reach their target, the TME; 2) avoid reticuloendothelial system (RES) clearance; 3) avoid mononuclear phagocyte system (MPS); 4) accumulate in the TME via tumor vasculature; 5) high-pressure penetration into the tumor fluid; and 6) arrive at the target and only interact with tumor cells [23]. The process of NP drug targeting is controlled by crucial factors such as surface functionalization, physicochemical features, and pathophysiological traits.

NPs potentially treating cancer typically vary in diameter from 10 to 100 nm. Discussing the targeting mechanisms to comprehend the connection and interplay between NP carriers, cancer cells, and tumor biology is crucial. Passive and active targeting are the two primary categories into which the targeting systems may be divided.

Passive targeting strategy:

Nanoparticles' capacity to circulate in circulation for longer will be increased by optimizing their size and surface properties, giving them a better chance of reaching particular tumor areas. The principal objective of a passive targeting technique is to preferentially concentrate macromolecules, including nanocarriers, in tumor tissues thanks to the unique pathophysiologic characteristics of tumor vasculature [24].

Moreover, rapidly expanding cancer cells have a high metabolic rate for which an adequate supply of oxygen and nutrients is often insufficient. Since tumor cells employ glycolysis to generate more energy, the environment is acidic [26]. The pH-sensitive nanoparticles, like liposomes, are made to be stable at physiologic pH (7.4) but break down and release the active form of pharmaceuticals when exposed to the acidic environment of tumor cells. Moreover, most of the linkers in medications with nanocarrier conjugation are peptidase-sensitive or acid-labile. For instance, preclinical and clinical investigations have shown that the matrix metalloproteinase-2 is overexpressed in melanoma. Matrix metalloproteinase-2 is essential for the breakdown of extracellular matrix and basement membranes. According to research by Mansour et al., a vital chemotherapy medication called doxorubicin has a water-soluble maleimide derivative with an octapeptide sequence unique to the enzyme matrix metalloproteinase-2. The cysteine-34 position of circulating albumin was discovered to have a significant affinity for this polymer-drug combination. The matrix metalloproteinase-2 effectively and precisely cleaved the albumin-bound form, releasing the free doxorubicin [27].

The targeted use of drug-loaded nanoparticles is another method that enables the passive delivery of therapeutic medicines using nanocarriers. Anticancer medications have been seen to be more effectively delivered to tumors using various techniques, such as intraperitoneal and intravesical injections, which provide the medication directly to the tumor tissue without circulating throughout the body. Another intriguing strategy has been looked at is the direct injection of the medication into tumors [28]. For instance, when mitomycin was administered directly into the target tissue, the drug's concentration at the tumor site was increased, and its toxicity decreased [46]. The drawback of targeted drug delivery by intratumoral injection is that such methods may expose patients to greater therapeutic agent concentrations, which is only sometimes practical and invasive. Moreover, the tumor's location is occasionally unclear, making it difficult to treat certain tumors, such as lung cancer, under such circumstances [26]. However, although including the fundamentals of clinical treatment, passive targeting techniques have several drawbacks that may prevent them from producing the desired clinical results.

Active Targeting:

Active targeting depends on specific molecules or ligands, such as transferrin and folate, which bind to molecules or receptors mainly expressed or overexpressed on the target cells (diseased organs, tissues, cells, or subcellular domains) [30]. Ligand-mediated targeting is the name given to this method of targeting. Here, the target must be close to the NPs with ligands with particular activities, such as retention and uptake, to increase affinity. This tactic increases the likelihood that NPs will connect to cancer cells, increasing medication penetration. The first evidence of this was found in 1980 when antibodies were grafted onto the surface of liposomes. Several other forms of ligands, such as peptides and aptamers, were then used. As a result, the principal strategy is to boost the crosstalk between NPs and the target without changing the overall biodistribution [31]. The target substrate receptors' identification of ligands is a critical component of active or ligand-mediated targeting. Proteins, peptides, antibodies, nucleic acids, carbohydrates, and tiny compounds like vitamins are illustrative ligands. The receptors for transferrin, folate, glycoprotein, and epidermal growth factor are often researched (EGFR). With receptors, ligand-target interaction causes the membrane to infold and endocytose NPs.

This method makes it feasible to decrease the blood supply to the cancer cells, resulting in hypoxia and necrosis. Tumor tissues have been discovered to be more acidic than healthy tissues, and the Warburg effect has been used extensively to explain this [33]. This explains why the metabolism of cancer cells switches to glycolysis, where lactic acid is produced. The cell perishes when lactic acid builds up in it. Cells begin over-expressing proton pumps, which release different lactic acids into the extracellular environment and raise the acidity. Thus, a pH-sensitive drug delivery system based on liposomes has been researched. The multivalent nature of the NPs enhances the crosstalk of ligand-coated NPs with target cancer cells. Such NPs need complicated design since NP architecture and ligand-target chemistry affect the whole method's effectiveness. The system's effectiveness is also influenced by other elements, including the administration route, the size of the NPs, and physicochemical characteristics like ligand density (Fig:2).

Nanoparticles for PTT and PDT

Nowadays, photothermal therapy (PTT) and photodynamic therapy (PDT) using nanoparticles (NPs) have shown the benefits of significant effectiveness, modest invasion, and common side effects for treating tumors. Photothermal and photo-dynamic immunotherapy, also known as PDT and PTT treatment, uses fragments of dead tumor cells created by PDT and PTT to treat tumors indirectly and directly [35]. Using a novel class of light-to-heat conversion nanomaterials called PTT nanoparticles, cancer cells may be killed by converting light energy into heat energy.  Nanoparticles offer several benefits over conventional photothermal conversion materials. By altering the particle surface, NPs may produce tumor-targeted aggregation, increasing the target tumor's capacity for enrichment [36].

In contrast to conventional photothermal materials, which can be precisely positioned by CT, MRI, and photoacoustic imaging, nanoparticles offer superior imaging capabilities [37]. By damaging the tumor cell nuclear DNA and impeding the DNA repair process, targeted nanoparticles created by Pan et al. may conduct PTT under 0.2 W/cm2 NIR to cause tumor cell death. Examples of recent NPs used in PDT and PTT are shown in Table 1. Moreover, several investigations have demonstrated that PTT mediated by nanoparticles may reverse tumor multidrug resistance (MDR). MDR in different malignancies is often thought to be caused by the overexpression of drug transporters, multidrug resistance-associated protein 1 (MRP1), and p glycoprotein (p-gp) [38]. By inhibiting the expression of MRP1 in PTT, for instance, Li et al. multifunctional.'s light-triggered nanoparticles may reverse the drug resistance of A549R cells.  According to Wang et al., carbon-based and gold nanoparticles may overcome DOX resistance by encouraging the expression of heat shock factor trimer in PTT, subsequently preventing the production of p-gp [39]. By disrupting the integrity of tumor cell membranes, nanoparticle-mediated PTT may also improve the efficacy of chemotherapy. PDT is a treatment that uses the selective retention of photosensitizing substances (PSs) in tumor tissue to produce singlet oxygen and other reactive oxygen species, which cause tumor cells to apoptosis and necrosis when activated by light of a particular wavelength and the presence of molecular oxygen. Traditional PS, however, is unstable, has low solubility, and has poor tumor targeting, making it susceptible to the internal environment [40]. Targeted molecules may be added to nanoparticle carriers to increase PS's stability, biocompatibility, and capacity to reach target cells, boosting effectiveness and lessening side effects. Moreover, several popular nanomaterials, like gold nanorods, exhibit fantastic PTT effects. For example, Vankayala et al. discovered that gold nanorods exposed to near-infrared light (915 nm) effectively promoted singlet oxygen production [41].

