A prodrug strategy based on chitosan for efficient intracellular anticancer drug delivery

Abstract

Doxorubicin (DOX), one of the most widely used anticancer drugs, is restricted in clinical application due to its severe side effects and inefficient cellular uptake. To overcome the drawbacks, herein, an endosomal pH-activated prodrug was designed and fabricated by conjugating DOX with chitosan via an acid-cleavable hydrazone bond. The resulting DOX conjugates can self-assemble into nano-sized particles, which were very stable and presented no burst release of DOX at a neutral pH condition. Notably, the nanoparticles exhibited excellent cell uptake properties and a remarkable drug accumulation in tumor cells. Once internalized into the cells, moreover, DOX can be fast released from the nanoparticles, and the release mechanism changed from the anomalous transport at pH 7.4 to the combination pattern of diffusion- and erosion-controlled release at pH 6.0 or 5.0. The prodrugs showed obvious cytotoxicity for HeLa cells with fairly low IC50 values, offering a new platform for targeted cancer therapy.

Multifaceted Applications of Chitosan in Cancer Drug Delivery and Therapy

“…The expression levels of these receptors in each cancer type varies; therefore, it is important to know the cell type and receptor expression levels before formulating targeted drug delivery systems. When conjugated with drug via pH-cleavable bonds, chitosan nanoparticles undergo dissociation of the assembly within the acidic pH of endo-lysosomes and release the drug into the cytoplasm [80]. Figure 4 shows the diagrammatic representation of stimuli responsive drug delivery of chitosan-based nanoparticles with acid-cleavable bonds conferred by a pH-sensitive linker.…”

Structure and dynamics of polypyrrole/chitosan nanocomposites

“…Owing to these unparalleled characteristics, Cs has found considerable applications in both industrial and biomedical sectors. Recently, Cs has been used in drug delivery, gene therapy, tissue engineering and wound healing . According to the aforementioned outstanding features along with the relevant potential applications of both PPy and Cs, subsequent studies have focused on utilizing PPy/Cs composites in biomedical applications .…”

Biodegradable Polysaccharides for Controlled Drug Delivery

“…[51,71] For example, doxorubicin (DOX) prodrug nanoparticles with pH-sensitived rug release properties and antitumor activity were designed and synthesized by conjugating the hydrophobic DOX with chitosan through an acid-cleavable hydrazone (hz) bond. [72] Chitosan-hz-DOX nanoparticles were stable at neutral pH and disassembled at pH 5.0, resultingi nt he burst release of DOX in HeLa cellst reated with the nanoparticles. The prodrug nanoparticles could be quickly internalized, leading to as ignificant DOX accumulation in the cells, demonstrating the potentialf or application in tumor-targeted drugd elivery.…”

“…Although synthetic, water‐soluble polymers have been widely utilized, natural polymers such as chitosan, dextran, cellulose, and hyaluronic acid are also used because of their remarkable potential as drug carriers . For example, doxorubicin (DOX) prodrug nanoparticles with pH‐sensitive drug release properties and antitumor activity were designed and synthesized by conjugating the hydrophobic DOX with chitosan through an acid‐cleavable hydrazone (hz) bond . Chitosan‐hz–DOX nanoparticles were stable at neutral pH and disassembled at pH 5.0, resulting in the burst release of DOX in HeLa cells treated with the nanoparticles.…”