Background

The field of medicine faces challenges for effectively addressing the complexities of cancer, a multifaceted group of diseases characterized by uncontrolled growth and spread of abnormal cells. Unlike normal cells, which follow a regulated life cycle, cancer cells disrupt this balance and undergo uncontrolled division, leading to the formation of tumor masses[1]. Many factors contribute to development of cancer, like—genetic predisposition, food habits, lifestyle changes, infection caused by harmful microorganisms, and environmental factors [2]. Cancer has become a global burden with approximately 10 million deaths in the year 2022 [3,4,5]. The conventional therapies include radiation therapy, chemotherapy or combination therapy, while immuno-therapy, gene therapy, cell therapy, photodynamic therapy, and antibody therapy have also gained momentum, however, there effectiveness is still under debate as it lacks site specificity and low build-up inside the tumor cells [6, 7]. As a consequence, cancer treatment has now turned toward tailoring approaches which are patient specific depending on the profiles and characteristic of the disease. In this era, nanotechnology being a blend of technology, biomedicine and biomaterials, has been growing as a plausible approach to overcome the current shortfalls. Of them, NCs have sparked a lot of interest in the field of cancer therapeutics, offering unique advantages over conventional drug delivery systems. These nanoscale particles possess the ability to precisely target tumor tissues, stimulate drug solubility, and enhance therapeutic efficacy, revolutionizing the landscape of cancer treatment. The application of NCs in cancer therapy is driven by their small size, large surface area, and unique physicochemical characteristics. These attributes enable efficient drug loading and controlled release, facilitate targeted drug delivery with minimizing side effects on healthy tissues. They have also shown potential to overcome biological barriers, penetrating deep into tumor tissues by both active and passive pathways, and reaching intracellular targets, thereby maximizing treatment outcomes [8, 9]. In addition to drug delivery, NCs play a pivotal role in cancer imaging techniques. Their unique optical and magnetic properties have transformed cancer imaging, providing high-resolution and sensitive modalities. NCs in the form of semiconductor quantum dots, exhibit size-dependent fluorescence emission and high photo-stability, making them exceptional candidates for precise tumor visualization. Similarly, surface modifications with targeting ligands, NCs can be used as contrast agents for imaging, enabling accurate diagnosis, staging, and real-time monitoring of treatment responses [10, 11]. The integration of NCs with imaging techniques allows for multimodal approaches, facilitating comprehensive cancer diagnosis and personalized treatment regimens. Furthermore, NCs offer a versatile platform for combining different therapeutic agents within a single system, enabling synergistic effects, improved drug ratio, and targeted release. This approach enhances therapeutic efficacy while minimizing systemic toxicity. Further by engineering NCs to respond to external stimuli, controlled drug activation and spatiotemporal release can be achieved, paving the way for treatment tailored to individual patient profiles [12, 13].

Despite their immense potential, the full utilization of NCs in cancer treatment requires addressing challenges associated with formulation stability, scalability, and establishing reliable quality control measures. Thus, the current review comprehensively focuses on unveiling the potential of NCs as targeted delivery for the management of cancer.

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Brief insights on nanocrystals and their fabricating method

NCs are nanometer-sized particles consisting purely of drug substances stabilized using suitable stabilizers [14]. The term "nanocrystals" is specifically used to refer to these crystalline nanoparticles or liquid crystalline nanoparticles. Comparing NCs to other carrier-based nanoparticles (NPs), nanocrystals exhibit a high drug loading which allows for a reduction in dose while still enhancing bioavailability and drug safety. Also, for formulating NCs, there is practically no use of organic solvents, making NCs devoid of residual solvents and solvent associated toxicity concerns. Additionally, improved solubility and dissolution rate will promote the pharmacokinetics and bio-distribution of drugs as suggested by Peltonen et al. [15].

