[PMID]: | 29193962 |
[Au] Autor: | Tan Z; Dhande YK; Reineke TM |
[Ad] Endereço: | Department of Chemistry, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States. |
[Ti] Título: | Cell Penetrating Polymers Containing Guanidinium Trigger Apoptosis in Human Hepatocellular Carcinoma Cells unless Conjugated to a Targeting N-Acetyl-Galactosamine Block. |
[So] Source: | Bioconjug Chem;28(12):2985-2997, 2017 Dec 20. |
[Is] ISSN: | 1520-4812 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | A series of 3-guanidinopropyl methacrylamide (GPMA)-based polymeric gene delivery vehicles were developed via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers have been evaluated for their cellular internalization ability, transfection efficiency, and cytotoxicity. Two homopolymers: P(GPMA ), P(GPMA ), were synthesized to study the effect of guanidium polymer length on delivery efficiency and toxicity. In addition, an N-acetyl-d-galactosamine (GalNAc)-based hydrophilic block was incorporated to produce diblock polymers, which provides a neutral hydrophilic block that sterically protects plasmid-polymer complexes (polyplexes) from colloidal aggregation and aids polyplex targeting to hepatocytes via binding to asialoglycoprotein receptors (ASGPRs). Polyplexes formed with P(GPMA ) (x = 20, 34) homopolymers were shown to be internalized via both energy-dependent and independent pathways, whereas polyplexes formed with block polymers were internalized through endocytosis. Notably, P(GPMA ) polyplexes enter cells very efficiently but are also very toxic to human hepatocellular carcinoma (HepG2) cells and triggered cell apoptosis. In comparison, the presence of a carbohydrate block in the polymer structures reduced the cytotoxicity of the polyplex formulations and increased gene delivery efficiency with HepG2 cells. Transfection efficiency and toxicity studies were also carried out with HEK 293T (human embryonic kidney) cells for comparison. Results showed that polyplexes formed with the P(GPMA ) homopolymers exhibit much higher transfection efficiency and lower toxicity with HEK 293T cells. The presence of the carbohydrate block did not further increase transfection efficiency in comparison to the homopolymers with HEK 293T cells, likely due to the lack of ASGPRs on the HEK 293T cell line. This study revealed that although guanidinium-based polymers have high membrane permeability, their application as plasmid delivery vehicles may be limited by their high cytotoxicity to certain cell types. Thus, the use of cell penetrating structures in polyplex formulations should be used with caution and carefully tailored toward individual cell/tissue types. |
[Mh] Termos MeSH primário: |
Acetilgalactosamina/química Apoptose/efeitos dos fármacos Carcinoma Hepatocelular/patologia Portadores de Fármacos/química Guanidina/química Neoplasias Hepáticas/patologia Polímeros/química
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[Mh] Termos MeSH secundário: |
Transporte Biológico Sobrevivência Celular/efeitos dos fármacos Portadores de Fármacos/metabolismo Portadores de Fármacos/toxicidade Células Hep G2 Seres Humanos Interações Hidrofóbicas e Hidrofílicas Polimerização Transfecção
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Drug Carriers); 0 (Polymers); JU58VJ6Y3B (Guanidine); KM15WK8O5T (Acetylgalactosamine) |
[Em] Mês de entrada: | 1801 |
[Cu] Atualização por classe: | 180105 |
[Lr] Data última revisão:
| 180105 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 171202 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1021/acs.bioconjchem.7b00598 |
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