Up-conversion (UC) nanoparticles' function in PDT has recently received much interest. The UC may replace the conventional ps-dependent short-wavelength excitation light with near-infrared light with excellent tissue penetration capacity thanks to the NPs' ability to transform long wavelength light excitation into numerous short wavelengths. For instance, Li et al. created PS carriers using dual-band luminous lanthanide nanoparticles. This UC nanoparticle uses the 808 nm excitation light wavelength to enable image-guided PDT without compromising imaging signals [42]. As metals comprise the majority of photosensitive materials used in phototherapy, more work must be done to increase the biocompatibility of NPs made for inorganic nanomaterials like metal ions. As the treatment uses the physical characteristics of NPs skeleton, NPs-mediated phototherapy is now attributed to its efficiency against tumors and the potential for spare internal space of nanoparticles. NPs often perform several functions as a result of PDT and PTT. Such NPs could one day be developed as specific NPs for tumor stem cells resistant to chemotherapy. Chemotherapy is ineffective against tumor stem cells because they have been inactive for a long time and contain a range of drug-resistant compounds; however, light therapy is more efficient since it physically kills the tumor stem cells. Nano-physical treatment may be used with various approaches in the future, such as the multifunctional NPs for photothermal treatment after cryosurgery. To the fullest extent possible, multifunctional NP-mediated treatment may use its advantages of reduced side effects, potent local lethality, and tumor stem cell eradication. Nano-physiotherapy may also treat tiny metastases since it has a local killing impact and may successfully eliminate tumor stem cells.

Table 1: Typical NPs platforms used in PDT and PTT

Mechanism of cancer immunotherapy

Understanding the workings of cancer immunotherapy is necessary before discussing the usage of nanoparticles to treat cancer. Cancer immunotherapy eliminates tumor cells through a cancer immunity cycle, as seen in Fig. 3. Tumor antigens are collected by APCs, such as dendritic cells, and displayed on significant histocompatibility complex when cancer cells die via apoptosis or necrosis (MHC). To stimulate developing T lymphocytes, dendritic cells carrying cancer antigens go to the lymph nodes. Activated tumor-specific cytotoxic T lymphocytes (TCLs) then invade the tumor site and connect with T-cell receptors and MHC complexes to detect tumor cells. Last, effector T cells boost the immune response by killing cancer cells by triggering apoptosis, which releases more cancer antigens. Each of these mechanisms is crucial for producing a potent anti-cancer reaction, and several factors nonetheless constrain the anti-cancer immune response's therapeutic effectiveness. When tumor-killing pro-inflammatory cells like tumoricidal M1-polarized macrophages destroy tumor cells, the dead cells produce immunosuppressive substances, including IL-10, TGF-, and sphingosine-1-phosphate (S1P), which induces macrophages to switch from M1 to M2 [47].

Moreover, apoptotic tumor cells release chemoattractants that cause monocytes to infiltrate the TME, such as monocyte chemoattractant protein-1 (MCP-1) and bombesin (BN) [48]. These monocytes undergo a process known as a tumor-associated macrophage (TAM) differentiation, which helps the tumor grow and evade immune surveillance [49]. Moreover, the infiltration of myeloid-derived suppressor cells (MDSCs) after tumor cell death aids in the inhibition of the immune response to cancer. Immunosuppressive regulatory T (Treg) cells are activated due to MDSCs' anti-inflammatory cytokine secretion. Dendritic cell maturation promotes tumor remission, while Treg prevents it [50].

To make matters worse, immune-suppressive molecules on tumor cells (such as PD-L1 and PD L2) and T cells (such as CTLA-4 and PD-1) suppress the activation of TCLs when they reach tumor tissues to kill the tumor cells, allowing the tumor to evade the anti-cancer immune response and ultimately limiting the efficacy of immunotherapy [51]. These events show how critical it is to get beyond the limits of the available cancer immunotherapies. Nanomaterials may intervene at different points during immunotherapy therapies to further boost anti-cancer immunity. Tumor antigens released from tumor cells are recognized by antigen presenting cells (APCs). Matured APCs migrate to the lymph nodes, leading to priming and proliferation of T cells. T cells activated by APCs are transferred to tumor tissues, where they kill tumor cells. Finally, tumor antigens from killed cancer cells induce another round of the immune response, leading to a cancer–immunity cycle.

Delivery of cancer antigens through nanoparticles:

Tumor antigens must be successfully delivered to APCs to promote tumor immunity. Tumor associated antigens (TAAs) and tumor-specific antigens are two categories for them (TSAs).  TAAs are antigens that manifest more often in cancer cells than in healthy cells or when cancer cells differentiate. TAAs may result in an autoimmune response if used as immunotherapeutic targets since they are also expressed on normal cells. TSAs, also known as neo-antigens, on the other hand, are only found in cancer cells. As a result, methods that target TSAs are immunological tolerance and autoimmune disease free. However, these endogenous tumor antigens have low immunogenicity because they are poorly transferred to immune cells and rapidly broken down by bodily enzymes. Tumor antigens must be appropriately transported to the lymph nodes to successfully trigger an anti-cancer immune response since the immune response is predominantly started in secondary lymphoid organs. In light of this, nanoparticles have been thoroughly investigated as delivery systems for securely delivering tumor antigens to lymph nodes. Nanoparticles are particularly advantageous because they may shield tumor antigens from the body's digestive enzymes and facilitate targeted distribution to the lymph nodes. APCs successfully absorb cancer antigen-containing nanoparticles after delivery [52].  While nanoparticle-mediated delivery systems may solve many of the challenges mentioned above, there are a few things to remember when using such techniques, especially concerning nanoparticle design.[53]

Particle shape is a significant component that affects lymph node drainage of nanoparticles in addition to particle size. Prior formulations of nanoparticles were primarily spherical, but more recent developments in nanoparticle engineering have produced many forms (rods, prisms, cubes, stars, and discs). It is well acknowledged that non-spherical particles with larger aspect ratios have faster blood flow, longer margination effects [54], and greater capacity for penetration into solid tissues and malignancies.

