PEGylation of biodegradable dextran nanogels for siRNA delivery

• Published in: European journal of pharmaceutical sciences Vol. 40; no. 4; pp. 342 - 351
• Main Authors: Naeye, B., Raemdonck, K., Remaut, K., Sproat, B., Demeester, J., De Smedt, S.C.
• Format: Journal Article
• Language: English
• Published: Kindlington Elsevier B.V 11.07.2010; Elsevier
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological and medical sciences; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell Membrane Permeability; Cell Survival - drug effects; Dextrans - adverse effects; Dextrans - chemistry; Dextrans - metabolism; Drug Carriers - administration & dosage; Drug Carriers - chemical synthesis; Drug Carriers - pharmacokinetics; Drug Carriers - pharmacology; Drug delivery; Drug Delivery Systems; Flow Cytometry; Gene Silencing - drug effects; General pharmacology; Genes, Reporter - drug effects; Humans; Hydrogel; Hydrogels; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Medical sciences; Methacrylates - adverse effects; Methacrylates - chemistry; Methacrylates - metabolism; Microscopy, Confocal; Nanostructures - adverse effects; Nanostructures - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyethylene glycol; Polyethylene Glycols - adverse effects; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - chemistry; Polyethylene Glycols - metabolism; Polyglutamic Acid - analogs & derivatives; Polyglutamic Acid - chemical synthesis; Polyglutamic Acid - chemistry; RNA interference; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - pharmacokinetics; RNA, Small Interfering - pharmacology; siRNA; Succinimides - chemistry; Drug delivery; siRNA; RNA interference; Hydrogel; Polyethylene glycol; Pharmaceutical technology; Biodegradability; Drug carrier; Dextran; Ethylene oxide polymer; Colloidal gel; Gene silencing; Cyclic ether polymer; Nanogel; Blood substitute; Dosage form; Oside polymer; Pegylated form
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2010.04.010

Delivering intact small interfering RNA (siRNA) into the cytoplasm of targeted cells in vivo is considered a major obstacle in the development of clinically applicable RNA interference-based therapies. Although dextran hydroxyethyl methacrylate (dex-HEMA) nanogels have been reported to be suitable carriers for siRNA delivery in vitro, and are ideally sized (approximately 180 nm) for intravenous delivery to tumors, they likely possess insufficient blood circulation times to enable an adequate extravasation and accumulation in the tumor tissue. PEGylation of these nanogels should not only improve their circulation time but also minimize their aggregation upon intravenous injection. For this reason, a new type of nanogels and three different methods of PEGylating dextran nanogels were evaluated. Covalent PEGylation of the siRNA-loaded nanogels using N-hydroxysuccinimidyl polyethylene glycol (NHS-PEG) was shown to be superior to the addition of both polyethylene glycol (PEG) and PEG grafted poly- l-glutamic acid (PGA-PEG). Flow cytometry and confocal microscopy revealed that PEGylated nanogels are still taken up efficiently by HuH-7 human hepatoma cells and A431 human epithelial carcinoma cells and that the process is cell type dependent. Moreover, PEGylated nanogels loaded with siRNA cause significant EGFP knockdown in a human hepatoma cell line (HuH-7_EGFP) and are non-toxic for these cells.