ABSTRACT
The improvement of the pharmacological profile of lipophilic drug formulations is one of the main successes achieved using nanoparticles (NPs) in medicine. However, the complex synthesis procedure and numerous post-processing steps hamper the cost-effective use of these formulations. In this work, an approach which requires only a syringe to produce self-assembling biodegradable and biocompatible poly(caprolactone)-based NPs is developed. The effective synthesis of monodisperse NPs has been made possible by the optimization of the block-copolymer synthesized via a combination of ring opening polymerization and reversible addition-fragmentation chain transfer polymerization. These NPs can be used to formulate lipophilic drugs that are barely soluble in water, such as trabectedin, a potent anticancer therapeutic. Its biodistribution and antitumor activity have been compared with the commercially available formulation Yondelis®. The results indicate that this trabectedin NP formulation performs with the same antitumor activity as Yondelis®, but does not have the drawback of severe local vascular toxicity in the injection site.
Subject(s)
Antineoplastic Agents, Alkylating , Nanoparticles , Trabectedin , Animals , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/pharmacokinetics , Female , Liposarcoma/drug therapy , Mice, Inbred C57BL , Mice, Nude , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Polymers/administration & dosage , Polymers/chemistry , Skin/drug effects , Skin/pathology , Solubility , Tissue Distribution , Trabectedin/administration & dosage , Trabectedin/chemistry , Trabectedin/pharmacokinetics , Water/chemistryABSTRACT
OBJECTIVE: Low water solubility, high systemic toxicity and insignificant cellular uptake have limited efficient clinical applications of the anti-tumor agent Paclitaxel (PTX). To overcome these limitations, a Novel Nanostructured Lipid Carrier (NLC) modified with Folic Acid (FA) and polyethylene glycol (PEG) was prepared by emulsion solvent evaporation method using cholesterol, α-tocopherol, lecithin and Poloxamer. A partial factorial design was applied to determine the appropriate levels of variables for optimized formulation. Formulations were evaluated for Particle Size (PS), Zeta Potential (ZP), Entrapment Efficiency (EE), and release efficiency (RE72%). FA- and PEGconjugated octadecylamine (FA-ODA and PEG-ODA) were synthesized and confirmed by FTIR and H-NMR and incorporated either alone or in combination with the optimized formulation whose properties were also evaluated. PTX-loaded optimized, targeted, pegylated, targeted/pegylated NLCs, pure PTX, and Anzatax® along with their respective controls were selected for toxicity evaluation on human breast cancer cell line, MCF-7, using MTT assay. METHODS: PS, ZP, EE%, and RE72% of the optimized formulation were 154.6 nm, -16.5 mv, 79.1% and 49.3%, respectively. Incorporation of α-tocopherol as the liquid lipid allowed for more efficient drug encapsulation, PS reduction, enhanced stability and sustained-release of the drug. Cytotoxicity of PTX-loaded NLCs modified with both FA-ODA and PEG-ODA was significantly enhanced compared to that of free PTX and other drug-loaded modified NLCs. RESULTS AND CONCLUSION: The results suggest that preparation of NLCs with synthesized conjugates might be a promising candidate for drug delivery of PTX to the cancerous cells and has a great potential as a carrier for tumor targeting in breast cancer.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Breast Neoplasms/drug therapy , Drug Carriers/chemistry , Nanostructures/chemistry , Paclitaxel/administration & dosage , Paclitaxel/pharmacology , Tocopherols/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Liberation , Drug Screening Assays, Antitumor , Female , Humans , MCF-7 Cells , Paclitaxel/chemistry , Particle Size , Surface PropertiesABSTRACT
PURPOSE: To evaluate the neuroprotective effect of combination therapy of polyethylene glycol (PEG) and magnesium sulfate (MgSO4) after a spinal cord injury. MATERIALS AND METHODS: Twenty Sprague Dawley male rats (300-350 gm) had a spinal cord injury after T9/10 laminectomy using an Ohio State University (OSU) impactor under intraperitoneal anesthesia. The animals were randomized to receive either PEG (1 g/kg)+MgSO4 (300 mg/kg) or saline (2 ml) via carotid vein after 2 hours of injury and then every 6 hours for 5 times. The behavioral outcome assessments were performed on days 2, 4 and 7, and then every week using the Basso, Bresnahan, and Beattie (BBB) score and subscore. The animals also underwent sensory threshold testing using a von Frey monofilament device and gait analysis with Catwalk program before and 6 weeks after cord injury. The animals were sacrificed at the end of 6 weeks and histologic assessment was performed to measure the areas of white and gray matter. RESULTS: For the animals treated with PEG+MgSO4 and saline, the mean BBB scores at 6 weeks post-injury were 13.3+/-0.3, 11.4+/-0.2 and the BBB subscores were 9.1+/-1.1, 4.4+/-1.2 respectively (p<0.05). No significant differences were found in sensory testing and gait analysis between the two groups. Histologic assessment revealed no significant difference in gray matter sparing but the areas of white matter at the lesion epicenter were 0.68+/-0.2, 0.41+/-0.04 mm2 in the PEG+MgSO4 and saline groups respectively, which indicated significant sparing of white matter in PEG+MgSO4 group (p<0.05). CONCLUSION: The combination therapy of polyethylene glycol and magnesium sulfate improved the motor function and showed significant histological sparing of the spinal cord after an acute spinal cord injury in rats.
