Click Nanogels from pH-Labile Dextran Prodrugs for Robust Solid Tumor Chemotherapy

Abstract

Bioresponsive prodrug nanogels are promising drug delivery systems for cancer chemotherapy due to their advantages such as a high drug-loading content (DLC) and colloidal stability. Herein, a group of polymeric nanogels from clickable dextran prodrugs (CDPs) were designed for pH-responsive drug release against solid tumors. The CDP nanogels were prepared by metal-free click-crosslinking between two clickable dextran-hydrazone-doxorubicin (DOX) prodrugs having azadibenzocyclooctyne and azide residues, respectively, also being termed as DDB/DOX and DAZ/DOX. By adjusting the amounts of these clickable residues and DOX, an equivalent molar amount of DDB/DOX and DAZ/DOX prodrugs containing five of clickable residues and three of DOX, respectively, were applied to produce the CDP5/DOX3 nanogels showing the smallest size (∼130 nm), a nearly neutral surface charge (+3.1 mV), and a high DLC (12.8%). In vitro accumulative drug release testing indicated that the CDP5/DOX3 nanogels displayed relatively slow DOX release under physiological conditions but faster DOX release in an acidic endosomal environment by virtue of the hydrolysis of acid-labile hydrazone. In vitro cytotoxicity testings supported that the CDP5/DOX3 nanogels afforded marked antitumor activity in CT-26 and LLC cancer cells as a result of the DOX delivery into the cellular nuclei. In vivo, compared to the free DOX group, the CDP5/DOX3 nanogel group possessed a higher level of DOX accumulation in CT-26 tumor xenografted in balb/c mice as well as improved DOX pharmacokinetics in the mice. Intravenous administration of the nanogels afforded significant growth repression of CT-26 tumor with a DOX dosage of 4.0 mg/kg, followed by minor systemic toxicity. Moreover, such an antitumor efficacy was much better for the nanogel group than for the free DOX group. This study highlights high potential of dextran prodrug nanogels for robust cancer chemotherapy.

Self‐assembled nanoprodrugs from reducible dextran‐diethyldithiocarbamate conjugates for robust tumor‐targeted chemotherapy

“…The chemical structures of disulfide-linked prodrugs based on DDTC or doxorubicin affect their drug release rates. 28 Compared to those reported prodrugs such as disulfide-linked poly(2-[pyridin-2-yldisulfanyl] ethyl acrylate)-DDTC conjugates 12 and dextran-doxorubicin prodrugs, 27 the DP10k and FADP10k nanoprodrugs display relative fast drug release with >90% of released DDTC within 40 min. This is likely ascribed to a high solubility of dextran and DDTC residues in comparison with hydrophobic polyacrylate and doxorubicin.…”

“…Drug repurposing takes a few advantages over developing entirely new drugs in low risk of failure and reduced time of drug development. We previously developed a few dextran prodrugs due to their favorable features such as a high drug content and flexible conjugation chemistries between drug and dextran 27 . The advantages thus promote us to develop a novel DSF‐based dextran prodrug (DP) for cancer therapy using a thiol‐orthopyridyl disulfide exchanging reaction (Figure 1a).…”

“…We previously developed a few dextran prodrugs due to their favorable features such as a high drug content and flexible conjugation chemistries between drug and dextran. 27 The advantages thus promote us to develop a novel DSF-based dextran prodrug (DP) for cancer therapy using a thiol-orthopyridyl disulfide exchanging reaction (Figure 1a). The disulfide bond is used to covalently link DDTC residues and dextran.…”

Surface Membrane Coating as a Versatile Platform for Modifying Antitumor Nanoparticles

“…Moreover, there are productive hydroxyl groups in the polysaccharide structure, which can develop new products and further chemically modify specific ligands to design and build novel coatings (see Figure 10B). 199,200 At present, pectin polysaccharide membrane has been applied to cell adhesion and drug release. Given the thermal response characteristics of pectin, its application in PTT tumor therapy can be explored.…”

“…There are abundant ligands and novel structures in the development of polysaccharide derivatives. Moreover, there are productive hydroxyl groups in the polysaccharide structure, which can develop new products and further chemically modify specific ligands to design and build novel coatings (see Figure B). , …”