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The potential of polymeric micelles in the context of glioblastoma therapy.

ABSTRACT: Glioblastoma multiforme (GBM), a type of malignant glioma, is the most common form of brain cancer found in adults. The current standard of care for GBM involves adjuvant temozolomide-based chemotherapy in conjunction with radiotherapy, yet patients still suffer from poor outcomes with a median survival of 14.6 months. Many novel therapeutic agents that are toxic to GBM cells in vitro cannot sufficiently accumulate at the site of an intracranial tumor after systemic administration. Thus, new delivery strategies must be developed to allow for adequate intratumoral accumulation of such therapeutic agents. Polymeric micelles offer the potential to improve delivery to brain tumors as they have demonstrated the capacity to be effective carriers of chemotherapy drugs, genes, and proteins in various preclinical GBM studies. In addition to this, targeting moieties and trigger-dependent release mechanisms incorporated into the design of these particles can promote more specific delivery of a therapeutic agent to a tumor site. However, despite these advantages, there are currently no micelle formulations targeting brain cancer in clinical trials. Here, we highlight key aspects of the design of polymeric micelles as therapeutic delivery systems with a review of their clinical applications in several non-brain tumor cancer types. We also discuss their potential to serve as nanocarriers targeting GBM, the major barriers preventing their clinical implementation in this disease context, as well as current approaches to overcome these limitations.

SUBMITTER: Morshed RA

PROVIDER: S-EPMC3874582 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The potential of polymeric micelles in the context of glioblastoma therapy.

Morshed Ramin A RA Cheng Yu Y Auffinger Brenda B Wegscheid Michelle L ML Lesniak Maciej S MS

Frontiers in pharmacology 20131230

Glioblastoma multiforme (GBM), a type of malignant glioma, is the most common form of brain cancer found in adults. The current standard of care for GBM involves adjuvant temozolomide-based chemotherapy in conjunction with radiotherapy, yet patients still suffer from poor outcomes with a median survival of 14.6 months. Many novel therapeutic agents that are toxic to GBM cells in vitro cannot sufficiently accumulate at the site of an intracranial tumor after systemic administration. Thus, new del ...[more]

PMID: 24416018

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Project description:meta-Tetra(hydroxyphenyl)chlorin (mTHPC) is one of the most potent second-generation photosensitizers, clinically used for photodynamic therapy (PDT) of head and neck squamous cell carcinomas. However, improvements are still required concerning its present formulation (i.e., Foscan, a solution of mTHPC in ethanol/propylene glycol (40:60 w/w)), as mTHPC has the tendency to aggregate in aqueous media, e.g., biological fluids, and it has limited tumor specificity. In the present study, polymeric micelles with three different diameters (17, 24, and 45 nm) based on benzyl-poly(ε-caprolactone)-b-poly(ethylene glycol) (PCLn-PEG; n = 9, 15, or 23) were prepared with mTHPC loadings ranging from 0.5 to 10 wt % using a film-hydration method as advanced nanoformulations for this photosensitizer. To favor the uptake of the micelles by cancer cells that overexpress the epidermal growth factor receptor (EGFR), the micelles were decorated with an EGFR-targeted nanobody (named EGa1) through maleimide-thiol chemistry. The enhanced binding of the EGFR-targeted micelles at 4 °C to EGFR-overexpressing A431 cells, compared to low-EGFR-expressing HeLa cells, confirmed the specificity of the micelles. In addition, an enhanced uptake of mTHPC-loaded micelles by A431 cells was observed when these were decorated with the EGa1 nanobody, compared to nontargeted micelles. Both binding and uptake of targeted micelles were blocked by an excess of free EGa1 nanobody, demonstrating that these processes occur through EGFR. In line with this, mTHPC loaded in EGa1-conjugated PCL23-PEG (EGa1-P23) micelles demonstrated 4 times higher photocytotoxicity on A431 cells, compared to micelles lacking the nanobody. Importantly, EGa1-P23 micelles also showed selective PDT against A431 cells compared to the low-EGFR-expressing HeLa cells. Finally, an in vivo pharmacokinetic study shows that after intravenous injection, mTHPC incorporated in the P23 micelles displayed prolonged blood circulation kinetics, compared to free mTHPC, independently of the presence of EGa1. Thus, these results make these micelles a promising nanomedicine formulation for selective therapy.

Project description:RNA interference (RNAi) drugs have significant therapeutic potential, but delivery systems with appropriate efficacy and toxicity profiles are still needed. Here, we describe a neutral, ampholytic polymeric delivery system based on conjugatable diblock polymer micelles. The diblock copolymer contains a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-(pyridin-2-yldisulfanyl)ethyl)methacrylamide) (poly[HPMA-co-PDSMA]) segment to promote aqueous stability and facilitate thiol-disulfide exchange reactions and a second ampholytic block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The poly[(HPMA-co-PDSMA)-b-(PAA-co-DMAEMA-co-BMA)] was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization with an overall molecular weight of 22 000 g/mol and a PDI of 1.88. Dynamic light scattering and fluorescence measurements indicated that the diblock copolymers self-assemble under aqueous conditions to form polymeric micelles with a hydrodynamic radius and critical micelle concentration of 25 nm and 25 μg/mL, respectively. Red blood cell hemolysis experiments show that the neutral hydrophilic micelles have potent membrane destabilizing activity at endosomal pH values. Thiolated siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was directly conjugated to the polymeric micelles via thiol exchange reactions with the pyridal disulfide groups present in the micelle corona. Maximum silencing activity in HeLa cells was observed at a 1:10 molar ratio of siRNA to polymer following a 48 h incubation period. Under these conditions 90% mRNA knockdown and 65% protein knockdown at 48 h was achieved with negligible toxicity. In contrast the polymeric micelles lacking a pH-responsive endosomalytic segment demonstrated negligible mRNA and protein knockdown under these conditions. The potent mRNA knockdown and excellent biocompatibility of the neutral siRNA conjugates demonstrate the potential utility of this carrier design for delivering therapeutic siRNA drugs.

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The potential of polymeric micelles in the context of glioblastoma therapy.

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The potential of polymeric micelles in the context of glioblastoma therapy.

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