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Applications of Polymer, Composite, and Coating Materials
Dual-responsive size-shrinking nanocluster with hierarchal disassemble capability for improved tumor penetration and therapeutical efficacy Xiaoyan Sun, Jiulong Zhang, Chunrong Yang, Ziyuan Huang, Menghao Shi, Shuang Pan, Haiyang Hu, Mingxi Qiao, Dawei Chen, and Xiuli Zhao ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b21580 • Publication Date (Web): 04 Mar 2019 Downloaded from http://pubs.acs.org on March 4, 2019
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ACS Applied Materials & Interfaces
Dual-Responsive
Size-Shrinking
Nanocluster
with
Hierarchal Disassemble Capability for Improved Tumor Penetration and Therapeutical Efficacy Xiaoyan Sun1, Jiulong Zhang1, Chunrong Yang2, Ziyuan Huang1, Menghao Shi1, Shuang Pan1, Haiyang Hu1, Mingxi Qiao1, Dawei Chen1, Xiuli Zhao1# 1
School of Pharmacy, Shenyang Pharmaceutical University. Shenyang, 110016, P.R. China. Fax: +86
24 23986306. 2
College Pharmacy of Jiamusi University, 148 Xuefu Street, Jiamusi, Heilongjiang, PR China, 154007
E-mail:
[email protected] (X, Sun);
[email protected] (X. Zhao)
Keywords ： dual-responsive;
self-adaptively transform; hierarchal disassemble; tumor
penetration, chemotherapy; systematic evaluation.
Abstract It is generally known that for nanoparticles in cancer therapy, sufficient tumor penetration need minor particle size while long in vivo circulation time need larger. It is hard to balance them, which are standing on the either side of seesaw. To address these two different requirements, a dual-responsive size-shrinking nanocluster can self-adaptively response to complicated tumor microenvironment and transform its particulate property to overcome sequential in vivo barriers and reach a preferable antitumor activity. The nanocluster (RPSPT@SNCs) could preferentially accumulate into tumor tissue and dissociate under extracellular matrix metalloproteinase-2 (MMP-2) to release small-sized micelle formulations (RPSPT). RPSPT owes favorable tumor penetration and tumor targeting capability to deliver antitumor agent paclitaxel (PTX) into deep region of solid tumor. Intracellular redox microenvironment can also accelerate drug accumulation. The prepared RPSPT@SNCs possesses enhanced cell cytotoxicity and tumor penetration capability on MCF-7 cells and a favorable antitumor activity on xenograft tumor mouse model.
1. Introduction Cancer is a great threat to human health, while nanomedicine has been proved to possess great promise for safer tumor therapy.1-4 Unlike intravenous administration of free anticancer drug, utilizing nanoparticle as a carrier to incorporate the drug could not only minimize systematic toxicity but also accelerate tumor accumulation via enhanced permeability and retention (EPR) effect.5-7 However, the success of nanomedicine was dramatically hampered with sequential drug delivery barriers, such as insufficient blood circulation process, in vivo rapid drug leakage and limited tumor penetration capability. Therefore, it is necessary to develop rational and sophisticated drug delivery system for the treatment of solid tumor. In comparison with conventional small-molecule drugs, nanoparticles owe larger particle size, which could possess favorable EPR effect. 8-9 However, the larger size is a double-edged
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sword as it would hamper the deep penetration of nanoparticles.10-12 Meanwhile, high interstitial fluid pressure (IFP) and dense extracellular matrix would also play a negative role in deep penetration of solid tumor.13-15 Conversely, nanoparticle with smaller particle size (
