Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes
Abstract Lipid carriers of hydrophobic paclitaxel (PTX) are used in clinical trials for cancer chemotherapy. Improving their loading capacity requires enhanced PTX solubilization. We compared the time-dependence of PTX membrane solubility as a function of PTX content in cationic liposomes (CLs) with...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Nature Publishing Group
2021-03-01
|
Series: | Scientific Reports |
Online Access: | https://doi.org/10.1038/s41598-021-86484-9 |
id |
doaj-4a4a7669b3fc46afba9e9581dfa348d3 |
---|---|
record_format |
Article |
spelling |
doaj-4a4a7669b3fc46afba9e9581dfa348d32021-04-04T11:33:38ZengNature Publishing GroupScientific Reports2045-23222021-03-0111111410.1038/s41598-021-86484-9Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapesYuhong Zhen0Kai K. Ewert1William S. Fisher2Victoria M. Steffes3Youli Li4Cyrus R. Safinya5College of Pharmacy, Dalian Medical UniversityMaterials, Physics, and Molecular, Cellular, and Developmental Biology Department, University of CaliforniaMaterials, Physics, and Molecular, Cellular, and Developmental Biology Department, University of CaliforniaMaterials, Physics, and Molecular, Cellular, and Developmental Biology Department, University of CaliforniaMaterials Research Laboratory, University of CaliforniaMaterials, Physics, and Molecular, Cellular, and Developmental Biology Department, University of CaliforniaAbstract Lipid carriers of hydrophobic paclitaxel (PTX) are used in clinical trials for cancer chemotherapy. Improving their loading capacity requires enhanced PTX solubilization. We compared the time-dependence of PTX membrane solubility as a function of PTX content in cationic liposomes (CLs) with lipid tails containing one (oleoyl; DOPC/DOTAP) or two (linoleoyl; DLinPC/newly synthesized DLinTAP) cis double bonds by using microscopy to generate kinetic phase diagrams. The DLin lipids displayed significantly increased PTX membrane solubility over DO lipids. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the solubility limit, which has been the focus of most previous studies and clinical trials) in DOTAP/DOPC CLs. The increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX, rather than by the transition in membrane structure from bilayers to inverse cylindrical micelles observed with small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against prostate cancer cells (their IC50 of PTX cytotoxicity) was unaffected by changing the lipid tails, and toxicity of the CL carrier was negligible. Moreover, efficacy was approximately doubled against melanoma cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. Our findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs.https://doi.org/10.1038/s41598-021-86484-9 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yuhong Zhen Kai K. Ewert William S. Fisher Victoria M. Steffes Youli Li Cyrus R. Safinya |
spellingShingle |
Yuhong Zhen Kai K. Ewert William S. Fisher Victoria M. Steffes Youli Li Cyrus R. Safinya Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes Scientific Reports |
author_facet |
Yuhong Zhen Kai K. Ewert William S. Fisher Victoria M. Steffes Youli Li Cyrus R. Safinya |
author_sort |
Yuhong Zhen |
title |
Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes |
title_short |
Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes |
title_full |
Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes |
title_fullStr |
Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes |
title_full_unstemmed |
Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes |
title_sort |
paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-03-01 |
description |
Abstract Lipid carriers of hydrophobic paclitaxel (PTX) are used in clinical trials for cancer chemotherapy. Improving their loading capacity requires enhanced PTX solubilization. We compared the time-dependence of PTX membrane solubility as a function of PTX content in cationic liposomes (CLs) with lipid tails containing one (oleoyl; DOPC/DOTAP) or two (linoleoyl; DLinPC/newly synthesized DLinTAP) cis double bonds by using microscopy to generate kinetic phase diagrams. The DLin lipids displayed significantly increased PTX membrane solubility over DO lipids. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the solubility limit, which has been the focus of most previous studies and clinical trials) in DOTAP/DOPC CLs. The increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX, rather than by the transition in membrane structure from bilayers to inverse cylindrical micelles observed with small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against prostate cancer cells (their IC50 of PTX cytotoxicity) was unaffected by changing the lipid tails, and toxicity of the CL carrier was negligible. Moreover, efficacy was approximately doubled against melanoma cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. Our findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs. |
url |
https://doi.org/10.1038/s41598-021-86484-9 |
work_keys_str_mv |
AT yuhongzhen paclitaxelloadingincationicliposomevectorsisenhancedbyreplacementofoleoylwithlinoleoyltailswithdistinctlipidshapes AT kaikewert paclitaxelloadingincationicliposomevectorsisenhancedbyreplacementofoleoylwithlinoleoyltailswithdistinctlipidshapes AT williamsfisher paclitaxelloadingincationicliposomevectorsisenhancedbyreplacementofoleoylwithlinoleoyltailswithdistinctlipidshapes AT victoriamsteffes paclitaxelloadingincationicliposomevectorsisenhancedbyreplacementofoleoylwithlinoleoyltailswithdistinctlipidshapes AT youlili paclitaxelloadingincationicliposomevectorsisenhancedbyreplacementofoleoylwithlinoleoyltailswithdistinctlipidshapes AT cyrusrsafinya paclitaxelloadingincationicliposomevectorsisenhancedbyreplacementofoleoylwithlinoleoyltailswithdistinctlipidshapes |
_version_ |
1721542491894710272 |