The researchers reported that a polysaccharide-based nano-prodrug crosslinked with stimulus-responsive synergistic prodrugs showed high tumor selectivity, stability and synergistic effect. As a result, such nano-prodrugs are in great demand.
Study: Dynamic nanometrugs based on carboxymethylchitosan accurately mediate potent synergistic chemotherapy. Image credit: Rapeepat Pornsipak / Shutterstock.com
Recently, a group of researchers has developed dynamic carboxymethylchitosan (CMCS) nanoproteins crosslinked with a water-soluble synergistic precursor that is highly effective for selective chemotherapy. This study is available as a pre-proof in Carbohydrate Polymers.
Polysaccharide based nanomedicines
Polysaccharide-based nano-prodrugs have been observed to exhibit stable drug delivery, robust antitumor activity, significant drug storage capacity, and circulation. Despite these advantages, they have not yet been used for cancer therapy because batch-to-batch variations present risks and insufficient therapeutic efficacy. Other limitations associated with the immunogenicity of polysaccharide-based nano-prodrugs are unjustified polysaccharide modifications, poor tumor selectivity, dose-dependent toxicity from low drug conjugate rates, etc.
Researchers believe that there is a need for suitable polysaccharides for the development of a new polysaccharide-based nano-prodrug that exhibits enhanced chemotherapeutic effects and reduced side effects.
Nano-prodrugs based on carboxymethylchitosan (CMCS).
Previous studies have revealed that CMCS is an important derivative of chitosan (CS), which has been approved for use by the US Food and Drug Administration. These studies further indicated that CMCS has many useful physicochemical and biological properties, such as the availability of many reaction sites such as amino and carboxyl groups, good water solubility, biodegradability, pH sensitivity, low immunogenicity and biocompatibility. In addition, it also shows promising antitumor properties based on inhibition of tumor cell proliferation, metastasis and angiogenesis. It also shows low affinity for sugar transporters on macrophages.
Although CMCS has interesting properties that could be used to develop a polysaccharide-based nano-prodrug, its molecular weight varies when obtained from different sources. This complicates the industrial production of CMCS-based nano-prodrugs. Another limitation of CMCS-based nano-prodrugs is their selectivity in addition to the effect of increased permeability and retention (EPR) at tumor sites.
A previous study indicated that irregular metabolism of cancer cells leads to an abnormal distribution of the acid gradient between the interstitial space, blood vessels, intracellular matrix, and high levels of intracellular glutathione (GSH). These irregularities could focus on the development of a new pH / GSH-oriented CMCS-based nano-prodrug for the treatment of a specific type of cancer.
The researchers reported that a 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 crosslinked with CMCS via an amide reaction in aqueous solution to develop CMCS-based dual pH / GSH responses.
Development of dynamic nano-prodrugs based on CMCS: A new study
Researchers have recently synthesized CMCS-Pt (IV) -1 through a crosslinking reaction between CMCS amino groups and Pt (IV) -1 carboxyl groups in deionized water. The feed molar ratio was 1: 0.488 to achieve an adequate drug grafting rate and complete crosslinking at both ends. The newly developed nano-prodrug was characterized by 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 crystal structure of CMCS-Pt (IV) -1.
Scanning electron microscopy analysis revealed that CMCS-Pt (IV) -1 in aqueous solution was present as 27.3 nm nanoparticles (NP). However, because small nanoparticles are not ideal for in vivo drug delivery, due to their easy removal by the reticuloendothelial system (RES), CMCS-Pt (IV) -1 size optimization is essential for drug delivery.
The researchers prepared the nanogel (NG) through a crosslinking reaction between CMCS-Pt (IV) -1 and glutaraldehyde in the aqueous state. They observed that the particle size of NG remained unchanged in various environments even after thirty days, indicating its circulating stability and its potential for long-term storage. This may be due to its double cross-linked structure, the presence of ester and imine bonds or unreduced cisplatin (IV) and negative zeta potentials under physiological conditions.
In this study, the researchers determined the impact of the physicochemical properties of NG pharmacokinetics. Mice with H22 tumor injected DDP / DMC and NG intravenously with the same concentration of cisplatin.
The researchers reported that NG showed longer circulatory stability than DDP / DMC due to its unique double cross-link structure, zeta potential, and suitable particle size, which prevented its removal from RES. In addition, NG has been found to reach tumor sites with improved efficacy. Increased NG accumulation at tumor sites was due to the EPR effect, long-term circulatory stability, increased tumor penetration, cell uptake, and retention through tumor extracellular amnio protonation.
The authors reported on the successful development of CMCS-based nano-prodrugs that were cross-linked between CMCS Pt (IV) -1 and further stabilized by glutaraldehyde. Importantly, compared to other polysaccharide-based nano-prodrugs crosslinked with a single drug, the newly synthesized nano-prodrug exhibited robust synergistic chemotherapy at a low level of drug binding rate with minimal side effects. The researchers therefore suggested that these synergistic nano-prodrugs based on CMCS cross-linked Pt (IV) -1 could be effectively used to treat cancer.
Wang, Z. et al. (2022). Dynamic nanometrugs based on carboxymethylchitosan accurately mediate robust synergistic chemotherapy. Carbohydrate polymers. https://doi.org/10.1016/j.carbpol.2022.119671
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