In addition to particle size and shape, the surface charge of the carrier is crucial for cellular internalization and immune response activation. The cell's ability to absorb nanoparticles may be impacted by surface charge. Positively charged nanoparticles often elicit a more robust immunological response than neutral or negatively charged ones. Nevertheless, due to their frequent immobilization in the negatively charged ECM, positively charged nanoparticles show lower tissue permeability [55]. Cationic nanoparticles are more readily taken up by specific dendritic cells than neutral or anionic-charged particles when confined at the injection site. However, carriers with a positive surface charge can cause hemolysis and platelet aggregation, leading to premature antigen release, differences in cellular uptake, and altered antigen transfer kinetics [56]. As a result, they can be problematic for lymphatic transport and trafficking in vessels.

Recent studies have shown that biomaterials containing hydrophobic domains, such as PLGA and chitosan, have intrinsic adjuvant action and may activate immune cells without external cues [57]. For instance, enhanced side-chain hydrophobicity in nanoparticles constructed of amphiphilic poly (gamma-glutamic acid) (PGA) improves antigen absorption and dendritic cell activation in vitro as well as cellular responses in vivo [58].

Modulation of the immune-suppressive TME using nanoparticles:

By producing an immunosuppressive TME, tumors may encourage the proliferation and spread of cancer cells. As a result, one key tactic in cancer immunotherapy is environment manipulation [59]. Immunosuppressive T cells called Tregs may stop anti-tumor T-effector cells from working. By immunological tolerance to autoantigens, Tregs help avoid autoimmune diseases, but in the case of cancer, they may suppress immune cells in the TME and impair anti-cancer immune actions.  It is feasible to functionally reduce or even eradicate the Tregs to generate anti-tumor immunity.  For instance, checkpoint blocking is a frequent strategy in cancer immunotherapy to regulate Treg function (e.g., anti–CTLA-4). Moreover, it is possible to create nanoparticles that may eliminate Tregs from the TME [60]. The TME has a large population of immune cells called TAMs. High amounts of the immune regulatory cytokines IL-10 and TGF- are produced by these cells, and they also generate inflammatory cytokines, including IL-12, IL-1b, TNF-, and IL-6, that suppress anti-cancer immune responses. As a result, eliminating TAMs from the TME is crucial for successful cancer immunotherapy. Surface-modified nanoparticles that can target and destroy TAMs have recently been used in many efforts to increase the efficacy of anti-cancer treatment. TGF-, an overexpressed cytokine in breast, liver, and lung cancer, suppresses immune cell activation, maturation, and differentiation. As a result, blocking the TGF-signaling pathway in the TME may trigger an immune response against the tumor. MDSCs are tumor-suppressor cells frequently found in the TME of breast, lung, gastrointestinal, and liver cancers. Recently, TGF-inhibitors encapsulated in lipid nanoparticles were delivered to the TME, inducing innate and adaptive immune responses, suppressing tumor growth, and improving survival in mice with metastatic melanoma. MDSCs produce IL-10, ARG1, NOS2, and indoleamine 2, 3-dioxygenase (IDO) to activate Tregs and squelch other immune cells. As a result, removing MDSCs might significantly enhance cancer immunotherapy. By either active transport using different targeted ligands or passive transport via the increased permeability and retention (EPR) effect, nanoparticles may transfer immune modulators to the TME. Immune-modulating drugs could be delivered to the TME. Recently, the Lin group reported a novel method for overcoming immune suppressive TME by combining nanotechnology and various therapeutic modalities [61]. Their trial included radiation, dynamic radiotherapy, an IDO inhibitor, and checkpoint blockade immunotherapy [62]. In a mouse tumor model, local tumor eradication was achieved by injecting nMOFs into the tumor and then treating it with low-dose X-ray radiation. When nMOF and an IDO inhibitor are administered together, abscopal reactions are induced [63], facilitating the effective treatment of distant tumors.

Figure 1: the schematic diagram of the sol-gel method. [78]

Figure 2: Pictorial representation of active cellular targeting. [86]

Figure 3: Cancer–immunity cycle [113].

Literature Review

Nanoparticle-Mediated Combination Therapy for cancer treatment

To address combination treatment employing NPs and anticancer medications, new advancements in research are being reported and analyzed in this review. We first give a thorough overview of angiogenesis and the various NP types currently being used to treat cancer; those highlighted in this review are metallic NPs used in combination therapy with different anticancer agents, liposomes, polymeric NPs, polymeric micelles (PMs), dendrimers, carbon NPs, nanodiamond (ND), fullerenes, carbon nanotubes (CNTs), and nanocomposites made of graphene oxide (GO). Convenient instruments for combination treatment have been made possible by nanotechnology; however, we need ongoing advancements in nanotechnology for clinical translation [63]

Nanoparticles as carriers for drug delivery in cancer treatment

Here we will concentrate on the types and properties of nanoparticles, the use of nanoparticles as drug delivery systems to kill cancer cells more efficiently, the reduction or elimination of drug resistance, and the development of nanoparticles to enhance their therapeutic efficacy and functionality in future cancer treatments. Eventually, learned how nanotechnology is used as a vital tool in Nanomedicine and cancer research [64].

Nanoparticles for Cancer Diagnosis and Treatment

This article tries to outline the current state of nanoparticle applications in tumor diagnostics and therapy. It also identifies the barriers to the clinical use of nanoparticles and suggests workable alternatives. Some of the following factors, such as the challenge of NP localization in vivo and the challenge of NP degradation in the human body, prevent the therapeutic use of NPs [65].

Targeting metallic nanoparticles for the promising strategy for cancer treatment

Describe the most current research on the capacity of nanostructures to induce autophagy overstimulation and cell death in malignant cells in this review. To provide the reader with a more thorough introduction to this subject, we have also included sections on autophagy, where its mechanics and ramifications are covered in depth, and various applications of nanomaterials in nanomedicine. [66]

Nanoparticles for Cancer Therapy: Current Progress and Challenges This review covers a wide range of nanoparticle kinds, targeting strategies, and approved nanotherapeutics for use in the treatment of cancer. Additionally, we summarize the merits, disadvantages, and present state of clinical translation [67].

