RESUMO
Described is the development of a polymeric micelle drug delivery platform that addresses the physical property limitations of many nanovectors. The system employs triblock copolymers comprised of a hydrophilic poly(ethylene glycol) (PEG) block, and two poly(amino acid) (PAA) blocks: a stabilizing cross-linking central block, and a hydrophobic drug encapsulation block. Detailed description of synthetic strategies and considerations found to be critical are discussed. Of note, it was determined that the purity of the α-amino acid-N-carboxyanhydrides (NCA) monomers and PEG macroinitiator are ultimately responsible for impurities that arise during the polymerization. Also, contrary to current beliefs in the field, the presence of water does not adversely affect the polymerization of NCAs. Furthermore, we describe the impact of poly(amino acid) conformational changes, through the incorporation of d-amino acids to form mixed stereochemistry PAA blocks, with regard to the physical and pharmacokinetic properties of the resulting micelles.
Assuntos
Aminoácidos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Compostos Férricos/química , Ácidos Hidroxâmicos/química , Polietilenoglicóis/química , Anidridos/química , Animais , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Daunorrubicina/farmacocinética , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Irinotecano , Micelas , Polimerização , Ratos , Ratos Endogâmicos F344 , EstereoisomerismoRESUMO
Nanoparticle drug carriers hold potential to improve current cancer therapy by delivering payload to the tumor environment and decreasing toxic side effects. Challenges in nanotechnology drug delivery include plasma instability, site-specific delivery, and relevant biomarkers. We have developed a triblock polymer comprising a hydroxamic acid functionalized center block that chelates iron to form a stabilized micelle that physically entraps chemotherapeutic drugs in the hydrophobic core. The iron-imparted stability significantly improves the integrity of the micelle and extends circulation pharmacokinetics in plasma over that of free drug. Furthermore, the paramagnetic properties of the iron-crosslinking exhibits contrast in the tumors for imaging by magnetic resonance. Three separate nanoparticle formulations demonstrate improved anti-tumor efficacy in xenograft models and decreased toxicity. We report a stabilized polymer micelle that improves the tolerability and efficacy of chemotherapeutic drugs, and holds potential for non-invasive MRI to image drug delivery and deposition in the tumor.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias da Mama/diagnóstico por imagem , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/química , Ferro/química , Micelas , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/farmacocinética , Feminino , Humanos , Imageamento por Ressonância Magnética , Camundongos Nus , Polímeros/química , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Azido-functionalized poly(ethylene glycol) (PEG) derivatives are finding ever-increasing applications in the areas of conjugation chemistry and targeted drug delivery by their judicious incorporation into nanoparticle-forming polymeric systems. Quantification of azide incorporation into such PEG polymers is essential to their effective use. 1H Nuclear Magnetic Resonance (NMR) analysis offers the simplest approach; however, the relevant adjacent azide-bearing methylene protons are often obscured by the PEG manifold signals. This study describes the synthesis of 1,2,3-triazole adducts from their corresponding PEG azides via a convenient, mild click reaction, which facilitates straightforward NMR-based quantitative end-group analysis.This method was found to be compatible with many examples of bifunctional azido PEGs with molecular weights ranging from 2 to 18 kDa bearing a variety of functional groups. © 2016 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016, 54, 2888-2895.
RESUMO
Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new gadolinium texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R.
Assuntos
Imageamento por Ressonância Magnética/métodos , Micelas , Polímeros/química , Receptor Tipo 1 de Melanocortina/química , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos SCIDRESUMO
The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engineered to overexpress MC1R, MC4R, or MC5R. Of these, compound 1 (4-phenylbutyryl-His-dPhe-Arg-Trp-NH(2)) exhibited high (0.2 nM) binding affinity for MC1R and low (high nanomolar) affinities for MC4R and MC5R. Functionalization of the ligand at the C-terminus with an alkyne for use in Cu-catalyzed click chemistry was shown not to affect the binding affinity. Finally, formation of the targeted polymer, as well as the targeted micelle formulation, also resulted in constructs with low nanomolar binding affinity.