Composite liposome-PEI/nucleic acid lipopolyplexes for safe and efficient gene delivery and gene KD

Significance

Gene therapy is potentially a viable treatment for chemotherapy-resistant cancers. However, gene therapy safety and efficacy are still not optimum. The main challenges to gene therapy have been cytotoxicity, rapid degradation, and low cellular up take. One of the most promising non-viral vectors used in gene therapy, polyethyleneimine (PEI) have been used widely. PEI has a high charge density that condenses the nucleic acids, protects them against nucleases, solving the challenge of rapid degradation. This protection is further enhanced by liposomal coating. The 22kDa lPEI has two key features that make it suitable for gene therapy: it is fully deacylated and lacks primary amines. The two elements, respectively, make it have higher transfection efficiency and less cytotoxicity than the branched chain variants.

Researchers led by Professor Udo Bakowsky at the University of Marburg in Germany developed a novel safer and more efficient vehicle . The research work is now published in journal , Colloids and Surfaces B: Biointerfaces. The researchers encapsulated linear PEI ( lPEI) complexed with nucleic acids within (1,2-Dioleoyl-sn-glycerol-3-phosphoethanolamine) (DOPE), (Dipalmitoylphosphatidylcholine) (DPPC), and cholesterol (DDC) liposomes to form lipopolyplexes . The liposomes, owing to their negative surface charge, shielded the positively charged PEI. thereby reducing its cytotoxicity dramatically.

The research was intended to help in improving the efficacy of gene therapy as a cancer treatment modality.

The results showed that the lipopolyplexes had superior features as a vehicle for transfecting cancer cells. The lipopolyplexes also showed good biocompatible and haemocompatible properties and were stable at physiological heparin concentrations.

The findings by the University of Marburg scientists will potentially improve the outcomes in the treatment of chemotherapy-resistant cancers, especially where gene therapy has failed because of cytotoxicity and adverse immune reactions. The gene delivery vehicles had the following advantages: better integrity and stability of the polyplexes; the liposomal layer around the polyplexes shielding against heparin and competing polyanions; ability to cross the plasma membrane.

The researchers propose the application of these lipopolyplexes for in vivo gene therapy. Its efficacy has been proven in vitro, and only needs a clinical trial on patients to bring on board other parameters that need consideration before its use in therapy.

 

Composite liposome-PEI/nucleic acid lipopolyplexes for safe and efficient gene delivery and gene KD - Medicine Innovates

About the author

Dr. Shashank R. Pinnapireddy studied Pharmacy at the Jawaharlal Nehru Technological University (Hyderabad, India) from 2007-2001 and pursued his Masters degree in Biomedical Engineering at the Martin Luther University Halle-Wittenberg (Halle, Germany) from 2011-2013. Dr. Pinnapireddy obtained his PhD with Distinction (summa cum laude) from the Department of Pharmaceutics and Biopharmaceutics at the University of Marburg (Marburg, Germany) under the supervision of Prof. Dr. U. Bakowsky for his work done on composite nano-scaled systems for gene delivery.

Dr. Pinnapireddy is a research group leader and project leader for gene therapy and genetic engineering at the Department of Pharmaceutics and Biopharmaceutics (University of Marburg, Germany) in the laboratory of Prof. Dr. U. Bakowsky. Dr. Pinnapireddy has 17 publications in peer-reviewed journals and has presented his research at numerous international research workshops and conferences.

Research interests: Composite drug/gene delivery systems, liposomes, nanoparticles; photo-enhanced and ultrasound enhanced drug/gene delivery, photodynamic therapy, synergistic therapies; monolayer studies; bio-imaging: electron microscopy, confocal microscopy, atomic force microscopy. Therapeutic targets: Head and neck carcinomas, lung carcinomas, arteriosclerosis and inflammation.

About the author

Prof. Dr. Udo Bakowsky studied Physical Chemistry at the Martin-Luther University Halle/Wittenberg (Germany) from 1985-1990 and obtained his PhD from the Department of Physiological Chemistry at the same University in 1995 for investigations into molecular organisations of channel-proteins in lipid model membranes (supervised by Prof. D. Oesterheldt, Martinsried, Germany and Dr. U. Rothe, Halle, Germany). From 1995 to 1999 he worked as research assistant at the Institute of Pharmaceutical Chemistry (Prof. P. Nuhn) in Halle.

In 1999 Prof. Bakowsky was awarded a personal fellowship by the “Stiftung Deutscher Naturforscher Leopoldina” which he used to conduct collaborative research at the Department of Membrane and Cell Biology (University of Groningen, The Netherlands) in the laboratory of Prof. D. Hoekstra and at the Department of Biopharmaceutics and Pharmaceutical Technology (Saarland University, Germany) in the laboratory of Prof. C.M. Lehr. Between September 2001 and 2003, Dr. Bakowsky served as an assistant professor at the Department of Biopharmaceutics and Pharmaceutical Technology at the Saarland University until he became a professor (C3) at the Department Pharmaceutics and Biopharmaceutics (University of Marburg, Germany) in October 2003. Since 2010 he is the Head of the Department (W3). Prof. Bakowsky is an author of more than 170 papers in peer reviewed journals, patent holder of nine patents, and a co-author of around 550 presentations at various international meetings.

Research interests: The main areas of interest are: colloidal drug delivery systems (biodegradable polymer nanoparticles, liposomes), diagnostics (MRI and ultrasound) molecular recognition, ligand receptor interactions, lipids, lipid model membranes and interactions thereof with proteins or DNA, surface modification of biomaterials or implants and the formulation of DNA/lipid complexes. The major application areas are the therapy of tumours (pancreatic, lung, ovarian, angiomas etc.), arteriosclerosis (ultrasound diagnostics and therapy) and coronary inflammation. A special field of interest is the application of scanning probe/atomic force microscopy techniques on biological systems.

Reference

Pinnapireddy, Shashank Reddy, et al. “Composite liposome-PEI/nucleic acid lipopolyplexes for safe and efficient gene delivery and gene knockdown.” Colloids and Surfaces B: Biointerfaces 158.2017 (2017): 93-101.

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