New opportunities for nanoparticles in cancer immunotherapy

In-depth analysis of current nanoparticle usage trends in cancer immunotherapy. We first outline the mechanisms underpinning cancer immunotherapy to highlight the unmet nanoparticle needs in this field. The function of nanoparticles in delivering cancer antigens and adjuvants is then discussed. The use of nanoparticles within the immune-suppressive TME is then covered.  Finally, we review the present and potential applications of image-guided interventional nanoparticles in cancer immunotherapy. [68]

Purpose of the study

1. To compile the most promising information about the nano particle-based cancer treatment.
2. To know the mechanism of cancer immunotherapy.
3. To know the organic nanoparticles, used in cancer therapy.
4. Compile Inorganic nanoparticles used in cancer treatment.
5. To know about targeting metal‐based nanoparticles as therapy in cancer diseases.
6. Compile the information about limitations of nano particle-based cancer treatment.
7. Compile for additional research purposes.

Methods

Method of searching

The following terms were used to analyze traditional books and databases like PubMed, SciFinder, Elsevier, Springer, Scopus, Science Direct, Google Scholar, and Web of Science between 2000-2022 on limitation & future prospects of Nanoparticles based cancer treatment.

 Inclusion Criteria

1. Mechanism of cancer immunotherapy
2. Inorganic and organic Nano particle used in cancer treatment 
3. Metal based particle used in cancer treatment 

Exclusion criteria:

• There is no Treatment able to Curable100% of cancer treatment.

Data analysis:

To study and create the objects, an exploratory reading of the numerous articles was done while evaluating the work's title and abstract. After finishing the exploratory analysis, read just the papers that discussed how Future potential for cancer treatment using nanoparticles and their limitations. Making a primary file, working on paraphrasing, and using Grammarly before producing a final review paper.

Results

Functional nanoparticles for medication delivery these submicron-sized particles (3-200 nm), devices, or systems may be created from a range of substances, such as lipids (liposomes), polymers (polymeric nanoparticles, micelles, or dendrimers), viruses (viral nanoparticles), and even organometallic compounds (Table 2).

Organic Nanoparticles use in cancer therapy

Polymeric Nanoparticles:

It is generally known that polymeric nanoparticles (PNPs) are "colloidal macromolecules" with a particular structural architecture created by various monomers. To accomplish controlled drug release in the target, the drug is either encapsulated or bonded to NPs exterior, generating a Nano sphere or a Nano capsule [66]. Originally, non-biodegradable polymers, including polyacrylamide, polymethylmethacrylate (PMMA), and polystyrene, were used to create PNPs.  Due to the difficulty in getting rid of them from the system, their buildup led to toxicity.  Poly (amino acids), chitosan, alginate, and albumin are examples of biodegradable polymers currently employed and are known to minimize toxicity while enhancing drug release and biocompatibility. This has been shown in the study by exploiting the polysorbates surfactant effect and coating PNPs with polysorbates. The blood-brain barrier's (BBB) endothelial cell membrane interacts more favorably with NPs when they are covered on the outside [67].

According to research, indomethacin-loaded nanocapsules significantly reduced tumor growth and increased survival in a rat xenograft glioma model. This sector is expanding, with more than ten polymeric NPs carrying anticancer medicines under clinical development. PEG-camptothecin (Prothecan), Modified dextran-camptothecin (DE 310), HPMA copolymer-DACH-platinate (AP5346), HPMA copolymer-platinate (AP 5280), HPMA copolymer-paclitaxel (PNU166945), and HPMA copolymer-doxorubicin galactosamine (PK2) are a few examples [68].

Dendrimers:

Dendrimers are spherical macromolecules made of polymers that have a distinct hyper-branched structure. Dendrimers are characterized by their highly branching architectures. Usually, an ammonia core and acrylic acid are reacted to begin the production of dendrimers. This reaction creates a "tri-acid" molecule, which then combines with ethylenediamine to produce "triamine,” a GO product. This item further interacts with acrylic acid to create hexa-acid, which then makes “hexa-amine" (Generation 1), and so on [69]. The dendrimers typically have sizes between 1 and 10 nm. The size, however, might be as large as 15 nm. They target nucleic acids because of their unique structure, including specified molecular weight, modifiable branching, bioavailability, and charge. Polyamidoamine (PAMAM), poly (ethylene glycol), polypropylene imine (PPI), and triethanolamine (TEA) are a few dendrimers that are often utilized [70]. Initially, a PAMAM dendrimer was intended to control MDR. PAMAM dendrimers made of DNA have received considerable description. The synthetic dendrimers markedly slowed the development of epithelial cancer xenografts compared to mice given single-agent treatment.

mAb Nanoparticles:

The ability of monoclonal antibodies to specifically target cancer cells makes them a standard component of cancer therapy. NPs are added to these mAb to create antibody-drug conjugates (ADCs). They are more powerful and precise than cytotoxic medications or mAb alone. In controlling HER2-positive breast epithelial cells, for example, an antibody-drug NP comprised of a paclitaxel core and a surface modified with trastuzumab showed higher anti-tumor activity and lower toxicity than single-agent paclitaxel or trastuzumab alone [71].

Liposomes:

These spherical vesicles, which may be unilamellar or multi-lamellar and contain phospholipids, encapsulate medicinal compounds. Because of their low inherent toxicity, little immunogenicity, and biological inertness, liposomes are exceptional in this regard. The first nanoscale medication, liposomes, received approval in 1965 [72]. "Hydrophobic phospholipid bilayer" and a "hydrophilic core" comprise the usual liposome structure. They may successfully preserve the entrapped medication from environmental deterioration in circulation because of their distinctive design, which allows them to trap both hydrophilic and hydrophobic drugs [73].

Inorganic nanoparticle in cancer therapy

Carbon Nanoparticles:

As the name implies, carbon serves as the basis for carbon nanoparticles. Because of their optical, mechanical, and electrical qualities and their biocompatibility, they have been extensively used in medical fields. Carbon nanoparticles (NPs) may encapsulate pharmaceuticals by stacking because of their inherent hydrophobicity. Graphene, carbon nanotubes, fullerenes, carbon nanohorns, and graphyne are other categories for carbon NPs [74]. While carbon-based, each has a different structure, morphology, and characteristics. Using an sp2-hybridized carbon sheet, "graphene" is a 2D crystal with exceptional mechanical, electrochemical, and high drug loading capabilities. Graphene may also be categorized into the following groups depending on its composition, characteristics, and composition: 1) single-layer graphene; 2) graphene oxide; 3) reduced graphene oxide; and 4) multi-layer graphene. Because of their capacity to address hypoxia and erratic angiogenesis in TME, GO, and rGOs are commonly employed. In cellular models of breast cancer, studies have shown that GO doxorubicin has more potent anticancer activity [75].

Large carbon-cage molecules known as fullerenes come in various conformations, including spherical, ellipsoid, and tube. Due to their characteristic structural, physical, chemical, and electrical features, they are the most extensively investigated nanocarriers [81]. They are used in photodynamic treatment because of their triple yield, capacity to absorb light, prolonged-conjugation, and generation of oxygen species. Fullerenes treated with PEG showed positive photodynamic effects on tumor cells [76].

