Title

Doxorubicin-loaded liposomes with a pH-sensitive conformational switch for anticancer drug delivery

Poster Number

22

Lead Author Affiliation

Pharmaceutics and Medicinal Chemistry

Introduction

Doxorubicin is an anthracyline compound, a broad spectrum anti-cancer drug to treat several cancers. However, nonselective cytotoxicity leading to many side effects limits its application. Nano level drug delivery system for doxorubicin is one of the targeting strategies, which fully takes advantage of enhanced permeability and retention (EPR) effect. By various triggered release design, sufficient release could be achieved by certain stimuli, such as different pH environment at tumor site to get therapeutically efficient drug concentration.

Purpose

A strategy was developed to render saturated and PEGylated liposomes pH-sensitive: a protonation-induced conformational switch of lipid tails, by using trans-2-aminocyclohexanol moiety (TACH) as a molecular trigger. Dipalmitoyl (C-16) TACH lipids have higher transition temperature than dilauroyl (C-12) lipids so that C-16 TACH liposomes would be more stable in blood circulation to facilitate applications in vivo. Such pH-sensitive lipids (flipids) and liposomes (fliposomes) were prepared and characterized to evaluate their potential as a triggered release system for anticancer drug delivery.

Method

Six novel flipids with C-16 hydrocarbon tails and various amine groups were designed. The flipids were synthesized based on our prior reports but with the additional use of Cu(BF4)2•6H2O as a catalyst to functionalize the epoxide intermediate (Scheme 1). Various fliposomes and control liposome were prepared by thin film hydration, freeze-thawing and polycarbonate membrane extrusion. Then doxorubicin was remotely loaded by transmembrane manganese sulfate gradient without resorting to low pH-gradient in order to avoid premature triggering of the fliposomes. Encapsulation efficiency, mean size diameter, zeta-potential and drug release at different pHs were characterized.

Results

Six novel C-16 flipds were synthesized with yields between 50% to 70%. Several TACH fliposomes containing doxorubicin were constructed with appropriate encapsulation efficiency (>59%, Table 1), mean particle size (<120 nm, Table 1), and neutral zeta-potential (Table 1). The fliposomes could release more than 40% doxorubicin at pH =6.5, and yet no detectable doxorubicin at pH =7.4, indicating that these fliposomes possess considerable pH-sensitivity.

Significance

Our preliminary data indicate that the C-16 TACH-based fliposomes are stable at neutral media but can release content drug (e.g. doxorubicin) in response to lowered pH, which could serve as a promising strategy to deliver and release doxorubicin into the acidic interstitium of solid tumors.

Location

DeRosa University Center, Stockton campus, University of the Pacific

Format

Poster Presentation

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Apr 25th, 10:00 AM Apr 25th, 12:00 PM

Doxorubicin-loaded liposomes with a pH-sensitive conformational switch for anticancer drug delivery

DeRosa University Center, Stockton campus, University of the Pacific

Doxorubicin is an anthracyline compound, a broad spectrum anti-cancer drug to treat several cancers. However, nonselective cytotoxicity leading to many side effects limits its application. Nano level drug delivery system for doxorubicin is one of the targeting strategies, which fully takes advantage of enhanced permeability and retention (EPR) effect. By various triggered release design, sufficient release could be achieved by certain stimuli, such as different pH environment at tumor site to get therapeutically efficient drug concentration.