The main excipient in fabricating NCs include a stabilizer. The primary function of a stabilizer is to prevent ostwald ripening or aggregation of intrinsically diminuted drug nanoparticles and to preserve them in nano-crystalline form [16]. The selection of stabilizer and its concentration form one of the critical process parameter [17]. Now-a-days, researchers have a wide list of stabilizer starting from non-ionic, ionic, amphoteric to polymeric. Polymeric stabilizers have gained an edge over the others due to their enhanced wetting and steric stabilization property. These stabilizers impart stability to NCs via electrostatic repulsion, van der Waals forces, steric stabilization, surface coating, reducing interfacial tension, etc., [18].

Production techniques of NCs are categorized as top-down, bottom-up and combination technologies (details briefed in Table 1), subsequent section describes briefly the different sub-types of these technologies explored by researchers across the globe.

Table 1 Different techniques for formulating nanocrystals, including both top-down and bottom-up approaches, as well as combinational technologies [19,20,21,22]
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Top-down techniques diminute the drug substances in micron size state to nanometer size. Different approaches include—media milling, high-pressure homogenization (HPH) (diagrammatically described in Fig. 1), and ultrasonication. Media milling, a mechanical technique used for size reduction, has demonstrated considerable efficiency in the production of NCs. This method employs milling media to fragment drug particles into smaller dimensions, milling agent such as beads/coated balls made of—glass, zirconium oxide, chromium, agate or some special polymers for grinding of drug particles and a stabilizer to ensure the stability of formulation. The main principle of media milling includes impact and attrition [23,24,25,26]. HPH is another top-down technique used for NC formulation. It involves subjecting the drug suspension to high pressure (ranging from 100 to 2000 bar)/ultra-sonication, forcing it through a narrow nozzle or valve. During this process, the particles under-go high shear stress resulting in generation of nano-sized crystalline particles [27, 28]. Dissocubes, Nanopure and Nanoedge are few patented technologies based on use of HPH [29]. Another approach, utilizes ultra-sonication as a means to reduce the particle size. Probe sonicator is a tool to transmit high and low power ultrasound cycles through the drug suspension. These cycles create alternative low and high pressure respectively in the suspension, causing formation of bubbles in low pressure cycle, which break during high pressure cycle. These results in cavitation effect causing reduction in particle size [30, 31].

Fig. 1
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Top-down approaches for fabrication of nanocrystals

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An alternative strategy for develo** NCs is through a "bottom-up" approach, where drug substances are precipitated to form nanoparticles with accurate control on particle growth. The critical aspect with this approach is controlling the size of re-crystallized particles, as uncontrolled growth might result in Oswald ripening. Some of the technologies using these approach include- high gravity controlled precipitation, sono-crystallization, liquid jet precipitation, rapid expansion of supercritical solution, super critical anti-solvent, multi-inlet vortex mixing, evaporative precipitation into aqueous solution, etc. All these approaches have their own applications, however, major limitation lies in the use of organic solvents [20, 32, 33]. Some of these techniques have been modified by using supercritical fluids instead of organic solvents. Rapid expansion of supercritical solutions (RESS) and supercritical solvent/anti-solvent (SAS) methods of fabricating drug NC are based on the solubility of drugs in supercritical fluids [34, 35]. Hydrosol® and Nanomorph® are the patented technologies to produce drug NCs with size less than 100 nm. An innovative work reported by Han et al., revealed fabrication of paclitaxel nanocrystals (PNC) using a novel approach of evaporation and precipitation technique. The PNC were coated with tannic acid and ferric chloride to enable them for dual therapy—photothermal-chemotherapy. The in-vivo results exhibited mild photothermal activity along with strong tumor inhibition [36]. Through such innovative approach, advancements in the field of cancer treatment are being made, offering the potential for more effective and targeted therapies.

