Potential applications of Folate-conjugated Chitosan Nanoparticles for Targeted delivery of Anticancer drugs

 

Prakash Nathaniel Kumar Sarella*, Pavan Kumar Thammana

Department of Pharmaceutics, Aditya College of Pharmacy, ADB Road, Surampalem,

Kakinada 533437, Andhra Pradesh, India.

 

ABSTRACT:

Folate-conjugated chitosan nanoparticles represent a promising nanoplatform for targeted delivery of anticancer drugs. The nanoparticle carrier can protect the therapeutic agents from degradation and offer the ability to target cancer cells overexpressing folate receptors. This review summarizes recent research progress in synthesizing folate-conjugated chitosan nanoparticles as well as evaluating their potential as targeted drug delivery systems. The chemical conjugation of folic acid to chitosan is first discussed followed by an overview of different techniques for preparation of stable folate-conjugated chitosan nanoparticles less than 200 nm in size. Recent studies loading various anticancer drugs into these nanoparticles and investigating their in vitro cytotoxicity against multiple cancer cell lines are then summarized. The results indicate that folate-conjugated nanoparticles exhibit higher cytotoxicity and targeting efficiency compared to non-conjugated nanoparticles due to receptor-mediated endocytosis. Lastly, future challenges and opportunities are outlined including in vivo investigations to determine the effectiveness, toxicity, and pharmacokinetics of folate-conjugated chitosan nanoparticle systems as well as their potential clinical translation as targeted drug carriers for cancer chemotherapy.

 

 

 

INTRODUCTION:

Nanoparticles are colloidal particles between 1 to 1000 nm in size that can be engineered for a variety of biomedical applications. One promising use of nanoparticles is as drug delivery vehicles for anticancer therapies. Nanoparticles can encapsulate or conjugate with antineoplastic drugs to improve their pharmacokinetics, stability and tumor accumulation while reducing side effects¹.

 

Upon reaching tumor tissues, nanoparticles can then release the encapsulated drug in a sustained or triggered manner. Several advantages make nanoparticles attractive as carriers for antineoplastic drugs: increased drug solubility and bioavailability, protection of drugs from degradation, prolonged drug retention at the tumor site, ability to incorporate targeting ligands for selective delivery to cancer cells².

 

Commonly studied nanoparticles for anticancer drug delivery include liposomes, dendrimers, polymeric nanoparticles and inorganic nanoparticles like gold and magnetic nanoparticles. The choice of nanoparticle carrier depends on factors like biocompatibility, drug encapsulation efficiency, controlled release capabilities and toxicity. The synthesis of folate-conjugated chitosan nanoparticles involves two key steps: 1) conjugating folic acid to chitosan and 2) precipitation of folate-conjugated chitosan to form nanoparticles. Folic acid conjugation is typically achieved using reductive amination where the amino groups of chitosan react with the aldehyde groups of folic acid in the presence of a reducing agent³. This forms an amide bond between chitosan and folic acid, resulting in folic acid conjugated chitosan. The degree of conjugation can be controlled by modifying reaction parameters to optimize folate receptor binding and nanoparticle targeting efficiency. Folate-conjugated chitosan is then used to prepare nanoparticles using various methods, with ionic gelation and self-assembly being the most common^4,5. During ionic gelation, polyanions such as tripolyphosphate interact electrostatically with chitosan, inducing nanoparticle formation. Self-assembly occurs when folate-conjugated chitosan chains come together in response to environmental triggers like pH or salt concentration changes. Nanoparticle synthesis parameters can be tuned to achieve desired characteristics like size (typically <200nm), shape, and loading capacity⁶. Folate conjugation enables targeted delivery applications while nanoparticle synthesis controls the delivery system's physicochemical properties^7,8. The main objective of this article is to provide a comprehensive review of recent advances in the synthesis, characterization and anticancer applications of folate-conjugated chitosan nanoparticles as targeted drug delivery systems. Particular focus will be given to studies investigating the loading of various antineoplastic drugs into these nanoparticles and evaluating their targeting efficiency and cytotoxicity against different cancer cell lines in vitro and in vivo. The synthesis of folate-conjugated chitosan nanoparticles and their mechanism of targeted delivery to folate receptor-overexpressing cancer cells is shown in Figure 1

 

Figure 1: Synthesis and mechanism of targeted delivery of folate-conjugated chitosan nanoparticles

 

Methods of conjugating folic acid to chitosan:

Methods that have been explored for folic acid conjugation are:

 

a) Reductive amination:

This is the most commonly used method for conjugating folic acid to chitosan. In this process, the amine groups on chitosan react with the aldehyde groups of folic acid in the presence of a reducing agent such as sodium cyanoborohydride. The reaction conditions, including folic acid concentration, pH, reaction time and temperature can be modified to control the degree of conjugation^9,10. Higher conjugation levels can generally be achieved at lower pH, higher folic acid concentration and longer reaction times.

