Chitosan-Based Drug Delivery Systems for Targeted Chemotherapy in Colorectal Cancer: A Scoping Review

In the paper

“Moreover, the biocompatible nature of CS and its derivatives contributed to reduced gastrointestinal irritation and improved tolerability, as reported in both in vitro and limited in vivo assessments.”

In the paper

“Despite these promising in vitro results, the translational maturity of ligand-modified CS-based DDS remains limited. Most studies were restricted to 2D monolayer models, with only one demonstrating in vivo targeting efficiency. Data on pharmacokinetics, biodistribution, and long-term biosafety are still lacking.”

In the paper

“This scoping review identified and analyzed a total of 25 original research articles that met the inclusion criteria. These studies were grouped into two categories based on the design of the DDS: (1) CS-based DDS without active targeting ligands, and (2) ligand-modified CS-based DDS for selective drug delivery to CRC cells.”

In the paper

“HA-based systems effectively targeted CD44, overexpressing CRC phenotypes, key drivers of stemness and metastasis, showing enhanced tumor accumulation, reduced migration, and selective cytotoxicity compared with free apigenin [70].”

What the sources say

• Check pendingcites [70] Yang, B., Mao, Y., Zhang, Y., Hao, Y., Guo, M., Li, B., and Peng, H. (2023). HA-coated PLGA nanoparticles loaded with apigenin for colon cancer with high expression of CD44. Molecules, 28. source

In the paper

“Moreover, the pharmacokinetic and immunogenicity profiles remain underreported for most systems.”

In the paper

“Only a few clinical trials (ClinicalTrials.gov, accessed 11 November 2025) involving CS in cancer therapy have been registered to date, and none directly evaluate CS-based nanocarriers for CRC.”

In the paper

“Consistent with these findings, FA-conjugated CS NPs demonstrated superior internalization in FR-overexpressing colorectal cancer cells and significantly enhanced the cytotoxicity of 5-FU and RSV/FER combinations compared with non-targeted CS carriers [67,69].”

What the sources say

• Check pendingcites [67] Ullah, S., Azad, A.K., Nawaz, A., Shah, K.U., Iqbal, M., Albadrani, G.M., Al-Joufi, F.A., Sayed, A.A., and Abdel-Daim, M.M. (2022). 5-fluorouracil-loaded folic-acid-fabricated chitosan nanoparticles for site-targeted drug delivery cargo. Polymers, 14. source
• ?Not checked — no full text of the sourcecites [69] Kumar, 2020, Targeted delivery and apoptosis induction of trans-resveratrol-ferulic acid loaded chitosan coated folic acid conjugate solid lipid nanoparticles in colon cancer cells, Carbohydr. Polym. source

In the paper

“Only one study demonstrated successful tumor accumulation in xenograft models, while the remaining investigations were restricted to 2D monolayer or co-culture systems.”

In the paper

“Among active targeting ligands, FA-based systems exhibited the most substantial receptor-mediated uptake and cytotoxic response, followed by HA- and Gal-functionalized formulations.”

In the paper

“These ligand-functionalized systems consistently demonstrated enhanced cellular uptake, improved cytotoxicity, and stronger tumor localization compared to non-targeted CS carriers.”

In the paper

“capecitabine (CTB)-loaded CS NPs resulted in approximately 72% tumor reduction within 21 days in a DMH-induced CRC mouse model, while concurrently downregulating pro-angiogenic and inflammatory mediators [52]”

What the sources say

• Check pendingcites [52] Bhattacharya, S., Page, A., and Shinde, P. (2024). Capecitabine loaded potato starch-chitosan nanoparticles: A novel approach for targeted therapy and improved outcomes in aggressive colon cancer. Eur. J. Pharm. Biopharm., 200. source

In the paper

“Overall, FA conjugation significantly improved selective drug internalization into FRα-overexpressing CRC cells, reduced off-target toxicity, and enhanced cytotoxicity for agents such as 5-FU, IMT, and polyphenols.”

In the paper

“Most of these formulations exhibited minimal drug release under gastric conditions and preferential release at colonic pH.”

In the paper

“FA and HA functionalization provided additional protection against premature drug release in neutral physiological conditions (pH 7.4) while enabling responsive release in mildly acidic or enzymatically active environments, consistent with CRC tumor pH gradients.”

In the paper

“However, such high inhibition rates were often reported from short-duration studies with unclear or unreported sample sizes, and lacking key methodological details.”

In the paper

“In vivo imaging confirmed efficient tumor accumulation of HA-coated NPs with minimal off-target distribution, validating CD44-mediated active targeting as a powerful strategy for CRC therapy.”

In the paper

“In contrast, non-targeted CS NPs primarily relied on electrostatic interactions or EPR effects, yielding slower uptake kinetics and higher IC50 values.”

