A ROS-responsive polymeric prodrug nanosystem with self-amplified drug release for PSMA (-) prostate cancer specific therapy

The selectively accumulate in tumor site and completely release drug within cancer cells great limit the therapeutic effect of nano-drug delivery system. Moreover, absence of appropriate biomarker is one of the major challenges for prostate specific membrane antigen negative (PSMA (-)) prostate canc...

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Bibliographic Details
Published in:	Journal of nanobiotechnology Vol. 17; no. 1; pp. 91 - 16
Main Authors:	Wang, Yifan, Zhang, Yanqiu, Ru, Zhengxing, Song, Wei, Chen, Lin, Ma, Hao, Sun, Lizhu
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 26-08-2019 BioMed Central BMC
Subjects:	Animals Anthracyclines Anticancer properties Antigens Antigens, Surface - metabolism Antitumor activity Biocompatibility Biomarkers Cancer cells Cancer therapies Cell Line, Tumor Chemical properties Doxorubicin Doxorubicin - chemistry Doxorubicin - pharmacology Drug delivery Drug delivery systems Drug Delivery Systems - methods Drug Liberation - drug effects Drug therapy Drugs Efficiency Glutamate Carboxypeptidase II - metabolism Humans Intracellular Intracellular ROS amplification Ligands Male Medical research Mice Mitochondria Nanoparticles Nanoparticles - chemistry Oncology PC-3 Cells Peptides PMSA Polymers - chemistry Prodrugs - chemistry Prodrugs - pharmacology Prostate - drug effects Prostate - metabolism Prostate cancer Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Reactive oxygen species Reactive Oxygen Species - metabolism ROS-responsive Self-accelerating Side effects Technology Therapy Tumors China Intracellular ROS amplification ROS-responsive Self-accelerating PMSA
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Summary:	The selectively accumulate in tumor site and completely release drug within cancer cells great limit the therapeutic effect of nano-drug delivery system. Moreover, absence of appropriate biomarker is one of the major challenges for prostate specific membrane antigen negative (PSMA (-)) prostate cancer therapy. Herein, a PSMA (-) prostate cancer specific targeted and intracellular reactive oxygen species (ROS) amplification for ROS-responsive self-accelerating drug release nanoplatform (ATD-NPs) was developed. ATD-NPs was formed by three parts, including PSMA (-) prostate cancer specifically targeted part (DUP-PEG-DSPE), ROS-sensitive doxorubicin (DOX) polymeric prodrug (P(L-TK-DOX)), and the ROS generation agent (α-tocopheryl succinate, α-TOS); and this delivery system is expected to enhance PSMA (-) prostate cancer therapeutic effect, increase selective accumulation at tumor site and overcome intracellular incomplete drug release. After administration i.v injection, ATD-NPs could specifically accumulate in tumor site and markedly be internalized by cancer cells based on the DUP-1 (a PSMA (-) cancer cells specific target peptide). Subsequently, ATD-NPs could be dissociated under the high concentration reactive oxygen species (ROS) condition, resulting in DOX and α-TOS release. Then, the released α-TOS could be reacted with mitochondria to produce ROS, which in turn accelerating the release of drugs. Finally achieved the purpose of enhancing therapeutic efficacy and reducing side effect. Both in vitro and in vivo experiments demonstrated that the combination of tumor actively-targeted and self-amplifying ROS-responsive drug release showed more significant antitumor activity in the human PSMA (-) prostate cancer. The described technology unifies the tumor actively targets, self-amplified drug release, and excellent biocompatibility into one formulation, are promising for cancer treatment.
ISSN:	1477-3155 1477-3155
DOI:	10.1186/s12951-019-0521-z