Combinational delivery of hydrophobic and hydrophilic anticancer drugs in single nanoemulsions to treat MDR in cancer.
In this study, we developed the core-matched nanoemulsions (NEs) functionalized by vitamin E (VE) and tocopherol poly(ethylene glycol)succinate (TPGS) to codeliver hydrophobic and hydrophilic drugs, paclitaxel (PTX) and 5-fluoroucacil (5-FU), in order to achieve synergistic effects and overcome PTX resistance in a multi-drug-resistant (MDR) human epidermal carcinoma cell line KB-8-5. Antitumor effect of the combination therapy based on core-matched technology (CMT) was evaluated in vitro and in vivo in mice. The core-matched NEs showed entrapment efficiency of >90% and were of nanoscale particle size and negative zeta-potential. The combined core-matched NEs exhibited concentration and time-dependent cytotoxicity against PTX-sensitive KB-3-1 cells and PTX-resistant KB-8-5 cells as well as an obviously increased G2/M phase block. The improvements in therapeutic response over either PTX-VE or 5-FU-TPGS therapy alone were demonstrated by the ability to effectively induce the apoptosis of tumor cells via up-regulation of tumor suppressor p53 and β-tubulin and by the significant inhibition of cell cycle progression. The combination therapy led to dramatic inhibition of tumor growth with little toxicity in vivo, especially in the PTX-resistant KB-8-5 tumors, whereas Taxol had little therapeutic effect. This was mainly ascribed to the synergism of PTX and 5-FU and the reverse of MDR by the inhibition of ATPase activity by VE and TPGS. Coencapsulation of two chemotherapeutic agents with different mechanisms allows simultaneous interruption of diverse anticancer pathways, resulting in increased therapeutic response and low toxicity. The CMT markedly facilitated the long circulation of PTX and 5-FU, which was closely associated with the high accumulation of chemotherapeutic agents within the tumors and the improvement of antitumor efficacy. The current study demonstrated the feasibility of incorporating PTX and 5-FU targeting to different pathways into a single core-matched NE for the reversal of MDR and synergism in cancer therapy.
Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Yan
Y
Ma
Dan
D
Liu
Dun
D
Wang
Yongjun
Y
Wang
Qiang
Q
Fu
John K
JK
Fallon
Xinggang
X
Yang
Zhonggui
Z
He
Feng
F
Liu
D000251:Adenosine Triphosphatases / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004655:Emulsions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine / Q000379:methods; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012878:Skin Neoplasms / Q000188:drug therapy; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry
D000970:Antineoplastic Agents; D004655:Emulsions; D014810:Vitamin E; D011092:Polyethylene Glycols; D000251:Adenosine Triphosphatases; C014225:tocophersolan; D017239:Paclitaxel; D005472:Fluorouracil