 

b) Carbodi-imide conjugation:

This process involves activating the carboxyl groups of folic acid using carbodiimide compounds like EDC, allowing reaction with the amine groups of chitosan. However, this method achieves lower conjugation efficiencies^11,12.

 

c) Click chemistry approaches:

Utilize rapid, highly selective reactions like Huisgen 1,3-dipolar cycloaddition between alkyne groups on folic acid and azide groups on chitosan. These reactions have high yields but require chemical modifications to incorporate reactive groups. The amount of folic acid conjugated can be quantified using measurements like elemental analysis and UV-Vis spectroscopy. Higher folate content generally results in better receptor-mediated endocytosis by folate receptor overexpressing cancer cells¹³. However, excessively high conjugation may hinder nanoparticle self-assembly and physicochemical properties.

 

Techniques for preparing folate-conjugated nanoparticles:

Once the folic acid is conjugated to chitosan, the next step is to prepare nanoparticles. This is can be achieved by any of the following methods:

 

a) Ionic gelation:

This is the most common method for preparing folate-conjugated chitosan nanoparticles. It involves the ionic interaction between the positively charged amine groups of chitosan and the negatively charged polyanions like sodium tripolyphosphate. The ionic crosslinking of chitosan chains induces nanoprecipitation and particle formation. Parameters like chitosan concentration and molecular weight, folic acid content, pH and ionic crosslinker concentration can be tuned to modulate nanoparticle size, encapsulation efficiency and stability ¹⁴.

 

b) Self-assembly:

Folate-conjugated chitosan chains can spontaneously assemble into nanoparticles in response to changes in environmental conditions like pH, temperature or addition of ions. Alterations in these conditions disrupt the solubility of chitosan and drive self-aggregation into nanoparticles. Self-assembly methods offer more simplicity and flexibility compared to ionic gelation¹⁵.

 

c) Emulsion/solvent evaporation:

This method involves dissolving folate-conjugated chitosan and the drug in an organic phase, which is then emulsified in an aqueous phase. Evaporation of the organic solvent drives nanoparticle formation at the oil-water interface. However, residual solvent and surfactants may remain in the nanoparticles. In general, ionic gelation is the most commonly used technique due to its simplicity, efficiency and ability to produce nanoparticles with suitable characteristics for drug delivery applications. Self-assembly and emulsion methods have also been investigated to optimize nanoparticle properties¹⁶.

 

Characterization of folate-conjugated chitosan nanoparticles:

Thorough characterization of folate-conjugated chitosan nanoparticles is essential to understand their physicochemical properties and suitability for biomedical applications. However, several challenges are involved in fully characterizing these complex nanoparticle systems. The need for nanoparticle characterization stems from the fact that properties like size, shape, charge and drug encapsulation efficiency critically impact nanoparticle performance as drug carriers^17,18. Variations in synthesis and formulation parameters can result in nanoparticles with very different characteristics, underlining the importance of routine characterization. However, characterizing folate-conjugated chitosan nanoparticles poses some difficulties. First, these nanoparticles are unstable in aqueous media and tend to aggregate, making accurate size and morphology analysis challenging. Second, multiple techniques are often needed to characterize different attributes like size, surface charge and drug encapsulation, increasing workload. Third, indirect characterization methods have to be used since chitosan is not detectable by common techniques like transmission electron microscopy^19,20. As a result, careful consideration of nanoparticle stability, possible interference and selection of appropriate techniques are crucial for meaningful characterization of these systems. Combining results from multiple complimentary techniques can also offer a more comprehensive profile of nanoparticle properties.

 

a) Particle size and zeta potential:

Particle size and surface charge (zeta potential) are two important characteristics that impact the performance of folate-conjugated chitosan nanoparticles as drug carriers. Various techniques can be used to measure these properties. Particle size is typically determined using dynamic light scattering (DLS). In DLS, the brownian motion of nanoparticles in suspension is measured by detecting the fluctuations in intensity of scattered light ^21,22. The diffusion coefficient is then calculated from these intensity fluctuations and converted to particle hydrodynamic diameter using the Stokes-Einstein equation:

 

D = kT /3πηd

 

Where D is the diffusion coefficient, k is the Boltzmann constant, T is the temperature, η is the viscosity and d is the particle diameter. In general, smaller nanoparticles (<200 nm) with narrow size distributions are preferred for drug delivery applications.

