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J Control Release. 2014 Oct 28;192:47-56. doi: 10.1016/j.jconrel.2014.06.051. Epub 2014 Jul 6.

Low-molecular-weight protamine-modified PLGA nanoparticles for overcoming drug-resistant breast cancer.

Author information

1
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai-ke Road, Shanghai 201203, China; Zhengzhou University College of Pharmaceutical Sciences, 100 Science Road, Zhengzhou 450001, China.
2
Zhengzhou University College of Pharmaceutical Sciences, 100 Science Road, Zhengzhou 450001, China.
3
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai-ke Road, Shanghai 201203, China.
4
Tianjin University School of Chemical Engineering and Technology, Tianjin 300072, China.
5
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
6
University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, MI 48109-1065, USA.
7
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, MI 48109-1065, USA. Electronic address: vcyang@umich.edu.
8
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai-ke Road, Shanghai 201203, China. Electronic address: yzhuang@simm.ac.cn.

Abstract

Multidrug resistance (MDR) is a major challenge for cancer therapy. Herein, we report a simple yet effective system, cell-penetrating peptide (CPP)-assisted poly(lactic-co-glycolic acid nanoparticles (PLGA NPs), for improving doxorubicin (DOX) delivery and overcoming MDR cancer. We selected the naturally derived CPP low-molecular-weight protamine (LMWP) to modify PLGA NP for enhanced drug delivery. We demonstrated that multiple mechanisms ("synergistic multipronged delivery") were responsible for the anti-MDR effects of LMWP/PLGA NP. This delivery system could boost intracellular and intranuclear delivery, thereby circumventing drug efflux. Use of a P-glycoprotein inhibitor did not further increase the efficiency of intracellular delivery of LMWP/PLGA/DOX NP, suggesting that delivery of LMWP-based NP was not affected by transporter-mediated drug efflux. Importantly, enhanced uptake and penetration within the tumor was found in mice given LMWP-based NP. LMWP/PLGA NP effectively arrested tumor growth in mice harboring drug-resistant breast tumors, thereby improving treatment outcomes without detectable toxicities. These data suggest that our system could provide effective yet safe anti-MDR cancer therapy based on a synergistic, multipronged drug-delivery strategy.

KEYWORDS:

Breast cancer; Cell-penetrating peptide; Doxorubicin; Low-molecular-weight protamine; Multidrug resistance; PLGA nanoparticle

PMID:
25003794
DOI:
10.1016/j.jconrel.2014.06.051
[Indexed for MEDLINE]
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