The combination technologies comprise of a two-step process—pre-treatment followed by processing. The pre-process step might be- pre-milling or precipitation, with a high-energy top-down process, such as milling or HPH, while the processing step includes evaporation, lyophilisation, etc. [37]. NANOEDGE®, was developed by Baxter, Inc., USA which involved precipitation of crystals as pre-treatment step and later the processing involved HPH to control the particle size and morphology [38]. More recent advancements have introduced- Nanopure® and SmartCrystal® technology into the market. Later technology integrated high-pressure homogenization with various pre-processes—like H42 (spray-drying pre-process), H69 (precipitation pre-process), H96 (lyophilization pre-process), and CT (media milling pre-process) [39, 40]. Hence, it could be summarized that all the different technologies are efficient enough for fabrication of different and stable NCs.

Role of nanocrystal technology in tumor targeting

Nanotechnology has sparked a lot of possibilities for effective delivery of poorly soluble drugs [41, 42]. They have emerged as a promising tool in the field of cancer therapy, offering unique properties and versatility to revolutionize treatment approaches [8]. One of the key advantage is their ability to serve as carriers for chemotherapy drugs by addressing crucial challenges of poor solubility, limited bioavailability, and systemic toxicity, thereby enhancing drug stability and solubility while enabling their efficient delivery to the tumor site. By modifying the surface of NCs with specific ligands, such as antibodies or peptides, they can be engineered to selectively recognize and bind to cancer cells. These targeted approach facilitates the direct delivery of therapeutic agents to the tumor site while minimizing exposure to healthy tissues [107].

Fig. 3
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Pharmacokinetics and bio-distribution of nanocrystals via different routes of administration

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Oral administration

NCs when administered via oral route enter into the GIT. A part of the NCs are absorbed via villi in the intestine, the remaining amount enters the blood stream while some still get excreted via feces. In the intestinal lumen they form complex with the bile acid, which later go across the mucus layer, epithelial layer and finally reach the blood capillary. In the blood stream, enzymes cause metabolism of the NCs in liver and spleen, a part of it is excreted via kidney and a fraction reaches the target site. In a study, PTX-NCs were administered orally to BALB/c tumor-bearing mice with two doses 80 mg/kg and 60 mg/kg. The tumor volume measured after day 6 of the treatment revealed reduction to one third volume when treated with NCs as compared to free PTX [108]. In another study PTX-NCs were coated with N-((2-hydroxy-3-trimethylammonium) propyl) chitosan chloride (HTCC) maintaining the average particle size around 130 nm, were observed to be localized in GIT within 3 h of oral administration. Eventually after 24 h, fluorescence signals showed their preferential accumulation in the tumor. The control group treated with taxol, also inhibited the tumor growth, however, the NCs had long residence time in tumor resulting in remarkable inhibition. The medial survival rates were lengthened even after discontinuation of the treatment [8, 109]. Thereby, such studies have unveiled the path traveled by NC after oral administration.

Parenteral administration

Upon i.v. administration the NCs enter the blood stream and bruit around in the body. During this journey they encounter interactions with different proteins and other elements present in the blood stream. While circulating, they stumble on with the mononuclear phagocytic system (MPS), the larger size NCs are taken up by these MPS present in organs. The smaller size NCs, take a french leave across the MPS and show prolong circulation in the blood. Upon reaching the tumor site, they penetrate through the leaky vasculature of the tumor cells and undergo the EPR effect resulting in accumulation of NCs. Some of NCs enter the lymphatic system via the lymph nodes of the tumor tissue and go efferent into the blood stream. The extended circulation of NCs ensure their extended residence in the tumor, resulting in better efficacy and lower toxicity to healthy tissues [110, 111].

