Title

DESIGN OF PH-TURNABLE LIPOSOMES FOR ANTICANCER DRUG DELIVERY

Introduction

Liposomal drug delivery inside the tumor cells has been a challenge due to either recognition of liposomes by reticuloendothelial cells or due to inefficient drug release from liposomes at the tumor site. We have strived to design and characterize imidazole-based pH-tunable liposomes composed of pH-titrable imidazole-based lipids (C-16 side chains), negatively charged DPPE-PEG (C-16 side chains) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, C-18 side chains). The membrane of each liposome remains as one phase at pH 7.4 where all the lipids comprising the formulation are homogenously distributed. As the pH decreases to 6.0, the imidazole-based lipids protonate and associate with negatively charged DPPE-PEG to form a two-phase liposome membrane, one phase rich in imidazole and DPPE-PEG lipids and the other rich in DSPC. The phase separation on the liposome membrane is driven by electrostatic interactions and vander waals interactions among lipids of similar chain length. The phase-separated liposomes show increased binding and aggregation with negatively charged model liposomes mimicking the cell membrane.

Method

Liposomes were prepared by lipid film hydration. As a control, liposomes were prepared without the pH-titrable lipids. The model liposomes were prepared with 15mol% negatively charged lipids (phosphatidylserine and phosphatidyl inositol). The phase separation of pH-tunable liposome at pH 6.0 was characterized by microcal VP-DSC. The protonation of pH-titrable lipids in the liposomes were characterized by Zeta-potential measurements. The interaction between pH-tunable liposomes and model liposomes was characterized by measuring the change of the hydrodynamic diameter of the liposomes.

Results

The average size of pH-tunable liposome was 214.47 nm, 219.9 nm and 233.16 nm at pHs 7.4, 6.5, and 6.0; the Zeta potential (mV) was -6.04 ± 0.679, -2.5 ± 0.85, 1.42 ± 0.39, 2.65 ± 0.68 at pHs 7.4, 7.0, 6.5, 6.0, respectively. The average size of the model liposome was 217.03 nm, 220.36 nm, and 228.8 nm at pHs 7.4, 6.5 and 6.0; the Zeta potential (mV) was -10.66 ± 0.95, -9.13 ± 0.98, -7.6 ± 1.03, -7.55 ± 0.92 at pHs 7.4, 7.0, 6.5, 6.0, respectively. The average size of equimolar mixture of pH-tunable and model liposome was 218.83 nm, 362.76 nm, and 713.4 nm at pHs 7.4, 6.5, and 6.0 respectively.

Significance

Conclusion: The pH-tunable liposome shows phase separation and increased binding with model liposome at lowered pH. Significance: The phase separated liposomal system will remain unrecognized by the reticuloendothelial system when in circulation but will show increased uptake by the tumor cells once at the tumor site.

Location

DeRosa University Center, Stockton campus, University of the Pacific

Format

Poster Presentation

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Mar 25th, 10:00 AM Mar 25th, 3:00 PM

DESIGN OF PH-TURNABLE LIPOSOMES FOR ANTICANCER DRUG DELIVERY

DeRosa University Center, Stockton campus, University of the Pacific

Liposomal drug delivery inside the tumor cells has been a challenge due to either recognition of liposomes by reticuloendothelial cells or due to inefficient drug release from liposomes at the tumor site. We have strived to design and characterize imidazole-based pH-tunable liposomes composed of pH-titrable imidazole-based lipids (C-16 side chains), negatively charged DPPE-PEG (C-16 side chains) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, C-18 side chains). The membrane of each liposome remains as one phase at pH 7.4 where all the lipids comprising the formulation are homogenously distributed. As the pH decreases to 6.0, the imidazole-based lipids protonate and associate with negatively charged DPPE-PEG to form a two-phase liposome membrane, one phase rich in imidazole and DPPE-PEG lipids and the other rich in DSPC. The phase separation on the liposome membrane is driven by electrostatic interactions and vander waals interactions among lipids of similar chain length. The phase-separated liposomes show increased binding and aggregation with negatively charged model liposomes mimicking the cell membrane.