The cylinder-shaped carbon nanotubes (CNTs), sometimes called rolls of graphene, were first identified in the late 1980s. One category includes single-walled CNTs, while the other includes multi-walled CNTs. As they are carbon-based, they may interact with immune cells to elicit an immunological response, inhibiting tumor development. They have traditionally been employed for thermal ablation treatment and as DNA delivery vectors. For instance, fluorescent single walled CNTs with mAb encapsulating doxorubicin are utilized to target colon cancer cells.  Doxorubicin is released intracellularly when such CNTs are successfully absorbed by cancer cells, but the CNTs themselves are kept in the cytoplasm [77].

Quantum Dots

To be extensively employed in biological imaging, quantum dots must have nanometer-scale semiconductors with a broad range of absorption, narrow emission bands, and outstanding photostability. They are classified into three categories based on carbon: graphene quantum dots, nanodiamond quantum dots, and carbon quantum dots. Quantum dots are being extensively researched for cancer therapy and biological imaging. Due to their intrinsic biocompatibility and quick elimination, graphene quantum dots are the most often employed quantum dots. For instance, prostate cancer cells are the target of quantum dots aptamer doxorubicin conjugate [78].  The main challenge is an optimal procedure for generating quantum dots.

Targeting with metal‐based nanoparticles as therapy in cancer diseases

The most current research on metallic nanoparticles' capacity to excessively induce autophagy and mitophagy in cancer cells is included in this section. This happens due to the deregulation of a few cellular signaling pathways, but it has little to no impact on the autophagy activity of non-cancerous cells. The effect of various nanomaterials on the control of autophagy and mitophagy provides an intriguing therapeutic strategy against various human malignancies.

Silver‐based nanoparticles: 

Many studies demonstrated that silver nanoparticles (Ag-NPs) have tremendous therapeutic potential against various cancer cells. These nanoparticles have been shown to have the ability to control autophagy and serve as cytotoxic agents alone, in conjunction with other therapies, and as nanocarriers for therapeutic compounds [79]. It has been shown, for instance, that Ag-NPs embedded in a particular exopolysaccharide (EPS) have a lethal impact on various cancer cell types. This happens due to the encouragement of ROS, which stimulates apoptosis and autophagy to cause cell death. These findings were further supported in SKBR3 cells after Ag In a separate study, HeLa cancer cells were exposed to Cisplatin and a reduced graphene oxide silver nanoparticle nanocomposite (rGO-Ag-NPs). The buildup of autophagosomes and autophagolysosomes, which were connected to the production of ROS and cell death, was interestingly more prominent when Cis and rGO-Ag-NPs were combined. Our results show that rGO-Ag-NPs may enhance Cis-induced cytotoxicity, apoptosis, and autophagy in HeLa cells; as a result, rGO-Ag-NPs may be used as a potent synergistic agent with Cis or any other chemotherapeutic agent to treat cervical cancer. Interestingly, A2780 ovarian cancer cells were much more cytotoxic and accumulated autophagolysosomes when combined with Salymicin (Sal) and Ag-NPs. Massive autophagy activation caused the mitochondrial malfunction and cell death, making it a practical therapeutic approach for managing ovarian cancer [81].

Moreover, it was shown that using radiation with Ag-NPs dramatically improved the cytotoxic effects on U251 glioblastoma cells in an orthotopic mouse brain tumor model. In addition, LC3- II protein level, acridine orange (AO), and mono dansyl cadaverine (MDC) staining showed that autophagy was significantly up-regulated after the treatment of Ag-NPs with ionizing radiation, suggesting that modulating the autophagy process may improve the therapeutic outcome for glioblastoma. A group of autophagic genes, including MAPLC3B, SQSTM1, UVRAG, WIPI, VPS11, VPS18, and ATG9B, are up-regulated by transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, to control autophagy [80]. Ag-NPs have recently been shown to decrease the expression of TFEB in A459 lung cancer cells, impacting lysosome activity and autophagic function and causing cellular damage [82].

Gold‐based nanoparticles:

Because of their low toxicity and immunogenicity, outstanding biocompatibility, and exceptional durability, gold nanoparticles (Au-NPs) have been thoroughly investigated in biomedical research as drug delivery scaffolds [83]. Surprisingly, chemotherapeutics, oligonucleotides, and proteins are simple to add to the surface of Au-NPs, making them effective delivery systems. According to a study, pH-sensitive polymeric nanoparticles containing gold (I) cause the death of MCF7 breast cancer cells by controlling oxidative stress and autophagy.

Metal oxide‐based nanoparticles:

Due to their appealing chemical characteristics, zinc oxide nanoparticles (ZnO-NPs) are often utilized in commercial goods and, more recently, in biological and cancer applications.  According to recent research, ZnO-NPs may significantly increase the cytotoxicity, apoptosis, and autophagy of SKOV3 ovarian cancer cells while also increasing intracellular ROS and oxidative stress. By triggering PINK1/Parkin-mediated mitophagy, ZnO-NPs have also been demonstrated to cause toxicity in the CAL27 oral cancer cell lines [92]. In MCF-7 and MDA-MB-468 breast cancer cells, it has been suggested that conjugating ZnO NPs with meso-tetra (4-carboxyphenyl) porphyrin (MTCP) might boost their lethal effects [93].  These data imply that ZnO-NPs may be used as anticancer agents. Iron oxide nanoparticles (IO-NPs) are employed extensively in biomedicine because of their super-paramagnetism and biocompatibility multi-functional qualities. They are also used to treat cancer due to their drug transport and multi-imaging capabilities. Unfortunately, several problems with their biological safety and therapeutic efficacy restricted their development and clinical translation. Interestingly, IO-NPs have been found to activate autophagy via various pathways, including ER stress, mitochondrial damage, and lysosome dysfunction [94]. By removing G2/M cell-cycle arrest, generating DNA damage, autophagy, and apoptosis, and inhibiting both in vitro and in vivo lung tumor development, IO/Au-NPs conjugated to anti-EGFR inhibit lung tumor growth.  Researchers created chitosan chloride (HTCC)/alginate-encapsulated Fe3O4 NPs (HTCC-MNPs) and used them on models of MDR gastric cancer in a definitive study. Interestingly, they found the new HTCC-MNPs to be more cytotoxic than the regular gastric epithelial cell line in the SGC7901 human gastric cancer cell line and the MDR variant cell line (SGC7901/ADR) (GES).  Moreover, the co-localization of LC3 with the lysosomal marker LAMP2 and an elevated LC3- II/LC3-I ratio demonstrated that HTCC-MNPs induced autophagy. As a result, our findings indicated that autophagy was to blame for the cytotoxicity brought on by HTCC-MNPs and that its regulation may help treat MDR gastric cancer [95]. Moreover, it has been shown that IO-NPs preferentially promote considerable autophagy-lysosome accumulation and cell death in lung and cervical cancer cells but not in normal cells via deregulation of the Akt/AMPK/mTOR pathway and in a dispersity-dependent manner [96].

