<p>Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics</p>

Abstract

Background: Nanomedicine can improve traditional therapies by enhancing the controlled release of drugs at targeted tissues in the body. However, there still exists disease-and therapyspecific 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. Methods: Biodegradable, 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. Results: For 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). 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.

Poly(ethylene glycol)–Poly(beta-amino ester)-Based Nanoparticles for Suicide Gene Therapy Enhance Brain Penetration and Extend Survival in a Preclinical Human Glioblastoma Orthotopic Xenograft Model

“…Modification of the surface of nanoparticles by conjugating neutral, water-soluble PEG molecules is a widely employed strategy to improve transport in physiological environments . We and other groups have reported that PEGylation not only reduces surface charge and thereby enhances potential safety of the vector , but also limits protein adsorption through steric hindrance, which allows for improved stability, , pharmacokinetics, and diffusivity into the brain parenchyma . These are important factors to enhance the distribution of the nanoparticles and enable a widespread effect against brain cancer.…”

Drug Delivery Nanosystems in Glioblastoma Multiforme Treatment: Current State of the Art

“…Verteporfin (VP) is a derivative of benzoporphyrin, a very hydrophobic molecule, and Yes-associated protein (YAP) inhibitor, expressed in tumors like GBM. VP was encapsulated in micelles of poly(ethylene glycol)-poly(β-amino ester)- poly(ethylene glycol) (PEG-PBAE-PEG) triblock copolymer [ 100 ] and tested against GBM cell lines. Two types of micelles were prepared to encapsulate the PV, spherical (sVPM) and filamentous (fVPM) micelles, using the nanoprecipitation method.…”

Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness

“…In addition, its mode of inhibition and mechanism of interaction with YAP remain unknown. Considering all, verteporfin might not be the most promising drug, nevertheless, some studies have shown that the loading of verteporfin into microparticles improves its specificity and pharmacokinetics, making it more suitable as a treatment (267)(268)(269). Similarly, the CA3 compound has been reported as a modulator of YAP/TEAD transcriptional activity through the inhibition of YAP, but it has drawbacks similar to those of verteporfin (270,271).…”