Zeta potential indicates the surface charge of nanoparticles and is measured based on electrophoretic mobility in an electric field using laser Doppler electrophoresis²¹. The Smoluchowski equation is used to convert electrophoretic mobility (μ) to zeta potential (ζ):

 

ζ = μη/ε

Where η is the viscosity and ε is the dielectric constant. Higher magnitude zeta potential (positive or negative) indicates more stable nanoparticles due to electrical repulsion between particles. A minimum of ±30mV zeta potential is recommended for good stability¹⁷.

 

b) Morphology:

The morphology or shape of folate-conjugated chitosan nanoparticles influences their properties and performance as drug carriers. Common morphological characteristics measured include sphericity, smoothness of surface and presence of aggregates. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) are the primary techniques used to examine nanoparticle morphology. In TEM, a beam of electrons is transmitted through a thin sample, interacting with the sample as it passes through. An image is formed from the electrons transmitted through the sample, allowing visualization of the nanoparticle morphology. In SEM, a focused beam of electrons is scanned across the sample surface, emitting signals that are used to form an image showing the surface topography and morphology of nanoparticles. Both TEM and SEM require samples to be coated with conductive materials like gold or carbon to prevent charge accumulation, which can distort the morphology²³. Sample preparation and dilution are also crucial as nanoparticles tend to aggregate, affecting the morphological analysis.

 

Spherical nanoparticles with smooth surfaces and no aggregates are typically preferred as drug carriers since: Spherical nanoparticles have larger surface area to volume ratios, enabling better drug loading capacities, Smooth surfaces minimize interactions with biological components, reducing non-specific uptake, absence of aggregates ensures uniform size, drug release and biodistribution profiles²⁴.

 

c) Drug encapsulation efficiency:

The drug encapsulation efficiency of nanoparticles indicates the proportion of drug payload successfully incorporated into the nanoparticulate system²⁵. It is an important parameter that impacts the drug loading capacity, release profile and stability of folate-conjugated chitosan nanoparticles.

 

Two methods are commonly used to determine drug encapsulation efficiency:

 

Direct method:

Involves measuring the total amount of drug added and total amount of drug encapsulated in nanoparticles. The encapsulation efficiency (EE) is then calculated as:

 

EE (%) = (Total drug added - Free drug)/(Total drug added) × 100

 

Indirect method: Involves measuring the free drug not encapsulated in nanoparticles. The encapsulation efficiency is then calculated as:

EE (%) = (Total drug added - Free drug)/(Total drug added) × 100

 

The indirect method is preferred since it avoids destroying nanoparticles to measure encapsulated drug content directly.

 

Drug loading capacity, an indicator of how much drug can be incorporated per unit mass of nanoparticle, is calculated as:

 

Drug loading (%) = (Amount of drug encapsulated/Amount of nanoparticles and drug) × 100

Higher encapsulation efficiency and drug loading are desirable as they minimize amount of free drug which may accumulate in tissues and cause toxicity, amount of nanoparticle carrier required for effective therapy and the cost of nanoparticle formulations²⁶.

 

IN vitro Cytotoxicity Studies:

In vitro cytotoxicity studies are fundamental to evaluating the anticancer potential of drug-loaded folate-conjugated chitosan nanoparticles. Such studies investigate the ability of nanoparticles to inhibit the growth and viability of cancer cell lines²⁷.

 

Common cancer cell lines used in cytotoxicity assays include breast cancer (MCF-7), liver cancer (HepG2) and lung cancer (A549) cells. Folate receptor-overexpressing cell lines are often selected to determine the effect of folate conjugation on targeted cytotoxicity. 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays are the most widely used techniques to assess nanoparticle cytotoxicity²⁸. In these assays, cells are incubated with different concentrations of drug-loaded nanoparticles. After exposure, a tetrazolium-based solution is added which is reduced by live cells to yield a colored formazan product. The absorbance of this product, which is proportional to the number of viable cells, is measured to determine the antiproliferative activity of nanoparticles. Folate-conjugated nanoparticles typically show higher cytotoxicity than non-conjugated nanoparticles at equivalent drug concentrations due to receptor-mediated endocytosis in folate receptor-positive cancer cells and sustained intracellular drug release enabled by nanoparticulate systems^29,30. The effect of PEGylation on various properties of folate-conjugated chitosan nanoparticles are shown in Table 1.

