ABSTRACT
Formulation of docetaxel (DOC), a hydrophobic anticancer drug, was successfully achieved in poly(gamma-benzyl L-glutamate)-block-hyaluronan polymersomes using a simple and reproducible nanoprecipitation method. The prepared DOC loaded polymersomes (PolyDOC) was stable either in solution or in a lyophilized form, and showed controlled release behaviour over several days. PolyDOC showed high in vitro toxicity after 24 h in MCF-7 and U87 cells compared to free DOC. Biodistribution data demonstrated that (99m)Tc labelled PolyDOC t(1/2) and MRT significantly increased compared to a DOC solution (DS). In addition, PolyDOC uptake in Ehrlich Ascites Tumor (EAT) tumor bearing mice was larger at each time point compared to DS, making such a polymer vesicle formulation an efficient drug nanocarrier for improved DOC cancer therapy.
Subject(s)
Antineoplastic Agents/administration & dosage , Delayed-Action Preparations/chemistry , Hyaluronic Acid/analogs & derivatives , Polyglutamic Acid/analogs & derivatives , Taxoids/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Capsules , Cell Line, Tumor , Docetaxel , Female , Humans , Hyaluronic Acid/chemistry , Mice , Mice, Inbred BALB C , Polyglutamic Acid/chemistry , Rabbits , Taxoids/pharmacokineticsABSTRACT
We have investigated the intracellular delivery of doxorubicin (DOX) loaded poly(gamma-benzyl L-glutamate)-block-hyaluronan (PBLG-b-HYA) based polymersomes (PolyDOX) in high (MCF-7) and low (U87) CD44 expressing cancer cell models. DOX was successfully loaded into polymersomes using nanoprecipitation method and in vitro drug release pattern were achieved at pH 5.5 and 7.4 up to 10 days. Block copolymer vesicles without loaded DOX were non cytotoxic in both cells at concentration 150-650 microg/mL. Flow cytometry data suggested successful uptake of PolyDOX in cells and high accumulation was found in MCF-7 than U87 cells. Microscopy imagings revealed that in MCF-7 cells PolyDOX was more in cytoplasm and free DOX in nuclei, whereas in U87 cells free DOX was also found in the cytoplasm. Cytotoxicity of the drug was concentration and exposure time dependent. In addition, PolyDOX significantly enhanced reactive oxygen species (ROS) level in both cells. PolyDOX also suppressed growth of breast tumor on female Sprague-Dawley (SD) rats as compared to phosphate buffer saline pH 7.4 (PBS) control group. In addition reduced level of serum enzymes (LDH and CPK) by PolyDOX formulation indicated less cardiotoxicity of DOX after loading in polymersomes. Results suggest that intracellular delivery of PolyDOX was depended on the CD44 expression level in cells due to presence of hyaluronic acid on the surface of polymersomes, and could be used as a self-targeting drug delivery cargo in over-expressed CD44 glycoprotein cells of breast cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/pharmacology , Drug Delivery Systems , Hyaluronic Acid/analogs & derivatives , Intracellular Space/metabolism , Polyglutamic Acid/analogs & derivatives , Animals , Cardiotoxins/pharmacology , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Creatine Kinase/blood , Doxorubicin/administration & dosage , Female , Flow Cytometry , Humans , Hyaluronan Receptors/metabolism , Hyaluronic Acid/pharmacology , Hydrogen-Ion Concentration/drug effects , Intracellular Space/drug effects , Kaplan-Meier Estimate , L-Lactate Dehydrogenase/blood , Microscopy, Electron, Transmission , Microscopy, Fluorescence , Polyglutamic Acid/pharmacology , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolismABSTRACT
The partial phase behavior, rheological, and drug release characteristics of an organogel (OG) composed of water, isooctane and sorbitan esters, sorbitan monopalmitate (Span-40) and poly(oxyethylene)sorbitan monostearate (Polysorbate-60) were studied. Phase diagrams showed decreasing areas of optically isotropic organogel region depending on the surfactant ratio, Kw and drug incorporation. The nonbirefringent, clear isotropic solution suggested the reverse micellar/microemulsion nature of the organogel without any molecular ordering. The increase in drug concentration in OGs leads to increase in the viscosity and sol-gel transition temperature (Tg). Fractal dimension (df) values calculated for different compositions suggested that the density of the tubular network increases with increasing drug concentration in OGs. The release rate of the drug from OGs was found to be non-Fickian through the dialysis membrane. The permeation rate of sumatriptan from pig skin was 0.231 mg/h/cm2 (781.9 nmol/h/cm2). The study indicates potential of OG as a reservoir system for transdermal drug delivery.
