pH and glutathion-responsive hydrogel for localized delivery of paclitaxel.
pH and glutathion (GSH)- responsive nanogels (NGs) based on poly-N-isopropylacrilamide (NIPA), N-hydroxyethyl acrylamide (HEAA) and tert-butyl 2-acrylamidoethyl carbamate (2AAECM) were synthesized by a microemulsion polymerization method using N, N'-cystaminebisacrylamide (CBA) as a crosslinking agent and evaluated for passive targeting of paclitaxel (PTX). Physicochemical characterizations of unloaded and PTX-loaded NGs, such as particle size, morphology, encapsulation efficiency and in vitro PTX release were also assessed. Electron microscopy techniques (SEM and TEM) as well as dynamic light scattering (DLS) analysis showed nanosized spherical hydrogels. FTIR spectra confirmed the synthesis of nanogels by free radical polymerization among vinyl groups of monomers. In vitro release was analyzed by high-performance liquid chromatography (HPLC) and differences between two NG formulations were obtained. Nanogels released almost 64% of PTX after 50h at GSH concentrations equivalent to that in the cellular cytosol, whereas less PTX was released from NGs at pH and GSH levels similar to plasma. Cellular uptake and cytotoxicity were also demonstrated by using coumarin-6 and MTT assays, respectively, for three tumor cell lines (MCF7, HeLa and T47D). Cellular uptake assays revealed rapid uptake within 2h and intracellular accumulation of coumarin-6-loaded nanogels after 48 h incubation. MTT assays showed changes in cell viability at different concentrations of PTX formulations, as well as pure PTX (10 μM, 20 μM and 30 μM). To investigate PTX effect on cell viability, changes in cell cycle were examined by flow cytometry and a G2/M cell arrest was demonstrated. Overall, synthesized nanogels may be used as potential carriers for hydrophobic anticancer drugs.
Polymeric Materials Group for the Controlled Release of Bioactive Compounds in Biomedicine, Biochemistry and Molecular Biology Department, Facultad de Medicina, Universidad Complutense de Madrid, Madrid 28040, Spain.
Elena
E
Pérez
Polymeric Materials Group for the Controlled Release of Bioactive Compounds in Biomedicine, Biochemistry and Molecular Biology Department, Facultad de Medicina, Universidad Complutense de Madrid, Madrid 28040, Spain.
Ana
A
Fernández
Polymeric Materials Group for the Controlled Release of Bioactive Compounds in Biomedicine, Biochemistry and Molecular Biology Department, Facultad de Medicina, Universidad Complutense de Madrid, Madrid 28040, Spain.
Rosa
R
Olmo
Polymeric Materials Group for the Controlled Release of Bioactive Compounds in Biomedicine, Biochemistry and Molecular Biology Department, Facultad de Medicina, Universidad Complutense de Madrid, Madrid 28040, Spain.
Jose M
JM
Teijón
Polymeric Materials Group for the Controlled Release of Bioactive Compounds in Biomedicine, Biochemistry and Molecular Biology Department, Facultad de Medicina, Universidad Complutense de Madrid, Madrid 28040, Spain. Electronic address: mdblanco@med.ucm.es.
M Dolores
MD
Blanco
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D005978:Glutathione / Q000138:chemical synthesis / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000138:chemical synthesis / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D010316:Particle Size; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013844:Thiazoles / Q000737:chemistry
D000970:Antineoplastic Agents; D003374:Coumarins; D004337:Drug Carriers; D013844:Thiazoles; C517282:coumarin 6; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D005978:Glutathione; D017239:Paclitaxel
Cancer cells; Drug release; Nanohydrogels; Paclitaxel; Passive targeting; Stimuli-responsive