 

Table 1: Effect of PEGylation on various properties of folate-conjugated chitosan nanoparticles

Sl. No.	Property	Folate-conjugated nanoparticles	PEGylated folate-conjugated nanoparticles
01	Size	Around 150 nm	Around 180-200 nm
02	Zeta potential	+35-40mV	Between -10 to -20 mV
03	Stability in serum	Aggregated within hours	Stable for over 24 hours
04	Accumulation in tumor	Moderate	Higher
05	Cellular uptake	High	Moderate
06	Drug release profile	Initial burst release	More sustained release
07	Cytotoxicity	Higher	Comparable

 

Anticancer drug-loaded nanoparticles:

Various antineoplastic drugs have been loaded into folate-conjugated chitosan nanoparticles for targeted cancer therapy. A list of anticancer drug encapsulated within folate-conjugated chitosan nanoparticles and the cancers against which they can be used are shown in Table 2.

 

Table 2: Anticancer drug encapsulated within folate-conjugated chitosan nanoparticles

Sl. No	Drug classification	Examples of drugs	Type of cancer
01	Chemotherapeutics	Doxorubicin, Paclitaxel, 5-Fluorouracil	Breast cancer, Colorectal cancer, Liver cancer9
02	Kinase inhibitors	Gefitinib, Imatinib, Sorafenib	Non-small cell lung cancer, Gastrointestinal stromal tumors, Hepatocellular carcinoma11
03	Tubulin inhibitors	Vinblastine, Vincristine	Cervical cancer, Ovarian cancer13
04	Monoclonal antibodies	Trastuzumab, Cetuximab	Breast cancer, Colorectal cancer 14

 

Cytotoxicity against different cancer cell lines:

Anticancer drug-loaded folate-conjugated chitosan nanoparticles have been shown to exhibit higher in vitro cytotoxicity against various cancer cell lines compared to non-conjugated nanoparticles.

 

a) Breast cancer cells: Studies have demonstrated that folate-conjugated nanoparticles loaded with drugs like doxorubicin or paclitaxel exhibit significantly higher cytotoxicity against MCF-7 and MDA-MB-231 breast cancer cells. This is attributed to their efficient internalization via folate receptor-mediated endocytosis in these cells³¹.

b) Lung cancer cells: Folate-conjugated nanoparticles loaded with drugs like gefitinib or cisplatin show enhanced growth inhibition of A549 and H1299 non-small cell lung cancer cells. The targeted uptake via folate receptors enables sustained intracellular drug release, improving antiproliferative activity⁷.

 

c) Liver cancer cells: Folate-conjugated nanoparticles loaded with 5-fluorouracil or sorafenib exhibit considerably higher cytotoxicity against HepG2 and SMMC-7721 hepatocellular carcinoma cells compared to free drugs or non-conjugated nanoparticles. The enhanced cytotoxicity is attributed to their active targeting and intracellular drug retention in these highly folate receptor-positive cancer cells²⁵.

 

d) Other cell lines: Similar effects have been observed in drug-loaded folate-conjugated nanoparticles against other cancer types that overexpress folate receptors, including ovarian cancer, cervical cancer, colorectal cancer, etc²⁶.

 

In vivo Biodistribution and Efficacy:

In vivo studies in animal models of cancer are important to validate the targeted delivery and antitumor effects of anticancer drug-loaded folate-conjugated chitosan nanoparticles observed in vitro. Common animal models used include mice bearing xenograft tumors derived from human cancer cell lines like MCF-7 breast cancer cells and HT-29 colorectal cancer cells²⁹. These models allow evaluation of nanoparticle biodistribution and antitumor efficacy following administration.

 

Biodistribution studies using techniques like fluorescence imaging, radiolabeling and inductively coupled plasma mass spectrometry can provide insights into the tissue distribution and tumor accumulation of nanoparticles over time in vivo. Folate conjugation typically results in enhanced nanoparticle uptake in folate receptor-positive tumors and reduced uptake in normal tissues⁹.

 

The antitumor efficacy of drug-loaded folate-conjugated nanoparticles is assessed by measuring key parameters like tumor volume, weight and histology along with animal survival. Folate-conjugated nanoparticles generally show improved inhibition of tumor growth and prolonged survival compared to non-targeted nanoparticles due to their active tumor targeting.

