Dataset Information

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery.

ABSTRACT: Tumor microenvironment has been widely utilized for advanced drug delivery in recent years, among which hypoxia-responsive drug delivery systems have become the research hotspot. Although hypoxia-responsive micelles or polymersomes have been successfully developed, a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear. Herein, we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based (^HPMPC) nanogel for tumor drug delivery. The obtained ^HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility, which leads to high and long-lasting accumulation in tumor tissue. Furthermore, ^HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment, which leads to the effective release of the loaded drug. Impressively, ^HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel, owing to the more complete drug release. Overall, the drug-loaded ^HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects, which showed great potential as nanocarrier for advanced tumor drug delivery.

SUBMITTER: Peng S

PROVIDER: S-EPMC7893141 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery.

Peng Shaojun S Ouyang Boshu B Xin Yongjie Y Zhao Wei W Shen Shun S Zhan Meixiao M Lu Ligong L

Acta pharmaceutica Sinica. B 20200826 2

Tumor microenvironment has been widely utilized for advanced drug delivery in recent years, among which hypoxia-responsive drug delivery systems have become the research hotspot. Although hypoxia-responsive micelles or polymersomes have been successfully developed, a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear. Herein, we reported the synthesis of a novel ...[more]

PMID: 33643831

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Project description:Hydrophilic nanosized particles consisting of the cross-linked cationic polymer network (Nanogels) are suggested as a drug delivery system for nucleoside analog 5'-triphosphates, an active form of cytotoxic anticancer drugs. Preparation, properties, and cellular effects of several polyplex Nanogel formulations with the 5'-triphosphate of cytotoxic 5-fluoroadenine arabinoside (fludarabine) (FATP) were examined and discussed here. The polyplexes have formed spontaneously by mixing solutions of FATP and Nanogels because of ionic interactions between protonated polyethylenimine (PEI) chains in Nanogel network with polyphosphate groups of the drug. Subsequent compaction of the flexible Nanogel network has resulted in an encapsulation of the FATP/PEI complex in a dense core surrounded by hydrophilic poly(ethylene glycol) (PEG) envelope. This structure has provided a sustained release of the drug, as well as an efficient protection of FATP against enzymatic degradation. The drug loading could reach up to 33% by weight of the drug-Nanogel formulation. In vitro 35% of loaded drug has released from Nanogel formulations during the first 24 h, and a slower additional release was observed during the next 2 days. Nanogels have protected 90% of the encapsulated FATP from enzymatic dephosphorylation during the first 60 min of incubation in vitro. The drug-Nanogel formulation compared to the drug has demonstrated a significantly enhanced cytotoxicity in cultured cancer cells. Cancer cell-targeting molecules, such as folate, could be easily attached to Nanogels and this modification has resulted in a strong 10-fold increase of the carrier's internalization in human breast carcinoma MCF-7 cells. Moreover, transcellular transport of the folate-Nanogel polyplexes was found to be 4 times more effective compared to the drug alone using Caco-2 cell monolayers as an in vitro intestinal model. The data demonstrate that this carrier-based approach to delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects related to systemic toxicity usually observed during cancer chemotherapy.

Dataset Information

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery.

Publications

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery.

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