TY - JOUR
T1 - Tailoring the lipid composition of nanoparticles modulates their cellular uptake and affects the viability of triple negative breast cancer cells
AU - Abumanhal-Masarweh, Hanan
AU - da Silva, Dana
AU - Poley, Maria
AU - Zinger, Assaf
AU - Goldman, Evgenya
AU - Krinsky, Nitzan
AU - Kleiner, Ron
AU - Shenbach, Gal
AU - Schroeder, Josh E.
AU - Shklover, Jeny
AU - Shainsky-Roitman, Janna
AU - Schroeder, Avi
N1 - Funding Information:
This work was supported by ERC - STG-2015-680242 . The authors also acknowledge the support of the Technion Integrated Cancer Center (TICC), the Russell Berrie Nanotechnology Institute , the Lorry I. Lokey Interdisciplinary Center for Life Sciences & Engineering especially Dr. Nitsan Dahan and Dr. Yael Lupu-Haber, The Israel Ministry of Economy for a Kamin Grant ( 52752 ); the Israel Ministry of Science Technology and Space – Office of the Chief Scientist ( 3-11878 ); the Israel Science Foundation ( 1778/13, 1421/17 ); the Israel Cancer Association ( 2015-0116 ); the German-Israeli Foundation for Scientific Research and Development for a GIF Young grant ( I-2328-1139.10/2012 ); the European Union FP-7 IRG Program for a Career Integration Grant ( 908049 ); the Phospholipid Research Center Grant ; a Mallat Family Foundation Grant ; The Unger Family Fund ; A. Schroeder acknowledges Alon and Taub Fellowships. We also thank E. Kesselman and Irena Davidovitch for assisting in acquiring CryoTEM images of the liposomes. H. Abumanhal and N. Krinsky wish to thank the Baroness Ariane de Rothschild Women Doctoral Program for its generous support.
Funding Information:
This work was supported by ERC-STG-2015-680242. The authors also acknowledge the support of the Technion Integrated Cancer Center (TICC), the Russell Berrie Nanotechnology Institute, the Lorry I. Lokey Interdisciplinary Center for Life Sciences & Engineering especially Dr. Nitsan Dahan and Dr. Yael Lupu-Haber, The Israel Ministry of Economy for a Kamin Grant (52752); the Israel Ministry of Science Technology and Space – Office of the Chief Scientist (3-11878); the Israel Science Foundation (1778/13, 1421/17); the Israel Cancer Association (2015-0116); the German-Israeli Foundation for Scientific Research and Development for a GIF Young grant (I-2328-1139.10/2012); the European Union FP-7 IRG Program for a Career Integration Grant (908049); the Phospholipid Research Center Grant; a Mallat Family Foundation Grant; The Unger Family Fund; A. Schroeder acknowledges Alon and Taub Fellowships. We also thank E. Kesselman and Irena Davidovitch for assisting in acquiring CryoTEM images of the liposomes. H. Abumanhal and N. Krinsky wish to thank the Baroness Ariane de Rothschild Women Doctoral Program for its generous support.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/8/10
Y1 - 2019/8/10
N2 - Lipid nanoparticles are used widely as anticancer drug and gene delivery systems. Internalizing into the target cell is a prerequisite for the proper activity of many nanoparticulate drugs. We show here, that the lipid composition of a nanoparticle affects its ability to internalize into triple-negative breast cancer cells. The lipid headgroup had the greatest effect on enhancing cellular uptake compared to other segments of the molecule. Having a receptor-targeted headgroup induced the greatest increase in cellular uptake, followed by cationic amine headgroups, both being superior to neutral (zwitterion) phosphatidylcholine or to negatively-charged headgroups. The lipid tails also affected the magnitude of cellular uptake. Longer acyl chains facilitated greater liposomal cellular uptake compared to shorter tails, 18:0 > 16:0 > 14:0. When having the same lipid tail length, unsaturated lipids were superior to saturated ones, 18:1 > 18:0. Interestingly, liposomes composed of phospholipids having 14:0 or 12:0-carbon-long-tails, such as DMPC and DLPC, decreased cell viability in a concertation dependent manner, due to