Journal
ACS NANO
Volume 13, Issue 6, Pages 7036-7049Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.9b02149
Keywords
polymeric micelle; nanodrug sequential drug release; multicell targeting; combination therapy
Categories
Funding
- National Natural Science Foundation of China [U1401242]
- National Basic Research Program of China [2015CB755500]
- Natural Science Foundation of Guangdong Province [2014A0303120182]
- Guangdong Innovative and Entrepreneurial Research Team Program [2013S086]
- Fundamental Research Funds for the Central Universities [17lgjc01]
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Among various inflammatory factors/mediators, autocrine and paracrine prostaglandin 2 (PGE(2)), which are abundant in various tumors, promote the proliferation and chemoresistance of cancer cells. Thus, eliminating the cytoprotective effect of PGE(2) may strengthen the antitumor effect of chemotherapy. Chemo/anti-inflammatory combination therapy requires the programmed activities of two different kinds of drugs that critically depend on their spatiotemporal manipulation inside the tumor. Here, a micellar polymeric nanosphere, encapsulating chemotherapeutic paclitaxel (PTX) in the core and conjugating anti-inflammatory celecoxib (CXB) to the shell through a peptide linker (PLGLAG), was developed. The PLGLAG linker was cleavable by the enzyme matrix metalloproteinase-2 (MMP-2) in the tumor tissue, causing CXB release and turning the negatively charged nanosphere into a positively charged one to facilitate PTX delivery into cancer cells. The released CXB not only acted on cyclooxygenase-2 (COX-2) to suppress the production of pro-inflammatory PGE(2) in multiple cell types but also suppressed the expression of the anti-apoptotic Bcl-2 gene to sensitize cancer cells to chemotherapy, thus resulting in a synergistic anticancer effect of PTX and CXB. This study represents an example of using a surface charge-switchable nanosphere with on-demand drug release properties to act on multiple cell types for highly effective chemo/anti-inflammatory combination therapy of cancer.
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