 

Studies in animal models of cancer:

Several studies have shown that folate-conjugated nanoparticles loaded with anticancer drugs exhibit enhanced tumor accumulation and antitumor efficacy in various animal models of cancer:

 

a) Xenograft models: Folate-conjugated nanoparticles loaded with drugs like doxorubicin, paclitaxel and sorafenib show significantly higher accumulation in folate receptor-positive MCF-7 breast tumor xenografts and HT-29 colorectal tumor xenografts in mice³². This results in more potent inhibition of tumor growth and increased survival compared to non-targeted nanoparticles.

 

b) Orthotopic models: In orthotopic models of breast cancer and liver cancer in mice, folate-conjugated nanoparticles loaded with drugs like gefitinib and 5-fluorouracil show preferential uptake in primary tumors and metastatic nodules along with marked reductions in tumor burden and dissemination³³.

 

c) Syngeneic models: Studies using CT-26 colon cancer and 4T1 breast cancer syngeneic models in mice also demonstrate that folate-conjugated nanoparticles loaded with drugs like doxorubicin and cisplatin achieve higher concentrations in tumors and greater inhibition of tumor growth compared to non-targeted formulations³⁴.

 

d) Mechanistic insights: Mechanistic studies reveal that folate-conjugated nanoparticles can accumulate in tumors via both active receptor-mediated endocytosis and the enhanced permeability and retention effect. Their sustained intratumoral drug release also contributes to the improved therapeutic efficacy³⁴.

 

Comparison of folate-conjugated versus non-conjugated nanoparticles:

Folate conjugation confers several advantages to chitosan nanoparticles for targeted cancer therapy by increasing their selectivity, tumor accumulation and efficacy.These benefits result from the targeting effects of folate conjugation which enable active receptor-mediated uptake by cancer cells overexpressing folate receptors^9,11. Table 3 summarizes the key differences between folate-conjugated and non-conjugated chitosan nanoparticles.

 

Table 3: Differences between folate-conjugated and non-conjugated chitosan nanoparticles

Sl. No	Parameter	Folate-conjugated nanoparticles	Non-conjugated nanoparticles
01	Cellular uptake in cancer cells	Higher via folate receptor-mediated endocytosis	Lower via nonspecific endocytosis
02	Cytotoxicity against cancer cells	Greater due to sustained drug release within cells and synergistic effects	Lower due to limited intracellular drug levels
03	Tumor accumulation in animals	Higher accumulation in folate receptor-positive tumors	Nonspecific distribution based on enhanced permeability and retention effect
04	Inhibition of tumor growth	Improved due to active targeting and intracellular drug retention	Limited due to lack of tumor specificity
05	Toxicity to normal tissues	Minimal interaction with normal cells lacking folate receptors	Nonspecific interaction and toxicity

 

CHALLENGES AND LIMITATIONS:

While folate-conjugated chitosan nanoparticles show potential for targeted drug delivery to cancer cells, there are several challenges and limitations that need to be addressed for successful clinical translation^6,31. Table 4 summarizes key challenges and limitations of folate-conjugated chitosan nanoparticles.

 

Table 4: Key challenges and limitations of folate-conjugated chitosan nanoparticles

Sl. No	Challenges	Explanation
01	Instability in physiological conditions	Nanoparticles tend to aggregate and degrade rapidly due to interactions with serum proteins and nucleases, limiting their circulation time.
02	Variable targeting effects	Folate receptor expression varies between tumor types and patients, leading to inconsistent targeting outcomes
03	Uptake by non-malignant cells	Some activated macrophages, epithelial and endothelial cells express folate receptors, allowing uptake.
04	Unknown long-term effects	Long-term safety and biological effects of nanoparticles, especially after repeated administration, remain uncertain
05	Optimization of multiple variables	Factors like size, shape, charge and folate content all impact targeting, making optimization difficult.
06	Lack of clinical translation	Despite promising preclinical results, few folate-conjugated nanoparticle formulations have advanced to clinical trials
07	Scale-up challenges	Scaling up nanoparticle production for clinical use and commercialization faces technical and cost-related hurdles
08	Gaps in characterization	Thorough characterization of nanoparticles using reliable techniques is still needed to enable clinical translation

 

Clinical Translation Prospects:

While several challenges remain, various strategies could help enable the clinical translation of folate-conjugated chitosan nanoparticles^14,25,33:

 

a) Target receptor profiling: Characterizing folate receptor expression levels in different tumors and patients can help identify those most likely to benefit from folate-targeted therapy.

