Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment.

Abstract

Multidrug resistance (MDR) remains the primary issue in cancer therapy, which is characterized by the overexpressed P-glycoprotein (P-gp)-included efflux pump or the upregulated anti-apoptotic proteins. In this study, a D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) and hyaluronic acid (HA) dual-functionalized cationic liposome containing a synthetic cationic lipid, 1,5-dioctadecyl-N-histidyl-L-glutamate (HG2C18) was developed for co-delivery of a small-molecule chemotherapeutic drug, paclitaxel (PTX) with a chemosensitizing agent, lonidamine (LND) to treat the MDR cancer. It was demonstrated that the HG2C18 lipid contributes to the endo-lysosomal escape of the liposome following internalization for efficient intracellular delivery. The TPGS component was confirmed able to elevate the intracellular accumulation of PTX by inhibiting the P-gp efflux, and to facilitate the mitochondrial-targeting of the liposome. The intracellularly released LND suppressed the intracellular ATP production by interfering with the mitochondrial function for enhanced P-gp inhibition, and additionally, sensitized the MDR breast cancer (MCF-7/MDR) cells to PTX for promoted induction of apoptosis through a synergistic effect. Functionalized with the outer HA shell, the liposome preferentially accumulated at the tumor site and showed a superior antitumor efficacy in the xenograft MCF-7/MDR tumor mice models. These findings suggest that this dual-functional liposome for co-delivery of a cytotoxic drug and an MDR modulator provides a promising strategy for reversal of MDR in cancer treatment.

• Authors: Assogba G Assanhou, Wenyuan Li, Lei Zhang, Lingjing Xue, Lingyi Kong, Hongbin Sun, Ran Mo, Can Zhang
• Journal: Biomaterials (Biomaterials) Vol. 73 Pg. 284-95 (Dec 2015) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 26426537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Indazoles
• Lipids
• Liposomes
• Vitamin E
• Polyethylene Glycols
• Adenosine Triphosphate
• Hyaluronic Acid
• tocophersolan
• Paclitaxel
• lonidamine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (chemistry)
• Adenosine Triphosphate (chemistry)
• Animals
• Antineoplastic Agents (administration & dosage)
• Apoptosis
• Cell Line, Tumor
• Drug Delivery Systems
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Hyaluronic Acid (chemistry)
• Indazoles (administration & dosage)
• Lipids (chemistry)
• Liposomes (chemistry)
• MCF-7 Cells
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (metabolism)
• Neoplasms (drug therapy)
• Paclitaxel (administration & dosage)
• Polyethylene Glycols (chemistry)
• Rats
• Rats, Sprague-Dawley
• Vitamin E (analogs & derivatives, chemistry)