Journal
JOURNAL OF CONTROLLED RELEASE
Volume 163, Issue 2, Pages 136-144Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2012.08.020
Keywords
Drug-resistance; Intracellular distribution; Small-interfering RNA; Major vault protein; Polyamidoamine; Hyaluronic acid
Funding
- National Natural Science Foundation of China [81102392]
- Natural Science Foundation of Zhejiang Province, China [Y2110124, Y2100645]
- Research Fund for the Doctoral Program of Higher Education of China [20090101120141]
- Fundamental Research Funds for the Central Universities, China
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Drug resistance is one of the critical reasons leading to failure in chemotherapy. Enormous studies have been focused on increasing intracellular drug accumulation through inhibiting P-glycoprotein (Pgp). Meanwhile, we found that major vault protein (MVP) may be also involved in drug resistance of human breast cancer MCF-7/ADR cells by transporting doxorubicin (DOX) from the action target (i.e. nucleus) to cytoplasma. Herein polyamidoamine (PAMAM) dendrimers was functionalized by a polysaccharide hyaluronic acid (HA) to effectively deliver DOX as well as MVP targeted small-interfering RNA (MVP-siRNA) to down regulate MVP expression and improve DOX chemotherapy in MCF-7/ADR cells. In comparison with DOX solution (IC50 = 48.5 mu M), an enhanced cytotoxicity could be observed for DOX PAMAM-HA (IC50 = 11.3 mu M) as well as enhanced tumor target, higher intracellular accumulation, increased blood circulating time and less in vivo toxicity. Furthermore, codelivery of siRNA and DOX by PAMAM-HA exhibited satisfactory gene silencing effect as well as enhanced stability and efficient intracellular delivery of siRNA, which allowed DOX access to nucleus and induced subsequent much more cytotoxicity than siRNA absent case as a result of MVP knockdown. This observation highlights a promising application of novel nanocarrier PAMAM-HA, which could co-deliver anticancer drug and siRNA, in reversing drug resistance by altering intracellular drug distribution. (c) 2012 Elsevier B.V. All rights reserved.
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