Diving into the fate, NCs are recognized and rapidly taken up by the phagocytic cells of macrophages. At this time, they are also labeled by opsonins, and immunoglobulins. They will be docked onto the receptors present on the macrophages, monocytes, and neutrophils, causing catastrophe of NCs via phagocytosis. The in-vivo fate is influenced by many factors- particle size, surface charge, surface hydrophilicity/hydrophobicity, morphology, dissolution rate, as well as concentration. Among these factors surface morphology influence the most [112]. Many anticancer drugs are delivered in the form of NCs—methoxyestradiol (2-ME), puerarin, and oridonin via i.v. injection [113, 114]. In a recent study consisting of PTX and campothecin NCs stabilized using pluronic-F127, significant inhibition of growth of human cancer and murine breast cancer, was observed [115, 116]. Similarly, PTX-NCs having nearly spheroid shape and hydrodynamic diameter of 419.9 ± 80.9 nm, were surface coated with polydopamine to form a reaction platform for effective PEGylation and RGD peptide conjugation. Cellular uptake and growth inhibition studies over A549 lung cells demonstrated superior activity over non-PEGylated NCs. The results suggest intratumor accumulation and retarded tumor growth, giving a hope toward coating being effective in functionalization of NCs for enhanced anti-cancer activity [117]. In another study, tocopheryl polyethylene glycol succinate (TPGS) stabilized PTX-NCs showed better therapeutic effect in taxol-resistant ovarian cancer both in-vivo and in-vitro [118]. Similarly, campothecin NCs were studied over lung metastasis of MDA-MB-231 and MCF-7 tumors. The results supported with the confocal images of the tumor sections revealed a better inhibition of tumor metastasis and apoptosis with NCs compared to campothecin salt solution and control group [116]. Such study reports supply glimpse of information depicting the in-vivo fate of NCs upon parenteral administration.

Applications of NC in cancer diagnostics and bio-imaging

NCs have also garnered significant attention in the field of bio-imaging offering promising prospects toward unambiguous detection. Cellulose NCs (CNCs) conjugated with fluorescent agents (rhodamine-B-isothiocyanate and FITC) have been explored for therapeutic imaging of tumors by measuring the acoustic signals. Similarly, non-conjugated CNCs were used for photoacoustic imaging of ovarian cancer in mouse models. The peak photoacoustic signal was reported at 700 nm with doses below 1.2 mg/mL in carcinomatous cells. For efficient bioimaging the NCs were conjugated fluorescent agent to passively trigger cell internalization with insignificant toxicity [119]. Mahmoud et al. proved the capability of fluorescent CNCs to penetrate the cancerous cells without a sign of toxicity and no effect on integrity of cell membrane. They also provided evidence of intake of positively charged CNC-RBITCs within the membranes of Spodoptera frugiperda (Sf9) and human embryonic kidney 293 (HEK 293) cells, while CNC-FITC were not taken-up owing to their negative charge. These reports suggest the relevance of surface charge of NCs with their uptake [120]. Magnetic-NCs in the form of magnetic probes have opened new avenues for bio-imaging with its signal enhancement capabilities. Although magnetic resonance imagining (MRI) is widely accepted diagnostic tool, its non-invasive nature, tomographic compatibilities and low-signal sensitivity hinders its applications. Iron-oxide-based magnetic NCs including superparamagnetic iron oxide (SPIO) are being used for enhancing the signal for better tomographic imaging. Recently, a water soluble magnetic iron-oxide NCs was fabricated with tunable MR signaling effect. The magnetic NC probes were successful in diagnosis of breast cancer tested over SK-BK-3 cell lines. Similar study was tested in breast cancer induce mice and the results suggest that the magnetic NC-antibody probe was able to signal the diagnosis of cancer with magnetic-field of 1.5 and 9.4 T. At higher magnetic-field Yong et al. [121] reported the detailed monitoring of cancer cells with complex vasculature and tumor tissues, thus suggesting the enlightening potential of magnetic NCs for diagnostics purposes.