According to further research, PEGylated IO-NPs significantly damaged the SKOV3 human ovarian cancer cells via various processes, including the creation of ROS and the activation of apoptosis. Interestingly, the scientists used TEM imaging and LC3-II level detection to track changes in autophagosome formation in SKOV3 cells treated with PEGylated-IO-NPs.  According to the authors' findings [97], autophagy induction may have a protective function against cytotoxicity brought on by IO-NPs. In a different research, it was shown that the photothermal action of IO-NPs might, in a laser dose-dependent way, induce autophagy in both MCF-7 cancer cells and the MCF-7 xenograft model. Inhibiting autophagy would improve photothermal cell death by boosting cell apoptosis.  As a result, this research may provide a viable treatment method that combines photothermal agents with autophagy modulators [98]. Other nanomaterials with biomedical applications include cuprous (Cu-NPs) and copper oxide nanoparticles (CO-NPs), which have shown potential pharmacological effects on tumor therapy by inducing apoptosis, preventing metastasis, and promoting autophagic cell death in leukemia, melanoma, lung, and breast cancers. [99]

NPs might trigger autophagy through the mTOR/AKT pathway. Also, they noticed that the creation of autophagosomes increased with time and concentration. Their research offers early support for CO-NPs' therapeutic potential in managing cervical cancer. Moreover, CO-NPs have been shown to time- and dose-dependently trigger autophagy in the MCF7 human breast cancer cell line. According to the study's authors, CO-NPs may cause autophagy as a cellular defense against their inherent toxicity. Autophagy suppression may be necessary to induce apoptosis in breast cancer cells [100].

Silica‐based nanoparticles:

Several studies have shown that amorphous silica nanoparticles (Si-NPs) offer unique qualities, including biocompatibility, variable pore size, large surface area, and simplicity of modification.  Si-NPs have been extensively used in drug administration, gene transfection, biosensing, and bioimaging. These nanostructures have been shown to stimulate autophagy and increase osteoblast differentiation. In hepatocytes, Si-NPs have also been shown to promote the production of ROS, oxidative stress, and ER stress, all of which activate autophagy through unfolded protein response (UPR) pathways [101]. Additional research revealed that Si-NPs negatively impact cancer cells via autophagy regulation, underlining their potential therapeutic benefit. As a possible therapeutic agent for treating glioblastoma multiforme, Si-NPs have been shown to induce apoptosis, mitophagy, autophagy, and ultimately ROS buildup in glioblastoma LBC3 cells [102].

It has been intriguingly shown that Si-NP accumulation in human cervical carcinoma cells may cause lysosomal dysfunctions and autophagy abnormalities, decreasing the metabolic activity of cancer cells. Genistein-PEGylated Silica Hybrid Nanomaterials (Gen-PEG-SiHNM) have recently been produced, and they can inhibit the proliferation of HT29 human colon cancer cells by inducing apoptosis and autophagy [103]. According to this research, Gen-PEG-SiHNM may soon be employed as a different therapy for colorectal cancer. In HCT-116 colon cancer cells, L02 and HepG2 hepatoma cells, ROS and autophagy dysfunction have also been observed to be induced by Si-NPs, offering new data for the research of Si-NPs' harmful effects and safety assessment. When these organelles are destroyed, a specific type of autophagy called endoplasmic reticulum-involved autophagy (ER autophagy) may capture them. Recently, it has been shown that Si-NPs cause HCT-116 human colon cancer cells to undergo endoplasmic reticulum (ER) autophagy without having a significant lethal impact. The rise in LC3-II, seen as a result of these nanomaterials' autophagy induction, was indicative of treatment duration rather than concentration. Our recent discoveries on Si-NPs-induced ER autophagy may pave the way for safely developing silica-based nanoparticles. They may even prove to be a useful therapeutic tool for conditions associated with autophagy [104]

Nanomedicine

One of the top businesses doing studies on nanomedicines for cancer therapy is CytImmune.  CytImmune, established in 1988, has evolved from a successful diagnostics firm into a clinical-stage nanomedicine company with a primary emphasis on researching, developing, and marketing multifunctional, tumor-targeted medicines (Table 3). With the successful conclusion of the Phase I clinical study of CYT-6091, the first in a line of products based on CytImmune’s Aurimune nanomedicine platform, it has established itself as a world leader in the area of nanomedicine (cytimmune.com). It uses colloidal gold nanoparticles to deliver medications directly to cancer tumors. To direct the nanoparticle into cancer tumors, CytImmune employs a variety of methods (Table 4). The nanoparticle is first made to be too large to leave the majority of healthy blood arteries. Nevertheless, some of the blood vessels around tumors are porous, which enables the nanoparticle to escape from the blood artery at the tumor location [29]. They also include molecules of Thiol-derivatized polyethylene glycol and tumor necrosis factor-alpha (TNF-), a tumor-killing drug, inside the nanoparticle (PEG-THIOL). PEG-THIOL shields the TNF containing nanoparticle from the immune system, enabling it to pass through the bloodstream unharmed. Bind the nanoparticle to cancer cells near a cancer tumor with a TNF molecule. The unique technique of CytImmune is based on colloidal gold particles that deliver specific medications to targets like cancer cells. [64]

Table 2: The variety of nanoparticles employed in cancer cell death and their mechanism of action.

Table 3: Nanoparticle in cancer treatment.

Table 4: Future prospective on nanomedicine for cancer treatment.

Discussion

Nanoparticles are intriguing for cancer treatment because of their diverse physicochemical properties. The ability of nanomaterials to carry vast quantities of agents, many medications, or probes onto the surface or inside of a cell without interfering with its function is due to their smaller size than that of a cell. Due to their small size, these particles may quickly infiltrate tissues and pass via tiny arteries. These particles improve the therapeutic index and half-life of the medicine in blood circulation, and there are fewer adverse effects and no platelet activation. Nanoparticles may also make water-insoluble medications more bioavailable and shield therapeutic molecules from physiological barriers. Such tiny particles provide enough surface area and delivery mechanisms for quick medication release. Therapeutic medications can be covalently bonded, adsorbed, or enclosed in nanoparticles. The therapeutic agents will release once the drug-loaded Nano carrier reaches the site of action. There is relentless work going on the world over towards achieving an effective alternative to chemotherapy and a better cure for cancer. Though efforts to treat cancer and improve the efficacy of drugs through nanotechnology are at the research or development stage, nanoparticles have been extensively used in biomedical applications. [105].

A completely new era has begun due to the use of nanotechnology in the diagnosis, management, and treatment of cancer. NPs increase the intracellular concentration of medications while preventing toxicity in healthy tissue by active or passive targeting. To establish and control the drug release, the targeted NPs can be created and modified to be either pH-sensitive or temperature-sensitive. The acidic TME can receive medications through the pH-sensitive drug delivery mechanism. Similarly, when sources like magnetic fields and ultrasonic waves cause temperature changes, temperature-sensitive NPs release the medicines at the target spot. The "physicochemical characteristics" of NPs, such as shape, size, molecular mass, and surface chemistry, play a considerable role in the targeted drug delivery system.

Because of unequal distribution and cytotoxicity, traditional chemotherapy and radiation therapy have several drawbacks regarding their efficacy and adverse effects. As a result, careful dosing is necessary to successfully destroy cancer cells without significantly increasing toxicity. The drug must successfully navigate multiple fortifications to reach the target site. The metabolism of drugs is a highly intricate process. Under physiological conditions, the medication must cross the TME, RES, BBB, and renal infiltration. "Blood monocytes, macrophages, and other immune cells" comprise the RES, also known as the macrophage system. When the medications interact with MPS in the liver, spleen, or lungs, "macrophages or leukocytes" are activated, which quickly remove the drug. This causes the drug's half-life to be brief. To get around this, NPs with "surface modification," like PEG, extend the "drug half-life" and get around this mechanism. Additionally, kidney function is an essential bodily process; thus, proper renal infiltration reduces the toxicity of NPs. The brain-blood barrier (BBB) is a unique defense mechanism that shields the central nervous system (CNS) from poisonous and damaging substances. The "brain capillary endothelial cells" are organized to form a wall that feeds the brain with vital nutrients. Since the BBB primarily aims to prevent hazardous substances from entering the brain, the only effective chemotherapeutic treatments for brain cancer are intraventricular or intracerebral infusions. But NPs have been known to cross the BBB. NPs are delivered using various methods, including transcytosis, targeted ultrasound, peptide-modified endocytosis, and the EPR effect.  Methotrexate absorption in rats was improved by glutathione PEGylated liposomes encapsulated with the drug. As they have been shown to assist in transporting medications that induce apoptosis, Au-NPs are frequently employed.

Since NPs are transporters, they also prevent the enclosed cargo from degrading, which increases the drug's stability. Furthermore, many pharmaceuticals can be possessed without experiencing a chemical reaction. Dry solid dose formulations are more stable than nano-liquid compounds.  Applying stabilizers can improve stability, and using porous NPs is another technique to enhance stability.

Limitations

The most prevalent malignant illness in both men and women, cancer has limits with current pharmacological treatment. Notwithstanding the therapeutic benefits of nanomaterials, it is essential to remember that these substances may sometimes cause toxicity, a phenomenon known as nanotoxicology. The modification of autophagy may cause the reported toxicity and therapeutic benefit. As an illustration, it has been demonstrated that Si-NPs can cause cytotoxicity and autophagy cell death in human umbilical vein, cerebral, and corneal endothelial cells through a variety of mechanisms, such as ROS production, dysregulation of the PI3K/Akt/mTOR pathway, affecting angiogenesis and cellular homeostasis, and causing mitochondrial instability and mitophagy [105]. It has also been shown that Si-NPs may cause cytotoxicity and autophagy dysfunction in human bronchial epithelial BEAS-2B cells, depending on their size. This was accomplished via upregulating the PI3K/Akt/mTOR pathway in a size- and dose-dependent manner and by upregulating the autophagy markers LC3 and p62 [1066]. This work demonstrates how Si-NPs may cause autophagy failure and cellular homeostasis impairment in the respiratory system. Si-NPs may also cause autophagy and cell death in neuronal PC12 cells, according to research. The stimulation of autophagy, with a rise in ROS and suppression of the ubiquitin-proteasome system (UPS), causes mutant-synuclein to aggregate, which is a substantial risk factor for the onset of Parkinson’s disease [107]. High levels of magnetic iron oxide nanoparticles (Fe3O4-NPs) have also been linked to cardiovascular illnesses, inflammatory conditions, and endothelial dysfunction in HUVECs via the stimulation of autophagy and the blocking of autophagy flux.

Titanium dioxide nanoparticles (TiO2-NPs) are semiconductor nanomaterials that have been investigated for use in medication delivery and are garnering more and more interest. While this nanomaterial’s significant cytotoxic impact on several cancer cells has received much research, HaCaT human keratinocyte cells may respond by going into autophagy [108]. In the BV-2 microglia cell line, autophagy, ROS level, and mitochondrial impairment were significantly and time-dependently elevated by ZnO-NPs, according to a recent study. It has also been found that PINK1/parkin-mediated mitophagy occurs in addition to alterations in autophagy markers.  According to the findings provided by the authors, ZnO-NP-induced toxicity in BV-2 cells may be mitigated by mitophagy. The specific neurotoxic activity of a copper-dopamine compound in neuronal RCSN-3 cells has also been found, despite the therapeutic promise of CO-NPs in a range of cancer cell lines. This happens by triggering mitochondrial autophagy, which is followed by caspase-3-independent apoptosis. By autophagy and lysosomal dysfunction, CO NPs also cause HUVEC cell death [109]. Ag-NPs coated with polyvinylpyrrolidone (PVP) have reportedly shown anti-leukemic effects on human myeloid leukemia cells. Ag-NPs have also been shown to activate cytotoxic autophagy in non-cancerous murine pro-B cells (Ba/F3) via manipulating the PI3K/mTOR signaling pathway as the production of ROS and the release of silver ions. Interestingly, some research suggests that metallic nanoparticles have inherent toxicity against immune system components because they regulate autophagy. Macrophages are diverse immune system cells that play a role in innate immune responses and adaptive immunity by digesting antigens [110]. According to studies, Ag NPs impede autophagy caused by lysosomal dysfunction, impairing monocyte-macrophage differentiation. Lysosomal dysfunction was seen in Ag-NP-treated THP-1 cells, and this is what is causing the blockage of autophagic flux. This work demonstrates that Ag-NPs' simultaneous induction of autophagy, lysosomal dysfunction, and monocyte differentiation all interact. In RAW264.7 cells originating from mouse peritoneal macrophages, Fe3O4-NPs have also been shown to activate pro-survival autophagy. The ERK pathway was activated for cell survival, together with the activation of autophagy markers and ROS levels following treatment with Fe3O4-NPs. It's interesting to note that autophagic immune cell death is reportedly caused by acute exposure to ZnO-NPs. This happens when free Zn (2+) is released and taken up by immune cells, which causes excessive intracellular ROS to be produced and aggravation of autophagy.  Several further investigations concluded that Si-NPs harm resistant system components by enhancing pro-inflammatory reactions, oxidative stress, and autophagy regulation [111]. Studies like these and others (reviewed in Peynshaert, 2014) suggest that autophagy regulation caused by inorganic NPs may pose a danger to the immune, cardiovascular, and neurological systems.  Before drawing any firm conclusions about these nanomaterials' actual cardiovascular and neurological risks and ultimately effectively targeting autophagy as a therapeutic strategy, it is necessary to investigate further the involvement and nature of autophagy deregulation in the pathogenesis of the diseases mentioned above.

