Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 12, Issue 16, Pages 18273-18291Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.0c00355
Keywords
dual redox-response; deep tumor penetration; hyaluronidase; tumor micro-environment; cancer therapy
Funding
- National Natural Science Foundation of China [81373363]
- China Postdoctoral Science Foundation [2018M632431]
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2015ZX09501001]
- Fundamental Research Funds for the Central Universities [PT2014YX0085]
- Innovation Project of Jiangsu Province [KYLX16_1178]
- Huahai Pharmaceutical Postgraduate Innovation Fund [CX14B-001HH]
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Deep tumor penetration, long blood circulation, rapid drug release, and sufficient stability are the most concerning dilemmas of nano-drug-delivery systems for efficient chemotherapy. Herein, we develop reduction/oxidation-responsive hierarchical nanoparticles co-encapsulating paclitaxel (PTX) and pH-stimulated hyaluronidase (pSH) to surmount the sequential biological barriers for precise cancer therapy. Poly(ethylene glycol) diamine (PEG-dia) is applied to collaboratively cross-link the shell of nanoparticles self-assembled by a hyaluronic acid-stearic acid conjugate linked via a disulfide bond (HA-SS-SA, HSS) to fabricate the hierarchical nanoparticles (PHSS). The PTX and pSH coloaded hierarchical nanoparticles (PTX/pSH-PHSS) enhance the stability in normal physiological conditions and accelerate drug release at tumorous pH, and highly reductive or oxidative environments. Functionalized with PEG and HA, the hierarchical nanoparticles preferentially prolong the circulation time, accumulate at the tumor site, and enter MDA-MB-231 cells via CD44-mediated endocytosis. Within the acidic tumor micro-environment, pSH would be partially reactivated to decompose the dense tumor extracellular matrix for deep tumor penetration. Interestingly, PTX/pSH-PHSS could be degraded apace by the completely activated pSH within endo/lysosomes and the intracellular redox micro-environment to facilitate drug release to produce the highest tumor inhibition (93.71%) in breast cancer models.
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