Gold-NCs with different size and shapes have potential to extend the resonance from visible to near infrared range where light can infiltrate into the tissues. At resonance wavelength gold can absorb and scatter the light, this property enables a distinct color to gold which is sensitive to be detected by naked eye, making gold NCs excellent for biomedical diagnostics. Typically, such gold NCs have been extensively used for immunogenic strip test. The surface electrons on the gold NCs can amplify Raman scattering signals, thus AuNCs with immune probes/antibodies significantly enhance sensitivity and contrast of detection which are stable with repetitive analysis, making it an important candidate as imaging agent for cancer cell identification and diagnosis [122]. In a study conducted with fabrication of Eu/Gd codo** HAP-NCs using co-precipitation technique possess a luminescence property, which enabled successful cell labeling and in-vivo imaging [149]. For the therapeutic purpose, researchers developed ZnO-nanoparticles loaded with DOX. This co-administration caused synergistic effect and enhanced cytotoxicity [150]. Additionally, ZnO can be used for biosensing, which enables the early identification of malignancy [151]. Moreover, the effect of zinc nanostructures on living cells, in particular cancer cells, is still under debate.

Gold nanoparticles (Au-NCs)

Over the period of time, novel delivery carriers resulted in reduction in dose dependent toxicity in comparison to conventional products. These lead to increase in research on exploring metallic materials for targeted delivery and diagnosis. Au-NC are aggregates of Au atoms ranging between 10 to 400 nm in size. The amount of gold, material of inorganic substrates, pH of medium, temperature and mechanical forces used during the synthesis governs the shaper of Au-NCs. The Au-NCs when conjugated with stimuli-responsive polymers, are found to be used for targeted delivery to specific organs of human body [152]. Various reports have successfully loaded anticancer drugs—campothecin, thymectacin, busulfan and cyclosporine using Au-NCs [8].

A study to treat metastatic breast cancer was carried out by Wang et al., using DOX decorated Au-nanorods. With irradiation of near-infrared light over these decorated Au-nanorods, caused increase in temperature along with release of DOX within the tumor as Au-NCs show a sharp absorption peak around 500–550 nm due to excitation of surface plasmons. These combination was observed to be more toxic in 4T1 breast cancer cells [153, 154]. A similar study was conducted over 4T1 breast cancer cells with Au-NCs loaded with 10-hydroxycampothecin. The AuNCs possessed average size of 130 nm with 75% drug loading, when administered i.v, showed a sustain drug release pattern and enhanced cytotoxicity [155]. A study conducted by Shen et al., revealed the use of Au-NCs for inhibition of retinal angiogenesis. The Au-NCs with average size of 26.2 nm and potential of 24.9 mV, were able to inhibit the cell proliferation to an extent of 50–72% and 54–83% inhibition of cell migration at concentration 10 µg/mL and 20 µg/mL, respectively [156]. Li et al., carried out a study to test Au-NCs as potential antiangiogenic agents. In this investigation, Au-NCs were used to target human recombinant endostatin (angiogenesis inhibitor). The results showed promising effects with tumor vascular normalization and strengthened blood vessel [157]. Au-NCs fabricated in conjugation with hydroxylcampothecin and polydopamine, when injected i.v. into the mice, showed accumulation and cytotoxicity in the tumor [162].

