TY - JOUR

T1 - Application of new lysine-based peptide dendrimers D3K2 and D3G2 for gene delivery

T2 - Specific cytotoxicity to cancer cells and transfection in vitro

AU - Gorzkiewicz, Michal

AU - Konopka, Malgorzata

AU - Janaszewska, Anna

AU - Tarasenko, Irina I.

AU - Sheveleva, Nadezhda N.

AU - Gajek, Arkadiusz

AU - Neelov, Igor M.

AU - Klajnert-Maculewicz, Barbara

PY - 2020/1

Y1 - 2020/1

N2 - In order to enhance intracellular uptake and accumulation of therapeutic nucleic acids for improved gene therapy methods, numerous delivery vectors have been elaborated. Based on their origin, gene carriers are generally classified as viral or non-viral vectors. Due to their significantly reduced immunogenicity and highly optimized methods of synthesis, nanoparticles (especially those imitating natural biomolecules) constitute a promising alternative for virus-based delivery devices. Thus, we set out to develop innovative peptide dendrimers for clinical application as transfection agents and gene carriers. In the present work we describe the synthesis of two novel lysine-based dendritic macromolecules (D3K2 and D3G2) and their initial characterization for cytotoxicity/genotoxicity and transfection potential in two human cell line models: cervix adenocarcinoma (HeLa) and microvascular endothelial (HMEC-1). This approach allowed us to identify more cationic D3K2 as potent delivery agent, being able to increase intracellular accumulation of large nucleic acid molecules such as plasmids. Moreover, the dendrimers exhibited specific cytotoxicity towards cancer cell line without showing significant toxic effects on normal cells. These observations are promising prognosis for future clinical application of this type of nanoparticles.

AB - In order to enhance intracellular uptake and accumulation of therapeutic nucleic acids for improved gene therapy methods, numerous delivery vectors have been elaborated. Based on their origin, gene carriers are generally classified as viral or non-viral vectors. Due to their significantly reduced immunogenicity and highly optimized methods of synthesis, nanoparticles (especially those imitating natural biomolecules) constitute a promising alternative for virus-based delivery devices. Thus, we set out to develop innovative peptide dendrimers for clinical application as transfection agents and gene carriers. In the present work we describe the synthesis of two novel lysine-based dendritic macromolecules (D3K2 and D3G2) and their initial characterization for cytotoxicity/genotoxicity and transfection potential in two human cell line models: cervix adenocarcinoma (HeLa) and microvascular endothelial (HMEC-1). This approach allowed us to identify more cationic D3K2 as potent delivery agent, being able to increase intracellular accumulation of large nucleic acid molecules such as plasmids. Moreover, the dendrimers exhibited specific cytotoxicity towards cancer cell line without showing significant toxic effects on normal cells. These observations are promising prognosis for future clinical application of this type of nanoparticles.

KW - VIRAL VECTORS

KW - POLYAMIDOAMINE DENDRIMERS

KW - CATIONIC POLYMERS

KW - THERAPY

KW - ASSAY

KW - DNA

KW - BIODISTRIBUTION

KW - POLY(L-LYSINES)

KW - MICROBICIDES

KW - MECHANISMS

UR - http://www.scopus.com/inward/record.url?scp=85076672322&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/19a56386-872c-3fef-9b70-38deeb048a21/

U2 - 10.1016/j.bioorg.2019.103504

DO - 10.1016/j.bioorg.2019.103504

M3 - Article

C2 - 31864904

AN - SCOPUS:85076672322

VL - 95

SP - 103504

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

SN - 0045-2068

M1 - 103504

ER -