Scientists have stated that polysaccharide-based nano-prodrug crosslinked by stimuli-responsive synergetic prodrugs exhibit great tumor selectivity, stability, and synergetic effect. As a result, such nano-prodrugs are in high demand.
Study: Dynamic carboxymethyl chitosan-based nano-prodrugs precisely mediate robust synergistic chemotherapy. Image Credit: Rapeepat Pornsipak/Shutterstock.com
Recently, a group of researchers has developed dynamic carboxymethyl chitosan (CMCS)-based nano-prodrugs crosslinked by water-soluble synergistic prodrug that is highly effective for selective chemotherapy. This study is available as pre-proof in Carbohydrate Polymers.
Polysaccharide-based nano-prodrugs have been seen to exhibit stable drug loading ability, robust antitumor activity, significant drug storage capacity, and circulation. Despite these advantages, they have not yet been used for cancer therapy since variations from batch to batch present risks and inadequate therapeutic efficiency. Other limitations associated with polysaccharide-based nano-prodrug immunogenicity are unwarranted modification of polysaccharides, poor tumor selectivity, dose-dependent toxicity from low drug conjugate rate, etc.
Researchers believe that there is a need for appropriate polysaccharides to develop a novel polysaccharide-based nano-prodrug that exhibits increased chemotherapeutic effects and reduced side effects.
Carboxymethyl Chitosan (CMCS)-based Nano-prodrugs
Previous studies have revealed that CMCS is an important derivative of chitosan (CS) that has received approval for usage from the US Food and Drug Administration. These studies have further reported that CMCS possesses many useful physicochemical and biological properties, for example, availability of multiple reaction sites like amino and carboxylic groups, good water solubility, biodegradability, pH sensitivity, low-immunogenicity, and biocompatibility. Additionally, it also exhibits promising antitumor properties based on inhibiting tumor cell proliferation, metastasis, and angiogenesis. It also shows a low affinity for sugar transporters on macrophages.
Although CMCS possesses interesting properties that could be used to develop polysaccharide-based nano-prodrug, its molecular weight varies when obtained from different sources. This makes industrial production of CMCS-based nano-prodrugs difficult. Another limitation of CMCS-based nano-prodrugs is their selectivity apart from the enhanced permeability and retention (EPR) effect at tumor sites.
A previous study has pointed out that the irregular metabolism of cancer cells leads to abnormal acid gradient distribution among interstitial space, blood vessel, intracellular matrix, and a high intracellular glutathione (GSH) level. These irregularities could be targeted to create a novel pH/GSH-oriented CMCS-based nano-prodrug to treat a specific type of cancer.
Scientists reported that small-molecule prodrug (Pt(IV)-1) containing demethylcantharidin (DMC) and cisplatin (DDP) showed promising water solubility and synergistic effect. Pt(IV)-1 can be crosslinked with CMCS through amide reaction in an aqueous solution for the development of a pH/GSH dual responsive CMCS-based nano-prodrugs.
Development of a Dynamic CMCS-based Nano-prodrugs: A New Study
Scientists have recently synthesized CMCS-Pt (IV)-1 through a crosslinking reaction between the amino groups of CMCS and carboxylic groups of Pt (IV)-1 in deionized water. The molar feeding ratio was 1:0.488 to attain an adequate drug grafting rate and complete crosslinking at both ends. The newly developed nano-prodrug was characterized using Fourier-transform infrared spectroscopy (FTIR) and Nuclear magnetic resonance (NMR), which confirmed the presence of amide groups. X-ray powder diffraction (XRD) analysis revealed the crystalline structure of CMCS-Pt (IV)-1.
Scanning Electron Microscopic analysis revealed that CMCS-Pt (IV)-1 in an aqueous solution was present as nanoparticles (NPs) of 27.3 nm size. However, as small-sized nanoparticles are not ideal for in vivo drug delivery, due to their easy removal by the reticuloendothelial system (RES), optimization of the size of CMCS-Pt (IV)-1 is essential for drug delivery application.
Researchers prepared nanogel (NG) via crosslinking reaction between CMCS-Pt(IV)-1 and glutaraldehyde in an aqueous condition. They observed that the particle size of NG remained unchanged in a varied environment even after thirty days, indicating its circulation stability and its potential for long-term storage. This might be due to its double crosslinked structure, presence of ester and imine linkages or unreduced cisplatin (IV), and negative zeta potentials at physiological conditions.
In this study, researchers determined the impact of physicochemical properties of NGs pharmacokinetics. They injected DDP/DMC and NGs with the same concentration of cisplatin intravenously into H22 tumor-bearing mice.
Scientists reported that NG showed longer circulation stability than DDP/DMC due to its unique double crosslinking structure, zeta potential, and appropriate particle size, which prevented its removal from RES. Additionally, NG was found to reach the tumor site with improved efficiency. The increased accumulation of NG in the tumor sites occurred due to the EPR effect, long-term circulation stability, enhanced tumor penetration, cellular uptake, and retention via tumoral extracellular amnio protonation.
The authors reported the successful development of CMCS-based nano-prodrugs, which were crosslinked between CMCS Pt(IV)-1 and further stabilized via glutaraldehyde. Importantly, compared to other polysaccharide-based nano-prodrugs crosslinked to a single drug, the newly synthesized nano-prodrug showed robust synergistic chemotherapy at a low level of drug coupling rate with minimal side effects. Therefore, researchers stated that these CMCS-based synergistic nano-prodrugs crosslinked by Pt(IV)-1 could be effectively used for cancer therapy.
Wang, Z. et al. (2022). Dynamic carboxymethyl chitosan-based nano-prodrugs precisely mediate robust synergistic chemotherapy. Carbohydrate Polymers. https://doi.org/10.1016/j.carbpol.2022.119671