According to Muhammad et al., AgNCs functionalized with PTX boost the anticancer activity in human cells. The PTX-NCs were surfaced with polydopamine, later the AgNPs and tumor targeting peptide NR1 was decorated onto the PDA. This grafted Ag-PTX-NC system dramatically enhanced the cellular absorption during in-vitro anticancer models. Additionally, the Ag-PTX-NCs showed synergistic influence causing cell membrane lysis, nucleus damage, mitochondrial dysfunction, ROS over production, and breakage of DNA. Such observations linked the potential application of NR1/Ag-NC decorated PTX for targeted therapy of anticancer drugs [163]. Liang et al., demonstrated the anticancer effect of camptothecin (CPT)/Ag-NCs. Silver exhibit excellent inhibitory effect on drug resistance related p-glycoprotein (Pgp) while CPT has proven data of being cytotoxic. The combination of both CPT/Ag-NCs was able to bypass the Pgp recognition resulting in indiscriminate cytotoxicity. In addition, the drastic release of CPT into the tumor triggered by cleavage of Ag-ions in acidic microenvironment led to chromatin structure breakage, DNA damage and apoptosis. Nevertheless, such exploration of molecular events needs support of in-vivo studies [164]. Kim et al. investigated the toxic effect of synthesized crystalline AgNPs on F9 cells. They identified the dose-dependent toxic effect of AgNPs was linked with leakage of lactate dehydrogenase, ROS, and mitochondrial dysfunctioning. At high concentration DNA fragmentation, neuronal differentiation, increased expression of apoptotic genes, and decreased expression of anti-apoptotic genes was reported. The results support the use of crystalline AgNPs for differentiation therapy in amalgamation with chemotherapeutic agents [165]. In a report published by Paul et al., the crystalline AgNPs were biosynthesized using ethanolic leaf powder extract of Premna serratifolia L. and possessed 22.97 nm size. Anticancer effect of the synthesized AgNPs was evaluated on Swiss albino mice induced with liver cancer. The results revealed AgNPs were non-toxic with protective effects of other organs while they sustained control over the cancer progression. Such studies open up ways toward cost-effective economic alternatives for anticancer therapy, however certain understanding of molecular mechanism restrain the use of synthesized Ag-NPs of P. serratifolia [166]. Nima et al. developed Ag–Au nanorods functionalized with certain molecules and antibodies improved photothermal contrast and surface-enhanced Raman scattering (SERS) for the diagnosis of breast cancer [167]. Thus, AgNCs embark great potential to be explored for diagnostic and therapeutic purposes. A brief list of metal based drug delivery explored for cancer therapeutics is reported in Table 5.

Table 5 Brief list of recent metallic based drug delivery explored for cancer therapeutics
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Regulatory challenges toward formulation of drug NCs

In addition to opportunities and challenges, hurdles pertaining to approval of NCs by the regulatory bodies are one of the major obstacle in its commercialization. A bridge needs to be build-up with validation, toxicity, reproducibility and stability of NCs produced in academic setting to enable collaboration with industries. A hel** hand with adopting minimal standards for conducting pre-clinical studies was offered by US-FDA and European medical agency (EMA), to promote clinical translation of academic-industry collaboration. On the other hand, following good manufacturing practice (GMP) becomes crucial while demonstrating the promise of technology for effective drug delivery and diagnostics. However, following GLP might increase the overall cost, but with previously demonstrated proof of concept, the collaborators may seek funding from different organization for the said purpose. Pre-clinical studies might also need placebo controlled treatment regimens for appropriate evaluation of safety and efficacy. In these context, FDA has initiated the Nanotechnology Regulatory Science Research Plan. The plan aims to address the gap in scientific knowledge required to make regulatory assessment of NCs hassle free. The plan includes major criteria- physio-chemical characterization, preclinical models, risk characterization, risk assessment, and risk communication open for discussion with collaborators [177]. A fruitful outcome of the plan is the establishment of Nanotechnology Characterization Lab, that performs characterization of the different nanoparticles received from government funded research labs, academia, and industry. These platform integrates academic-industry collaborations to gather relevant data for filing Investigational New Drug application. Thus, such resource utilization enables academic-industry collaborations for effective translation of the NC-based therapeutics established by academic to reach market [178].

A part from these, a significant consideration must also be given to selection of demographics for performing clinical trials. Recently, a phase 2 clinical study failed to achieve its primary end point for treating lung cancer, and prostate cancer using BIND-014 (PSMA-targeted docetaxel nanocrystals). This results reflect the need for designing clinical trials, considering selection of patients based on EPR, tumor heterogeneity, presence of target receptors, ability of NCs to bind to receptors, and the simultaneous need for diagnostics during the study are some of the crucial parameters for achieving better outcomes [175]. Another NC-based product called as Panzem Nanocrystal Colloidal Dispersion is currently under phase 2 clinical trials, being explored for its potential effect on prostrate and ovarian cancer. Some of the NC-based formulation approved for commercialization by FDA are listed in Table 6. A pioneering effort in this direction was adopted by Merrimack Pharmaceuticals, to determine the accumulation of ferumoxytol iron nanoparticles (FMX) using quantitative MRI and may predict the response to nanoliposomal-irinotecan. The study concluded that the tumors with high accumulation of FMX were more responsive to nano-liposomes [176]. This study was based on simultaneous quantitative estimation using MRI, and we believe that such initiatives along with pre-selection of patients will turn out to be a bridging bench-bed gap. Thereby promoting the commercialization of highly potent NCs with detailed safety and efficacy profiles along with backbone of clinical data.

