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Article

Cholesterol Sequestration from Caveolae/Lipid Rafts Enhances Cationic Liposome-Mediated Nucleic Acid Delivery into Endothelial Cells

by
Santhosh Chandar Maddila
1,2,†,
Chandrashekhar Voshavar
3,†,
Porkizhi Arjunan
1,
Rashmi Prakash Chowath
1,
Hari Krishna Reddy Rachamalla
4,
Balaji Balakrishnan
5,6,
Poonkuzhali Balasubramanian
6,
Rajkumar Banerjee
6 and
Srujan Marepally
1,*
1
Centre for Stem Cell Research (CSCR) (A Unit of inStem, Bengaluru), Christian Medical College Campus, Bagayam, Vellore 632002, TN, India
2
Rutgers Biomedical and Health Sciences Rutgers, RWJMS-Institute for Neurological Therapeutics, The State University of New Jersey, 683 Hoes Lane West, Piscataway, NJ 08854, USA
3
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
4
Chemical Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 560007, TS, India
5
Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore 632014, TN, India
6
Department of Hematology, Christian Medical College (CMC), Vellore 632004, TN, India
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2021, 26(15), 4626; https://doi.org/10.3390/molecules26154626
Submission received: 3 June 2021 / Revised: 12 July 2021 / Accepted: 18 July 2021 / Published: 30 July 2021
(This article belongs to the Special Issue Nano-particulate Drug Delivery System: Current Status and Future Perspective)
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Abstract

Delivering nucleic acids into the endothelium has great potential in treating vascular diseases. However, endothelial cells, which line the vasculature, are considered as sensitive in nature and hard to transfect. Low transfection efficacies in endothelial cells limit their potential therapeutic applications. Towards improving the transfection efficiency, we made an effort to understand the internalization of lipoplexes into the cells, which is the first and most critical step in nucleic acid transfections. In this study, we demonstrated that the transient modulation of caveolae/lipid rafts mediated endocytosis with the cholesterol-sequestrating agents, nystatin, filipin III, and siRNA against Cav-1, which significantly increased the transfection properties of cationic lipid-(2-hydroxy-N-methyl-N,N-bis(2-tetradecanamidoethyl)ethanaminium chloride), namely, amide liposomes in combination with 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (AD Liposomes) in liver sinusoidal endothelial cells (SK-Hep1). In particular, nystatin was found to be highly effective with 2–3-fold enhanced transfection efficacy when compared with amide liposomes in combination with Cholesterol (AC), by switching lipoplex internalization predominantly through clathrin-mediated endocytosis and macropinocytosis.
Keywords: cationic lipids; clathrin-mediated endocytosis; caveolae-mediated endocytosis; macropinocytosis; transfection; endothelial cells cationic lipids; clathrin-mediated endocytosis; caveolae-mediated endocytosis; macropinocytosis; transfection; endothelial cells
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MDPI and ACS Style

Maddila, S.C.; Voshavar, C.; Arjunan, P.; Chowath, R.P.; Rachamalla, H.K.R.; Balakrishnan, B.; Balasubramanian, P.; Banerjee, R.; Marepally, S. Cholesterol Sequestration from Caveolae/Lipid Rafts Enhances Cationic Liposome-Mediated Nucleic Acid Delivery into Endothelial Cells. Molecules 2021, 26, 4626. https://doi.org/10.3390/molecules26154626

AMA Style

Maddila SC, Voshavar C, Arjunan P, Chowath RP, Rachamalla HKR, Balakrishnan B, Balasubramanian P, Banerjee R, Marepally S. Cholesterol Sequestration from Caveolae/Lipid Rafts Enhances Cationic Liposome-Mediated Nucleic Acid Delivery into Endothelial Cells. Molecules. 2021; 26(15):4626. https://doi.org/10.3390/molecules26154626

Chicago/Turabian Style

Maddila, Santhosh Chandar, Chandrashekhar Voshavar, Porkizhi Arjunan, Rashmi Prakash Chowath, Hari Krishna Reddy Rachamalla, Balaji Balakrishnan, Poonkuzhali Balasubramanian, Rajkumar Banerjee, and Srujan Marepally. 2021. "Cholesterol Sequestration from Caveolae/Lipid Rafts Enhances Cationic Liposome-Mediated Nucleic Acid Delivery into Endothelial Cells" Molecules 26, no. 15: 4626. https://doi.org/10.3390/molecules26154626

APA Style

Maddila, S. C., Voshavar, C., Arjunan, P., Chowath, R. P., Rachamalla, H. K. R., Balakrishnan, B., Balasubramanian, P., Banerjee, R., & Marepally, S. (2021). Cholesterol Sequestration from Caveolae/Lipid Rafts Enhances Cationic Liposome-Mediated Nucleic Acid Delivery into Endothelial Cells. Molecules, 26(15), 4626. https://doi.org/10.3390/molecules26154626

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