Cholesterol-based cationic lipids for gene delivery: contribution of molecular structure factors to physico-chemical and biological properties.
In this work, we prepared a series of cholesterol-based cationic (Cho-cat) lipids bearing cholesterol hydrophobe, natural amino acid headgroups (lysine/histidine) and linkage (carbonate ester/ether) bonds. In which, the natural amino acid headgroups made dominant contribution to their physico-chemical and biological properties. Among the lipids, the l-lysine headgroup bearing lipids (Cho-es/et-Lys) showed higher pDNA binding affinity and were able to form larger sized and higher surface charged lipoplexes than that of l-histidine headgroup bearing lipids (Cho-es/et-His), they also demonstrated higher transfection efficacy and higher membrane disruption capacities than that of their l-histidine headgroup bearing counterparts. However, compared to the contributions of the headgroups, the (carbonate ester/ether) linkage bonds showed much less affects. Besides, it could be noted that, Cho-es/et-Lys lipids exhibited very high luciferase gene transfection efficiency that almost reached the transfection level of "gold standard" bPEI-25k, made them potential transfection reagents for practical application. Moreover, the results facilitated the understanding for the structure-activity relationship of the cholesterol-based cationic lipids, and also paved a simple and efficient way for achieving high transfection efficiency by modification of suitable headgroups on lipid gene carriers.
Laboratory for Polymer Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China; Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Ruilong
R
Sheng
Laboratory for Polymer Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Ting
T
Luo
Laboratory for Polymer Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Hui
H
Li
Laboratory for Polymer Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Jingjing
J
Sun
Laboratory for Polymer Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Zhao
Z
Wang
Laboratory for Polymer Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China; Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. Electronic address: acao@mail.sioc.ac.cn.
Amin
A
Cao
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D002412:Cations / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D008055:Lipids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010316:Particle Size; D013329:Structure-Activity Relationship; D013499:Surface Properties
D000596:Amino Acids; D000970:Antineoplastic Agents; D002412:Cations; D008055:Lipids; D002784:Cholesterol
Cholesterol cationic lipids; Gene delivery; Intracellular uptake; Structure–activity relationship