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

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 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.

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.

Keywords:

• GBM
• verteporfin
• micelle
• anisotropic
• poly(ethylene glycol)
• PEG
• poly(beta-amino ester)
• PBAE

Acknowledgments

The authors thank Drs J. Laterra and A. Vescovi for access to GBM1A cells. The authors thank the NIH for support (R01CA228133, R43CA221490, R01CA200399, R01EB016721, R01CA183827, R01CA195503, R01CA216855).

Disclosure

A.Q.H. was supported by the Mayo Clinic Professorship and a Clinician Investigator award. J.J.G. was supported by the Bloomberg~Kimmel Institute for Cancer Immunotherapy. J.K. received fellowship support from Samsung Scholarship. The authors report no other conflicts of interest in this work.