Balancing gene transfection and cytotoxicity of nucleic acid carriers with focus on ocular and hepatic disorders: evaluation of hydrophobic and hydrophilic polyethyleneimine derivatives

Autor(es)

de Oliveira, Fernando A. ; Albuquerque, Lindomar J. C. ; Nascimento-Sales, Michelle ; Christoffolete, Marcelo A. ; Bellettini, Ismael C. ; Giacomelli, Fernando C.

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF MATERIALS CHEMISTRY B; v. 11, n. 20, p. 16-pg., 2023-04-24.

Resumo

Polyethyleneimine (PEI) derivatives substituted by lactose, succinic acid or alkyl domains were evaluated as nonviral gene delivery vectors towards balancing gene transfection and cytotoxicity. The investigations were focused on pDNA transfection into arising retinal pigment epithelia (ARPE-19) and human hepatocellular carcinoma (HepG2) cell lines. The first mentioned cell line was chosen as motivated by the non-negligible number of ocular disorders linked to gene aberrations, whereas the second one is a cell line overexpressing the asialoglycoprotein receptor (ASGP-R), which can bind to galactose residues. The presence of short alkyl domains (C-4 and C-6), and particularly the succinylation of the PEI chains, improved the biological outputs of the gene vectors. The presence of hydrophobic units possibly enhances lytic activity, whereas the incorporation of succinic acid slightly reduces polymer-DNA interaction strength, thereby enabling more efficient intracellular unpacking and cargo release. Succinylation is also supposed to decrease cytotoxicity and avoid protein adsorption to the polyplexes. The presence of long carbon chains (for instance, C-12) nevertheless, results in higher levels of cytotoxicity and respective lower transfection rates. The sugar-decorated polyplexes are overall less cytotoxic, but the presence of lactose moieties also leads to larger polyplexes and notably weak polymer-DNA binding, which compromise the transfection efficiency. Yet, along with the presence of short lytic alkyl domains, the double-substitution of PEI synergistically boosts gene transfection probably due to the uptake of higher DNA and polymer amounts without cell damage. Overall, the experimental data suggest that ocular and hepatic gene therapies may be potentialized by fine-tuning the hydrophobic-to-hydrophilic balance, and succinic acid is a favorable motif for the modification of PEI. (AU)

• Processo FAPESP: 19/20470-8 - Sistemas poliméricos supramoleculares sensíveis a variações de pH como agentes não-virais para a entrega intracelular de DNA terapêutico: construindo a nova geração de nanomedicamentos para oftalmologia
• Beneficiário: Fernando Carlos Giacomelli
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/12071-6 - Arquitetando coloides via interações supramoleculares: de fundamentos a aplicações
• Beneficiário: Watson Loh
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/12944-0 - Avaliação estrutural e biológica de poliplexos formados a partir da complexação de DNA e derivados de polietilenimina contendo cadeias alquílicas e lactose para utilização no tratamento de anomalias oculares genéticas
• Beneficiário: Fernando Augusto de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado