ABSTRACT
Multilayered, multifunctional polymer coatings were grafted onto carbon nanotubes (CNTs) using a one-pot, ring-opening polymerization in order to control the release kinetic and therapeutic efficacy of dasatinib. Biocompatible, biodegradable multilayered coatings composed of poly(glycolide) (PGA) and poly(lactide) (PLA) were polymerized directly onto hydroxyl-functionalized CNT surfaces. Sequential addition of monomers into the reaction vessel enabled multilayered coatings of PLA-PGA or PGA-PLA. Poly(ethylene glycol) capped the polymer chain ends, resulting in a multifunctional amphiphilic coating. Multilayer polymer coatings on CNTs enabled control of the anticancer drug dasatinib's release kinetics and enhanced the in vitro therapeutic efficacy against U-87 glioblastoma compared to monolayer polymer coatings.
Subject(s)
Cell Proliferation/drug effects , Drug Delivery Systems , Glioblastoma/drug therapy , Lactic Acid/chemistry , Nanoparticles/chemistry , Nanotubes, Carbon/chemistry , Polyglycolic Acid/chemistry , Pyrimidines/pharmacology , Thiazoles/pharmacology , Dasatinib , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Kinetics , Microscopy, Electron, Transmission , Polylactic Acid-Polyglycolic Acid Copolymer , Polymerization , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/administration & dosage , Thiazoles/administration & dosage , Tumor Cells, CulturedABSTRACT
Though progress in the use carbon nanotubes in medicine has been most encouraging for therapeutic and diagnostic applications, any translational success must involve overcoming the toxicological and surface functionalization challenges inherent in the use of such nanotubes. Ideally, a carbon nanotube-based drug delivery system would exhibit low toxicity, sustained drug release, and persist in circulation without aggregation. We report a carbon nanotube (CNT) coated with a biocompatible block-co-polymer composed of poly(lactide)-poly(ethylene glycol) (PLA-PEG) to reduce short-term and long-term toxicity, sustain drug release of paclitaxel (PTX), and prevent aggregation. The copolymer coating on the surface of CNTs significantly reduces in vitro toxicity in human umbilical vein endothelial cells (HUVEC) and U-87 glioblastoma cells. Moreover, coating reduces in vitro inflammatory response in rat lung epithelial cells. Compared to non-coated CNTs, in vivo studies show no long-term inflammatory response with CNT coated with PLA-PEG (CLP) and the surface coating significantly decreases acute toxicity by doubling the maximum tolerated dose in mice. Using polymer coatings, we can encapsulate PTX and release over one week to increase the therapeutic efficacy compared to free drugs. In vivo biodistribution and histology studies suggests a lower degree of aggregation in tissues in that CLP accumulate more in the brain and less in the spleen than the CNT-PLA (CL) formulation.
ABSTRACT
There are approximately 420 venomous species of snakes living on the earth. Their venoms, each unique, can affect multiple organ systems. The venoms have a predilection for the peripheral nervous system where the neuromuscular junction is a favorite target. Those venoms affecting the release of acetylcholine from the presynaptic membrane are called beta-neurotoxins and those affecting the postsynaptic membrane are called alpha-neurotoxins. alpha-Bungarotoxin has been used in quantitative studies of acetylcholine receptor density and turnover and for the assay of antibodies directed against the acetylcholine receptor. A unique feature of timber rattlesnake venom is its ability to cause clinical myokymia. This likely results from a blockade of voltage gated K+ antibodies.
