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ACS Appl Mater Interfaces. 2017 Sep 13;9(36):30519-30535. doi: 10.1021/acsami.7b10148. Epub 2017 Sep 1.

Enzymatic PEG-Poly(amine-co-disulfide ester) Nanoparticles as pH- and Redox-Responsive Drug Nanocarriers for Efficient Antitumor Treatment.

Author information

1
Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University , Guangzhou, Guangdong 510006, China.
2
Department of Neurosurgery and Department of Biomedical Engineering, Yale University , New Haven, Connecticut 06511, United States.
3
Department of Biomedical Engineering, Molecular Innovations Center, Yale University , 600 West Campus Drive, West Haven, Connecticut 06516, United States.

Abstract

We have designed and constructed novel multifunctional nanoparticle drug-delivery systems that are stable under physiological conditions and responsive to tumor-relevant pH and intracellular reduction potential. The nanoparticles were fabricated from enzymatically synthesized poly(ethylene glycol) (PEG)-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG-PPMD) and PEG-poly(ε-caprolactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG-PCMD) block copolymers via self-assembly processes in aqueous solution. At acidic pH and in the presence of a reductant (e.g., d,l-dithiothreitol or glutathione), the nanosized micelle particles rapidly swell and disintegrate due to the protonation of amino groups and reductive cleavage of disulfide bonds in the micelle cores. Consistently, docetaxel (DTX)-loaded PEG-PPMD and PEG-PCMD micelles can be triggered synergistically by acidic endosomal pH and a high intracellular reduction potential to rapidly release the drug for efficient killing of cancer cells. The drug formulations based on PEG-PPMD and PEG-PCMD copolymers exhibited a substantially higher potency than free DTX in inhibiting tumor growth in mice, whereas their therapeutic effects on important organ tissues were minimal. These results demonstrate that PEG-PPMD and PEG-PCMD nanoparticles have a great potential to serve as site-specific, controlled drug-delivery vehicles for safe and efficient antitumor treatment.

KEYWORDS:

PEGylation; anticancer treatment; drug delivery; lipase; nanoparticle; pH-responsive; poly(amine-co-disulfide ester); redox-responsive

PMID:
28819967
DOI:
10.1021/acsami.7b10148
[Indexed for MEDLINE]

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