Optimized DOX Drug Deliveries via Chitosan-Mediated Nanoparticles and Stimuli Responses in Cancer Chemotherapy: A Review

Abstract

Chitosan nanoparticles (NPs) serve as useful multidrug delivery carriers in cancer chemotherapy. Chitosan has considerable potential in drug delivery systems (DDSs) for targeting tumor cells. Doxorubicin (DOX) has limited application due to its resistance and lack of specificity. Chitosan NPs have been used for DOX delivery because of their biocompatibility, biodegradability, drug encapsulation efficiency, and target specificity. In this review, various types of chitosan derivatives are discussed in DDSs to enhance the effectiveness of cancer treatments. Modified chitosan-DOX NP drug deliveries with other compounds also increase the penetration and efficiency of DOX against tumor cells. We also highlight the endogenous stimuli (pH, redox, enzyme) and exogenous stimuli (light, magnetic, ultrasound), and their positive effect on DOX drug delivery via chitosan NPs. Our study sheds light on the importance of chitosan NPs for DOX drug delivery in cancer treatment and may inspire the development of more effective approaches for cancer chemotherapy.

Keywords: chemotherapy; chitosan NPs; drug delivery; drug resistance; stimuli-sensitive.

Figure 4

Chitosan-based NP drug delivery mechanisms. (A) Passive targeting mechanism: leaky tumor vessels release the DOX-loaded chitosan NPs at the cancer site via the EPR effect. (B) Active targeting mechanism: DOX-loaded chitosan NPs accumulate in cancerous cells via ligand-mediated endocytosis [139].

Figure 1

(A) N-acetyl-D-glucosamine unit, (B) glucosamine unit, and (C) β 1-4 linkage in the structure of chitosan.

Figure 2

Several approaches (the emulsion cross-linking method, precipitation/coacervation method, and ionic gelation method) of chitosan NP preparation [18].

Figure 3

Schematic explanation of the chemical structure of DOX and its binding capability to DNA molecules, and the inhibition of the DNA synthesis. (A) The structure of DNA, including the intercalating DOX molecule. (B) The binding of DOX into double-stranded DNA molecules, adapted from Ref. [111].

Figure 5

DOX–PP–CNP-based immunotherapy for ICD and PD-L1 degradation. All-in-one NPs, anti-PD-L1 peptide-conjugated, and DOX-loaded glycol chitosan NPs (DOX–PP–CNPs) were created, and both passive and active tumor targeting allowed the DOX–PP–CNPs to aggregate in targeted tumor cells. Then, the DOX–PP–CNPs improved the PD-L1 multivalent binding on the surface of tumor cells, which internalized to favor the PD-L1 intracellular trafficking to lysosomes as an alternative to recycling endosomes. Reprinted with permission from Ref. [146]. Copyright 2023, Elsevier.

Figure 6

Various chitosan-based NP approaches for the DOX drug codelivery with genes leads to a modification in gene expression and cell apoptosis in cancer treatment. Reprinted from Ref. [201]. Copyright 2023, AIChE.

Figure 7

The controlled release of acid-sensitive micelles (GA-CS-PEI-HBA-DOX@siRNA) were produced. These micelles are excellent in delivering both DOX and siRNA to the tumor location, laying the groundwork for effective combined therapy. Adopted with permission from Ref. [241]. Copyright 2023, Elsevier.

Figure 8

Schematic presentation of the production of LDC (a compound of laponite (LP), doxorubicin (DOX), and chito-oligosaccharides (COS)) NPs and their anticancer activity. Due to the presence of enzymes in the tumor microenvironment, LDC NP sizes become smaller, from 100 nm to 30 nm. After cellular uptake, the enzymatic and acidic pH environment enhances the DOX release. Reprinted with permission from Ref. [262]. Copyright 2023, Elsevier.