Conclusion

The interaction of hereditary and environmental variables brings on complex diseases like human malignancies. In addition to the numerous cellular and genetic modifications, cancer cells have several shared characteristics that account for their phenotypic manifestations, such as unchecked growth and proliferation, dysregulation of apoptosis and sensitivity, and severe metabolic changes [112]. Damaged macromolecules and organelles are sent to lysosomes during autophagy, a closely controlled cellular degradative process, where they are eventually destroyed. Although autophagy is frequently dysregulated in tumors, its role in maintaining cancer cell survival or death is still hotly contested. It depends on the cells' metabolic context and microenvironmental circumstances [113]. According to several research studies, basal autophagy may protect cancer cells by giving them the nutrients they need to grow unchecked and promoting cancer cell survival in numerous hypoxic tumor microenvironments. However, it is also widely accepted that excessively activating the autophagy machinery can result in cell death, commonly known as cell death-type II, which is most likely brought on by the excessive destruction of cellular components and organelles essential for maintaining cellular homeostasis [114]. There is growing evidence that inhibiting autophagy may be used as a standalone treatment or boost the effectiveness of anticancer medicines [105]. The field of nanotechnology is rapidly developing and offers the tools required to surpass the limitations commonly encountered with conventional therapies.

An overview of the most recent studies on NP-mediated autophagy changes and their effects on nanomedicine is provided in this review. Several studies have demonstrated that by modifying autophagy, nanomaterials can be used to treat cancer, especially in particular metallic nanoparticles. These nanostructures may also encourage a variety of conditions that lead to the activation of mitophagy, oxidative stress, and autophagic cell death, including mitochondrial damage, lysosome dysfunction, ER stress, and signaling pathway changes. In contrast to non-cancerous cells, these materials have demonstrated innate selectivity in activating autophagy in cancer cells. Metal-based nanomaterials can activate pro-survival autophagy in cancer and normal cells, suggesting they may play opposing roles in determining a cell's fate [108,109]. Medicinal plants provide a diverse range of bioactive compounds used in treating various diseases. These natural products exhibit pharmacological properties, making them ideal for integration with nanoparticles to enhance therapeutic efficacy. Nanoparticles act as efficient delivery systems, improving the bioavailability and targeting of plant-based medicines, offering innovative solutions for disease treatment. [115-121].

Nanoparticles can be engineered to specifically deliver plant-derived anticancer compounds directly to cancer cells, overcoming challenges like poor solubility and rapid metabolism. Furthermore, nanoparticles enable controlled drug release, allowing for sustained therapeutic effects. This combination of plant-based bioactive compounds with nanoparticle-based drug delivery systems offers innovative solutions for cancer treatment, improving precision, reducing side effects, and enhancing the overall therapeutic outcome [122-127].

Declarations

Acknowledgments

We thank members of our groups for insightful discussions during this study.

Disclosure statement: The authors have no conflicts of interest.

Funding

This study received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of generative AI and AI-assisted technologies in the writing process

No AI and AI-assisted technologies used in the writing process

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119. Momin, M. A. M., Bellah, S. F., Khan, M. R., Raju, M. I. H., Rahman, M. M., & Begum, A. A. (2013). Phytopharmacological evaluation of ethanolic extract of Feronia limonia leaves. America Journal of Scientific and Industrial Research Science, 4(5), 468-472.
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120. Momin, M. A. M., Bellah, S. F., Rahman, S. M. R., Rahman, A. A., Murshid, G. M. M., & Emran, T. B. (2014). Phytopharmacological evaluation of ethanol extract of Sida cordifolia L. roots. Asian Pacific journal of tropical biomedicine, 4(1), 18-24.
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121. Bellah, S. F., Raju, M. I. H., Billah, S. S., Rahman, S. E., Murshid, G. M. M., & Rahman, M. M. (2015). Evaluation of antibacterial and antidiarrhoeal activity of ethanolic extract of Feronia limonia Leaves. The Pharma Innovation, 3(11, Part B), 50.
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122. Bellah, S. F., Islam, M. N., Karim, M. R., Rahaman, M. M., Nasrin, M. S., Rahman, M. A., & Reza, A. A. (2017). Evaluation of cytotoxic, analgesic, antidiarrheal and phytochemical properties of Hygrophila spinosa (T. Anders) whole plant. Journal of basic and clinical physiology and pharmacology, 28(2), 185-190.
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123. Bellah, S. F., & Mostaharul, I. M. (2012). Development and Validation of Method for Determination of Esomeprazole by HPLC. The International Research Journal of Pharmacy, 3(7), 147-152.
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124. Momin Mohammad, A. M., Sharif, M. A., Begum, A. A., Bellah, F. S., Islam, M. M., & Talukder, P. (2013). Development and validation of method for determination of ciclesonide in (micronized) by HPLC. International Research Journal of Pharmacy, 4(7), 55-59.
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125. Ashrafudoulla, M., Faisal, S. S., Kairm, M. R., & Bellah, S. F. (2015). Hypoglycemic complications with diabetes mellitus management: the predominant adverse drug reaction presenting to the accident and emergency patient of Birdem hospital Dhaka, Bangladesh. The Pharma Innovation, 4(10, Part B), 97.
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126. Ashrafudoulla, M., Bellah, S. F., Alam, F., Faisal, S. S., Kafi, M. A. H., & Fuad, F. (2016). Phytochemical screening of Solanum nigrum L, S. myriacanthus Dunal, Solanum melongena and Averrhoa bilimbi in Bangladesh. J Med Plants Stud, 4, 35-38.
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127. Md. Rezaul Karim, Md. Abdul Aziz, Sm Faysal Bellah, Md. Nasir Uddin, Md. Sultan Mahmud, 2018. Comparative free radical scavenging, thrombolytic, cytotoxic, antimicrobial and analgesic activities of different parts of Centella asiatica (Apiaceae) Britsh Journal of Pharmaceuticals and Medical Research. 3(2); 885-890.
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128. Ferdous, M. R., Ashrafudolla, M., Hossain, M. S., & Bellah, S. F. (2018). Evaluation of antioxidant, analgesic and antidiarrheal activities of methanolic extract of Litsea monopetala (roxb.) leaves. Clin Pharmacol Biopharm, 7(3), 185.
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