Abstract
BackgroundNanomedicine can improve traditional therapies by enhancing the controlled release of drugs at targeted tissues in the body. However, there still exists disease- and therapy-specific barriers that limit the efficacy of such treatments. A major challenge in developing effective therapies for one of the most aggressive brain tumors, glioblastoma (GBM), is affecting brain cancer cells while avoiding damage to the surrounding healthy brain parenchyma. Here, we developed poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE) (PEG-PBAE)-based micelles encapsulating verteporfin (VP) to increase tumor-specific targeting.MethodsBiodegradable, pH-sensitive micelles of different shapes were synthesized via nanoprecipitation using two different triblock PEG-PBAE-PEG copolymers varying in their relative hydrophobicity. The anti-tumor efficacy of verteporfin loaded in these anisotropic and spherical micelles was evaluated in vitro using patient-derived primary GBM cells.ResultsFor anisotropic micelles, uptake efficiency was ~100% in GBM cells (GBM1A and JHGBM612) while only 46% in normal human astrocytes (NHA) at 15.6 nM VP (p ≤ 0.0001). Cell killing of GBM1A and JHGBM612 vs NHA was 52% and 77% vs 29%, respectively, at 24 hrs post-treatment of 125 nM VP-encapsulated in anisotropic micelles (p ≤ 0.0001), demonstrating the tumor cell-specific selectivity of VP. Moreover, anisotropic micelles showed an approximately fivefold longer half-life in blood circulation than the analogous spherical micelles in a GBM xenograft model in mice. In this model, micelle accumulation to tumors was significantly greater for anisotropic micelle-treated mice compared to spherical micelle-treated mice at both 8 hrs (~1.8-fold greater, p ≤ 0.001) and 24 hrs (~2.1-fold greater, p ≤ 0.0001).ConclusionOverall, this work highlights the promise of a biodegradable anisotropic micelle system to overcome multiple drug delivery challenges and enhance efficacy and safety for the treatment of brain cancer.
Highlights
Glioblastoma (GBM), a grade IV astrocytoma, is one of the most elusive cancers to current treatment options of radiation and chemotherapy.[1,2] The administration of the commonly used chemotherapeutic drug, Temozolomide (TMZ), in combination with radiation, post resection, has only extended the median lifespan of GBM patients to 15 months with a 5-year survival rate of less than 5% following diagnosis.[3]
After following a similar protocol and confirming the synthesis of the VP-loaded micelles of two different morphologies, we investigated the effect of VP-encapsulated micelles on two patient-derived GBM cell lines and normal human astrocytes (NHA), representing the non-transformed brain parenchyma
This study investigated engineered verteporfin (VP)-loaded spherical and filamentous micelles for use as a safe therapy for GBM
Summary
Glioblastoma (GBM), a grade IV astrocytoma, is one of the most elusive cancers to current treatment options of radiation and chemotherapy.[1,2] The administration of the commonly used chemotherapeutic drug, Temozolomide (TMZ), in combination with radiation, post resection, has only extended the median lifespan of GBM patients to 15 months with a 5-year survival rate of less than 5% following diagnosis.[3] A major submit your manuscript | www.dovepress.com. We developed poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE) (PEG-PBAE)-based micelles encapsulating verteporfin (VP) to increase tumor-specific targeting. Conclusion: Overall, this work highlights the promise of a biodegradable anisotropic micelle system to overcome multiple drug delivery challenges and enhance efficacy and safety for the treatment of brain cancer.
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