In the paper

“Similarly, FA-functionalized CS-coated Zn–MOF nanocomposites exhibited pronounced FR-mediated uptake and vigorous proapoptotic and autophagic activity in HCT116 cells [68].”

What the sources say

• ?Not checked — no full text of the sourcecites [68] Mokri, 2022, Chitosan-coated Zn-metal-organic framework nanocomposites for effective targeted delivery of LNA-antisense miR-224 to colon tumor: In vitro studies, Gene Ther. source

In the paper

“Most formulations exhibited controlled or pH-responsive release profiles.”

In the paper

“Only a minority included in vivo validation, and the depth of pharmacokinetic or immunogenicity analyses was generally insufficient to support translational development.”

In the paper

“None of the included studies systematically optimized ligand density or assessed saturation kinetics, which are crucial for translational performance.”

In the paper

“whereas Gal-ASGPR interactions enhanced selectivity and minimized fibroblast toxicity.”

In the paper

“SN-38 CS-based systems co-administered with Bifidobacterium bifidum, achieved approximately 80% tumor suppression, doubling the efficacy observed without probiotic co-treatment [43].”

What the sources say

• ?Not checked — no full text of the sourcecites [43] Wu, 2024, Chitosan nanomedicines-engineered bifidobacteria complexes for effective colorectal tumor-targeted delivery of SN-38, Int. J. Pharm. source

In the paper

“Carbohydrate-mediated targeting was further demonstrated in galactosylated CS-functionalized MSNPs, which achieved selective cytotoxicity toward HT-29 colon cancer cells via ASGPR recognition, while exhibiting reduced toxicity toward normal fibroblasts [71].”

What the sources say

• Check pendingcites [71] Liu, 2018, Galactosylated chitosan-functionalized mesoporous silica nanoparticles for efficient colon cancer cell-targeted drug delivery, R. Soc. Open Sci. source

In the paper

“In summary, ligand modification significantly outperformed non-targeted CS-DDS in terms of cellular uptake, cytotoxicity, and tumor-specific accumulation, while maintaining excellent biocompatibility.”

In the paper

“several in vivo studies reported superior tumor suppression, reduced systemic toxicity, and prolonged survival in CRC models.”

In the paper

“HA-based CS or PLGA nanocarriers exploited CD44 overexpression, a major driver of CRC stemness and metastasis, to achieve enhanced tumor uptake, robust anti-proliferative activity, and reduced cell migration compared with free apigenin or uncoated NPs [70].”

What the sources say

• Check pendingcites [70] Yang, B., Mao, Y., Zhang, Y., Hao, Y., Guo, M., Li, B., and Peng, H. (2023). HA-coated PLGA nanoparticles loaded with apigenin for colon cancer with high expression of CD44. Molecules, 28. source

In the paper

“Accordingly, IC50 values were significantly reduced, and therapeutic efficacy was improved both in vitro and, in one instance, in vivo.”

In the paper

“Overall, ligand modification of CS-based DDS consistently enhanced tumor-selective uptake, reduced IC50 values, and induced stronger apoptotic responses compared to non-targeted systems and free drugs.”

In the paper

“FA- and HA-modified CS-DDS showed up to a 1.5–3-fold increase in cellular uptake in FRα+ and CD44+ colorectal cancer cells, respectively.”

In the paper

“Similarly, mesoporous silica nanoparticles (MSNPs) functionalized with FA exhibited strong FR-mediated uptake and selective cytotoxicity toward HT-29 cells, confirming the effectiveness of FA as a targeting ligand for site-specific CRC therapy [68].”

What the sources say

• ?Not checked — no full text of the sourcecites [68] Mokri, 2022, Chitosan-coated Zn-metal-organic framework nanocomposites for effective targeted delivery of LNA-antisense miR-224 to colon tumor: In vitro studies, Gene Ther. source

In the paper

“Although nine studies were initially identified, two review articles [64,65] were excluded as non-original research. Among the remaining seven experimental papers, two were removed during full-text screening due to the absence of active ligand-receptor targeting.”

What the sources say

• ?Not checked — no full text of the sourcecites [64] Bhirud, 2024, Bioengineered carbohydrate polymers for colon-specific drug release: Current trends and future prospects, J. Biomed. Mater. Res. Part A source
• Check pendingcites [65] Sharma, 2023, A shift in focus towards precision oncology, driven by revolutionary nanodiagnostics; revealing mysterious pathways in colorectal carcinogenesis, J. Cancer Res. Clin. Oncol. source

In the paper

“Additionally, high molecular weight HA may exhibit slower internalization rates, whereas low molecular weight HA may induce pro-inflammatory signaling—factors not systematically assessed in current studies [88].”

What the sources say

• Check pendingcites [88] Rayahin, 2015, High and low molecular weight hyaluronic acid differentially influence macrophage activation, ACS Biomater. Sci. Eng. source

In the paper

“Furthermore, most in vivo studies relied on xenograft models in immunocompromised mice, which do not replicate the human immune response, stromal architecture, or cytokine profile influencing NPs clearance and tumor penetration.”

