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.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Liu HN,Guo NN,Wang TT,Guo WW,Lin MT,Huang-Fu MY,Vakili MR,Xu WH,Chen JJ,Wei QC,Han M,Lavasanifar A,Gao JQdoi
10.1021/acs.molpharmaceut.7b00793subject
Has Abstractpub_date
2018-03-05 00:00:00pages
882-891issue
3eissn
1543-8384issn
1543-8392journal_volume
15pub_type
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