Scientists have claimed that nanopharmaceuticals based on polysaccharides crosslinked by stimulus-responsive synergistic drugs have high tumor selectivity, stability, and synergistic effect. As a result, these nanopharmaceuticals are in high demand.
Study: Dynamic nanopropharmaceuticals based on carboxymethyl chitosan accurately mediated robust synergistic chemotherapy. Image credit: Rapeepat Pornsipak / Shutterstock.com
Recently, a group of researchers has developed dynamic nanopharmaceuticals based on carboxymethyl chitosan (CMCS) crosslinked by water-soluble synergistic prodrugs that are very effective for selective chemotherapy. This study is available as a preliminary test on carbohydrate polymers.
Nanomedicines based on polysaccharides
Polysaccharide-based nanopropharmaceuticals have been shown to have stable drug loading capacity, robust antitumor activity, significant drug storage capacity, and circulation. Despite these benefits, they have not yet been used for cancer therapy, as variations from one batch to another present risks and inadequate therapeutic efficacy. Other limitations associated with the immunogenicity of polysaccharide-based nanopharmaceuticals are unjustified modification of polysaccharides, low tumor selectivity, dose-dependent toxicity of low drug conjugate rate, and so on.
Researchers believe that there is a need for adequate polysaccharides to develop a new polysaccharide-based nanopropharmaceutical that shows increased chemotherapeutic effects and reduced side effects.
Carboxymethyl Chitosan-Based Nanopharmaceuticals (CMCS).
Previous studies have revealed that CMCS is an important derivative of chitosan (CS) that has received approval for use by the U.S. Food and Drug Administration. These studies have also reported that CMCS possesses many useful physicochemical and biological properties, for example, availability of multiple reaction sites such as amino and carboxylic groups, good water solubility, biodegradability, pH sensitivity, low immunogenicity, and biocompatibility. In addition, it also exhibits promising antitumor properties based on inhibition of tumor cell proliferation, metastasis, and angiogenesis. It also shows a low affinity for macrophage sugar transporters.
Although CMCS has interesting properties that could be used to develop nanopharmaceuticals based on polysaccharides, their molecular weight varies when obtained from different sources. This hinders the industrial production of CMCS-based nanopharmaceuticals. Another limitation of CMCS-based nanopharmaceuticals is their selectivity, in addition to the enhanced permeability and retention effect (EPR) at tumor sites.
An earlier study found that irregular metabolism of cancer cells leads to an abnormal distribution of the acid gradient between the interstitial space, the blood vessel, the intracellular matrix and a high level of intracellular glutathione (GSH). . These irregularities could be aimed at creating a new pH / GSH-oriented CMCS-based nanopropharmaceutical to treat a specific type of cancer.
The scientists reported that the small molecule prodrug (Pt (IV) -1) containing demethylcantaridine (DMC) and cisplatin (DDP) showed promising water solubility and a synergistic effect. Pt (IV) -1 can be linked to CMCS by the reaction of amide in an aqueous solution for the development of a CMCS-based nanopropharmaceutical with dual pH / GSH response.
Development of a dynamic nanopropharmaceutical based on CMCS: a new study
Scientists have recently synthesized CMCS-Pt (IV) -1 through a crosslinking reaction between the CMCS amino groups and the Pt (IV) -1 carboxylic groups in deionized water. The molar feed ratio was 1: 0.488 to achieve an adequate drug graft rate and complete crosslinking at both ends. The newly developed nanopropharmaceutical was characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR), which confirmed the presence of amide groups. Powder X-ray diffraction (XRD) analysis revealed the crystal structure of CMCS-Pt (IV) -1.
Analysis by scanning electron microscopy revealed that CMCS-Pt (IV) -1 in an aqueous solution was present as nanoparticles (NP) measuring 27.3 nm. However, because small-sized nanoparticles are not ideal for in vivo drug delivery, due to their easy elimination by the reticuloendothelial system (RES), the size optimization of CMCS-Pt (IV) -1 is essential for drug delivery application.
The researchers prepared nanogel (NG) by crosslinking reaction between CMCS-Pt (IV) -1 and aqueous glutaraldehyde. They observed that the size of NG particles remained unchanged in a varied environment even after thirty days, indicating their circulation stability and long-term storage potential. This could be due to its crosslinked double structure, presence of ester and imine or unreduced cisplatin (IV) bonds, and negative zeta potentials under physiological conditions.
In this study, researchers determined the impact of the physicochemical properties of the pharmacokinetics of NGs. They injected DDP / DMC and NGs with the same concentration of cisplatin intravenously into mice carrying H22 tumors.
The scientists reported that NG showed longer circulation stability than DDP / DMC due to its unique double crosslinking structure, zeta potential, and adequate particle size, which prevented its removal of RES. In addition, NG was found to reach the tumor site with improved efficiency. Increased NG accumulation at tumor sites was due to the EPR effect, long-term circulatory stability, improved tumor penetration, cell uptake, and retention. by protonation of tumor extracellular amnion.
Concluding remarks
The authors reported the successful development of CMCS-based nanopharmaceuticals, which were linked between CMCS Pt (IV) -1 and further stabilized by glutaraldehyde. Importantly, compared to other single-drug crosslinked polysaccharide-based nanopropharmaceuticals, the newly synthesized nanopropharmaceutical showed robust synergistic chemotherapy at a low rate of drug coupling rate with minimal side effects. Therefore, the researchers stated that these Pt (IV) -1 crosslinked CMCS-based synergistic nanopharmaceuticals could be used effectively for cancer therapy.
Reference
Wang, Z. et al. (2022). Dynamic nanopropharmaceuticals based on carboxymethyl chitosan accurately mediate robust synergistic chemotherapy. Carbohydrate polymers. https://doi.org/10.1016/j.carbpol.2022.119671
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