In the paper

“Four independent reviewers conducted the screening and data extraction, while discrepancies were resolved through discussion with a fifth reviewer.”

In the paper

“However, ASGPR expression in CRC is heterogeneous within CRC lesions [94]. Therefore, while Gal enhances uptake in some CRC models, its broader applicability may be limited.”

What the sources say

• Check pendingcites [94] Ramezani, S., Parkhideh, A., Bhattacharya, P.K., Farach-Carson, M.C., and Harrington, D.A. (2021). Beyond colonoscopy: Exploring new cell surface biomarkers for detection of early, heterogenous colorectal lesions. Front. Oncol., 11. source

In the paper

“This scoping review was conducted in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines [95].”

What the sources say

• Not checked yetcites [95] Arksey, 2005, Scoping studies: Towards a methodological framework, Int. J. Soc. Res. Methodol. source

In the paper

“Nonetheless, clinical translation is currently constrained by methodological inconsistencies, limited long-term toxicity data, and insufficient pharmacokinetic characterization.”

In the paper

“Across diverse drug classes, including fluoropyrimidines, kinase inhibitors, topoisomerase inhibitors, and phytochemicals, CS-based carriers consistently improved antitumor activity through better drug retention, controlled release, and preferential tumor targeting in preclinical screening, but current evidence is insufficient to support translation.”

In the paper

“Although CS has numerous valuable advantages, it also has several limitations that affect its use in the delivery of anticancer drugs. These include low thermal stability [11,12] and ductility [13,14], poor solubility of CS above pH 6.5 [15,16], high hydrophilicity and swelling properties, which may lead to premature drug release and reduced structural stability.”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Neto, 2005, Thermal analysis of chitosan based networks, Carbohydr. Polym. source
• ?Not checked — no full text of the sourcecites [12] Zawadzki, 2010, Thermal treatment of chitosan in various conditions, Carbohydr. Polym. source
• ?Not checked — no full text of the sourcecites [13] Kolhe, 2003, Improvement in ductility of chitosan through blending and copolymerization with PEG: FTIR investigation of molecular interactions, Biomacromolecules source
• ?Not checked — no full text of the sourcecites [14] Wahba, 2020, Enhancement of the mechanical properties of chitosan, J. Biomater. Sci. Polym. Ed. source
• ?Not checked — no full text of the sourcecites [15] Qin, 2006, Water-solubility of chitosan and its antimicrobial activity, Carbohydr. Polym. source
• ?Not checked — no full text of the sourcecites [16] Sogias, 2010, Exploring the factors affecting the solubility of chitosan in water, Macromol. Chem. Phys. source

In the paper

“Moreover, surface binding limits deeper tumor penetration, a phenomenon not addressed in current studies [78].”

What the sources say

• ?Not checked — no full text of the sourcecites [78] Xia, 2010, Folate-targeted therapies for cancer, J. Med. Chem. source

In the paper

“Overall, intravenous CS-based DDS demonstrated improved tumor targeting, controlled release within the TME, and enhanced therapeutic efficacy compared with free drugs.”

In the paper

“Yang et al. [20] demonstrated that steam sterilization significantly darkens CS powder, gamma irradiation causes strong depolymerization above 10 kGy, and ethylene oxide induces only minor changes in crystallinity and structure.”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Yang, 2007, The effect of different sterilization procedures on chitosan dried powder, J. Appl. Polym. Sci. source

In the paper

“the absence of standardized experimental methodologies and heterogeneous in vivo endpoints further undermine comparability and reproducibility.”

In the paper

“To date, CS-based DDSs have been confirmed to have excellent anticancer properties [23]. Among other things, they are effective against oral cancer, breast cancer, prostate cancer, glioblastoma multiforme, liver cancer, and colon cancer, while also demonstrating satisfactory biocompatibility with typically developing cells and/or tissues.”

What the sources say

• Check pendingcites [23] Piotrowska, U., and Orzechowska, K. (2024). Advances in chitosan-based smart hydrogels for colorectal cancer treatment. Pharmaceuticals, 17. source

In the paper

“Nonetheless, CD44 expression varies widely between CRC stages [86,87]. This heterogeneity may limit uniform nanoparticle uptake across entire tumors.”

What the sources say

• ?Not checked — no full text of the sourcecites [86] Huh, 2009, Expression of standard CD44 in human colorectal carcinoma: Association with prognosis, Pathol. Int. source
• Check pendingcites [87] Wang, Z., Tang, Y., Xie, L., Huang, A., Xue, C., Gu, Z., Wang, K., and Zong, S. (2019). The prognostic and clinical value of CD44 in colorectal cancer: A meta-analysis. Front. Oncol., 9. source

In the paper

“Due to inconsistent reporting, direct comparisons between formulations are limited and broader generalization is not possible.”