Table 6 Drug NCs with approval of commercialization
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Conclusion and future prospects

Delivery of BCS class II and IV is challenging yet a promising pitch for research. NC-based drug delivery has emerged with incomparable drug loading over other carrier-based drug delivery systems for poorly soluble drug substances. Over the last two decades, NC technology have shown useful and prevailing role in the treatment of cancer providing improved drug targeting and delivery. Current research on these drug substances deals with strategies to improve their absorption and selective delivery to tumor cells, leading to emergence of surface functionalization and usage of novel excipients. To add cherry on the top, their functionalization with targeting ligands offers excellent dynamism to control the growth of tumors. With the on-going research, different new techniques have also evolved for the production of NCs. These techniques involve combination of top-down and bottom-up approaches to effectively rationalize their advantages. Nevertheless, the clinical efficacy of drug NCs depends on number of factors. The present review highlighted multifaceted applications of different types of NCs in the management of cancer. Metal based NCs have offered simultaneous application in diagnostic and therapy with targeted drug delivery, thereby revolutionizing cancer management and therapy. The drug-metal NC complex enable tracking within the body owing to their interaction with light, thus offer an efficient therapy in addition to chemotherapy. Despite these facts, their clinical translation and market authorization is challenging due to certain bottlenecks. Toxic effects are possible due to their tiny size and large surface area which boosts reactivity with the biological targets. Numerous problems with respect to long-term sustainability and safety of nanoparticles has always remained unresolved. Inflammation, genotoxicity, and organelle failure in cells are few dose dependent toxic effects of nanocrystalline particles. Also, the activation of oxidative enzymes results in increase in concentration of free radicals and in-turn increase oxidative stress and cell damage. Moreover, they have a great potential if the risks and toxicity are controlled from production to treatment. Certain ways including coating with polymers and with the concept of green synthesis, a relatively safe way for the use of metallic nanoparticles can be en-routed.

As far as biological challenges are concerned, the bridge between the disease pathology and human heterogeneity is required. Also, the physicochemical properties of drug NCs should primarily focus on overcoming biological barriers to achieve target and reduce build-up in nonspecific organs. Unfortunately, lack of attention toward these aspects, cause failure observed during the translation of promising NCs in clinical trials. These factors could be deterrent for pharmaceutical industries for investing on commercialization of NC-based products. To cope with this challenge, there is a dire need for inclusive evaluation of preclinical data with special emphasis on efficacy, safety, pharmacokinetics (ADME profile), targeting efficiency and stability with appropriate tumor induced animal models. Also, reproducibility of the results must be validated using different animal models, such practise will boost the reliability toward the anticancer therapy. For most of commercialized products, EPR-mediated accumulation has been reported in most of the animal models. Moreover, the tumors are heterogeneous and may possess inter and intra patient variability. With NC-based products, the amount of cellular uptake and drug release kinetics inside the target sites can be tailored, moving away from the traditional concept of one-size-fits all.

Although most of the research about drug NCs on cancer therapy are still in preclinical development, the motivation arises from those products which have reached the market, with enhanced circulation time, site specific cellular uptake, long retention in tumor environment and reduction in dose-dependent toxicity. Also, decorated NCs with targeting ligands have generated a ray of hope for cancer therapy. Even, NCs can be labeled with dyes/contrast agents to further augment visualization and theranostic applications. In nutshell, NC technology has profound opportunities to mitigate cancer therapy and with gradual maturation of drug NCs, commercialization of NC-based products will emerge like a boon for cancer therapeutics.