 

b) Functionalization with multiple ligands: Conjugating nanoparticles with both folate and other tumor-targeting ligands may offer synergistic targeting effects with improved outcomes.

c) Co-delivery of combination therapies: Incorporating multiple drugs within folate-conjugated nanoparticles could produce synergistic anticancer effects while overcoming resistance.

 

d) PEGylation and surface modification: Coating nanoparticles with polymers like PEG can improve their stability, biocompatibility and pharmacokinetics, enabling clinical use.

 

e) Multi-arm clinical trials: Conducting extensive Phase I, II and III clinical trials in large patient cohorts is needed to thoroughly evaluate the safety, efficacy and outcomes of folate-conjugated nanoparticle therapies.

 

f) Rigorous nanoparticle characterization: Thorough physicochemical and biological characterization of nanoparticles using reliable techniques is essential before clinical use.

 

g) Scale-up and automation of synthesis: Large-scale, GMP-compliant and automated production of folate-conjugated nanoparticles is needed to meet clinical demands.

 

h) Combination with existing therapies: Combining folate-conjugated nanoparticulate therapy with conventional treatments may offer synergistic clinical benefits and faster approval.

 

i) Computer-aided modeling: In silico modeling approaches could help optimize nanoparticle formulation, minimize the need for animal testing and speed up clinical translation.

 

While currently few folate-conjugated nanoparticle formulations have progressed to clinical trials, various strategies including receptor profiling, surface modification, thorough characterization, automation, combination therapies and modeling could help address current challenges and enable their safe and effective clinical translation and commercialization.).

 

FUTURE RESEARCH DIRECTIONS:

While folate-conjugated chitosan nanoparticles have shown promising results for targeted cancer therapy in preclinical studies, further research is needed to optimize their performance and translate this technology into clinical applications^17,19,21. Potential future research directions could include:

 

a) Clinical validation: Conducting extensive Phase I, II and III clinical trials is imperative to thoroughly evaluate the safety, efficacy and outcomes of folate-conjugated nanoparticle therapies in large patient cohorts. This will help establish clinical relevance.

 

b) Receptor profiling: Investigating folate receptor expression levels in different tumor types and patients can help identify those most likely to benefit from folate-targeted therapy. This can guide patient selection.

 

c) Combination therapies: Co-delivery of multiple drugs or combining nanoparticle therapy with conventional treatments may offer synergistic clinical benefits and should be explored to enhance therapeutic efficacy.

 

d) Surface modification: Employing various surface modifications like PEGylation, lipid coating and antibody conjugation could help improve nanoparticle stability, biocompatibility and pharmacokinetics for clinical translation.

 

e) In vivo imaging: Incorporating imaging agents within nanoparticles may enable noninvasive monitoring of their in vivo fate and biodistribution, offering insights for further optimization.

 

f) Automation of synthesis: Developing large-scale, GMP-compliant and automated processes for nanoparticle production is essential to meet clinical demands and commercialization requirements.

 

g) Computer modeling: In silico modeling approaches could help optimize nanoparticle formulations, predict their behaviors in vivo and minimize the need for animal testing.

 

h) Combinatorial development: Employing high-throughput screening and combination strategies may accelerate the discovery and optimization of folate-conjugated nanoparticle systems with improved clinical potential.

 

CONCLUSION:

Folate-conjugated chitosan nanoparticles have potential as targeted drug delivery systems for cancer therapy. Folic acid conjugation improves targeted delivery to folate receptor-overexpressing cancer cells, resulting in better cytotoxicity and antitumor efficacy. Folate-conjugated nanoparticles offer advantages such as active tumor targeting, sustained drug release, and higher selectivity, but further optimization, characterization, safety evaluation, clinical validation, and scale-up are necessary for clinical use. Folate-conjugated chitosan nanoparticles could be effective in overcoming drug resistance and improving cancer treatment outcomes with appropriate advances.

 

CONFLICT OF INTEREST:

The authors declare no conflicts of interest.

 

 

ACKNOWLEDGMENTS:

The authors would like to thank Dr. K. Ravishankar, Principal, Aditya College of Pharmacy for his kind support during the preparation of this work.

 

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Received on 04.06.2023         Modified on 06.07.2023

Accepted on 26.07.2023   ©AandV Publications All Right Reserved