Design and Evaluation of Gemini Surfactant-Based Lipoplexes Modified with Cell-Binding Peptide for Targeted Gene Therapy in Melanoma Model

Abstract

Purpose Achieving successful gene therapy requires delivery of a gene vector specifically to the targeted tissue with efficient expression and a good safety profile. The objective of this work was to develop, characterize and determine if a novel gemini surfactant-based lipoplex systems, modified with a cancer-targeting peptide p18-4, could serve this role. Methods The targeting peptide p18-4 was either chemically coupled to a gemini surfactant backbone or physically co-formulated with the lipoplexes. The influence of targeting ligand and formulation strategies on essential physicochemical properties of the lipoplexes was evaluated by dynamic light scattering and small angle X-ray scattering techniques. In vitro transfection activity and cellular toxicity of lipoplexes were assessed in a model human melanoma cell line. Results All lipoplexes zeta potential and particle size were optimal for cellular uptake and physical stability of the system. The lipoplexes adopted an inverted-hexagonal lipid arrangement. The lipoplexes modified with the peptide showed no significant changes in physicochemical properties or lipoplex assembly. The modification of the lipoplexes with the targeting peptide significantly enhanced protein expression 2-6 fold compared to non-modified lipoplexes. In addition, p18-4 modified lipoplexes significantly improved the safety of the lipoplexes. The ability of the p18-4 modified lipoplexes to selectively express the model protein was confirmed by using healthy human epidermal keratinocytes (HEKa). Conclusion The gemini surfactant-based lipoplexes modified with p18-4 peptide showed significantly higher efficiency and safety compared to the system that did not contain a cancer targeting peptide and provided evidence for their potential application to achieve targeted melanoma gene therapy.

Carriers Break Barriers in Drug Delivery: Endocytosis and Endosomal Escape of Gene Delivery Vectors

“…44 They proposed a correlation between nonlamellar lipid organization in lipoplexes with transfection efficiency. The correlation between a nonbilayer phase of the lipoplex and its high transfection activity is still being reported in literature, 45,46 but does not seem to be a general finding. For example, Tassler et al found that lysine-based amino-functionalized lipids, that varied in their chain length and (un)saturation, formed cubic or lamellar lipoplexes.…”

Targeted Nanotherapeutics Using LACTB Gene Therapy Against Melanoma

“…The obtained iDPP/LACTB nanocomplex had a high transfection efficiency over PEI25K and Lipo3000, which benefited from the specific binding of iRGD to the integrin receptors overexpressed on the surface of melanoma cells. 34,35 After intravenous administration, the iDPP/LACTB nanocomplex could efficiently target and transfect cancer cells, resulting in the effective cancer treatment.…”

Current status of gene therapy in melanoma treatment

“…In an attempt to ensure the effectiveness and safety, a cancer-targeting peptide p18-4 was modified with the lipoplexes. The p18-4 in the lipoplexes system demonstrated high efficiency in human malignant melanoma (A375) cells (Mohammed-Saeid et al, 2018).…”