a destabilizing effect these lipids had on the cancer cell membrane. Contrarily, liposomes composed of phospholipids having longer carbon tails (16:0 and 18:0), such as DPPC and HSPC, enhanced cancer cell proliferation. This effect is attributed to the integration of the exogenous liposomal lipids into the cancer-cell membrane, supporting the proliferation process. Cholesterol is a common lipid additive in nanoscale formulations, rigidifying the membrane and stabilizing its structure. Liposomes composed of DMPC (14:0) showed increased cellular uptake when enriched with cholesterol, both by endocytosis and by fusion. Contrarily, the effect of cholesterol on HSPC (18:0) liposomal uptake was minimal. Furthermore, the concentration of nanoparticles in solution affected their cellular uptake. The higher the concentration of nanoparticles the greater the absolute number of nanoparticles taken up per cell. However, the efficiency of nanoparticle uptake, i.e. the percent of nanoparticles taken up by cells, decreased as the concentration of nanoparticles increased. This study demonstrates that tuning the lipid composition and concentration of nanoscale drug delivery systems can be leveraged to modulate their cellular uptake.
AB - Lipid nanoparticles are used widely as anticancer drug and gene delivery systems. Internalizing into the target cell is a prerequisite for the proper activity of many nanoparticulate drugs. We show here, that the lipid composition of a nanoparticle affects its ability to internalize into triple-negative breast cancer cells. The lipid headgroup had the greatest effect on enhancing cellular uptake compared to other segments of the molecule. Having a receptor-targeted headgroup induced the greatest increase in cellular uptake, followed by cationic amine headgroups, both being superior to neutral (zwitterion) phosphatidylcholine or to negatively-charged headgroups. The lipid tails also affected the magnitude of cellular uptake. Longer acyl chains facilitated greater liposomal cellular uptake compared to shorter tails, 18:0 > 16:0 > 14:0. When having the same lipid tail length, unsaturated lipids were superior to saturated ones, 18:1 > 18:0. Interestingly, liposomes composed of phospholipids having 14:0 or 12:0-carbon-long-tails, such as DMPC and DLPC, decreased cell viability in a concertation dependent manner, due to a destabilizing effect these lipids had on the cancer cell membrane. Contrarily, liposomes composed of phospholipids having longer carbon tails (16:0 and 18:0), such as DPPC and HSPC, enhanced cancer cell proliferation. This effect is attributed to the integration of the exogenous liposomal lipids into the cancer-cell membrane, supporting the proliferation process. Cholesterol is a common lipid additive in nanoscale formulations, rigidifying the membrane and stabilizing its structure. Liposomes composed of DMPC (14:0) showed increased cellular uptake when enriched with cholesterol, both by endocytosis and by fusion. Contrarily, the effect of cholesterol on HSPC (18:0) liposomal uptake was minimal. Furthermore, the concentration of nanoparticles in solution affected their cellular uptake. The higher the concentration of nanoparticles the greater the absolute number of nanoparticles taken up per cell. However, the efficiency of nanoparticle uptake, i.e. the percent of nanoparticles taken up by cells, decreased as the concentration of nanoparticles increased. This study demonstrates that tuning the lipid composition and concentration of nanoscale drug delivery systems can be leveraged to modulate their cellular uptake.
KW - Cancer
KW - Cell signaling
KW - Lipid
KW - Liposome
KW - Metabolism
KW - Targeting
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U2 - 10.1016/j.jconrel.2019.06.025
DO - 10.1016/j.jconrel.2019.06.025
M3 - Article
C2 - 31238049
AN - SCOPUS:85068533225
SN - 0168-3659
VL - 307
SP - 331
EP - 341
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -