Mitochondrial Targeted Doxorubicin-Triphenylphosphonium Delivered by Hyaluronic Acid Modified and pH Responsive Nanocarriers to Breast Tumor: in Vitro and in Vivo Studies.

TitleMitochondrial Targeted Doxorubicin-Triphenylphosphonium Delivered by Hyaluronic Acid Modified and pH Responsive Nanocarriers to Breast Tumor: in Vitro and in Vivo Studies.
Publication TypeJournal Article
Year of Publication2018
AuthorsLiu H-N, Guo N-N, Wang T-T, Guo W-W, Lin M-T, Huang-Fu M-Y, Vakili MReza, Xu W-H, Chen J-J, Wei Q-C, Han M, Lavasanifar A, Gao J-Q
JournalMol Pharm
Volume15
Issue3
Pagination882-891
Date Published2018 Mar 05
ISSN1543-8392
Abstract

Multidrug resistance (MDR) is the major obstacle for chemotherapy. In a previous study, we have successfully synthesized a novel doxorubicin (DOX) derivative modified by triphenylphosphonium (TPP) to realize mitochondrial delivery of DOX and showed the potential of this compound to overcome DOX resistance in MDA-MB-435/DOX cells. (1) To introduce specificity for DOX-TPP to cancer cells, here we report on the conjugation of DOX-TPP to hyaluronic acid (HA) by hydrazone bond with adipic acid dihydrazide (ADH) as the acid-responsive linker, producing HA- hydra-DOX-TPP nanoparticles. Hyaluronic acid (HA) is a natural water-soluble linear glycosaminoglycan, which was hypothesized to increase the accumulation of nanoparticles containing DOX-TPP in the mitochondria of tumor cells upon systemic administration, overcoming DOX resistance, in vivo. Our results showed HA- hydra-DOX-TPP to self-assemble to core/shell nanoparticles of good dispersibility and effective release of DOX-TPP from the HA- hydra-DOX-TPP conjugate in cancer cells, which was followed by enhanced DOX mitochondria accumulation. The HA- hydra-DOX-TPP nanoparticles also showed improved anticancer effects, better tumor cell apoptosis, and better safety profile compared to free DOX in MCF-7/ADR bearing mice.

DOI10.1021/acs.molpharmaceut.7b00793
Alternate JournalMol. Pharm.
PubMed ID29357260

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