Introduction: We engineered a PEGylated polymer nanoparticle (PNP) encapsulating the potent Class 1 HDAC inhibitor romidepsin and demonstrated its superior tolerability and efficacy compared to free romidepsin T-cell lymphoma models. The PNP was optimized with focus on physicochemical properties like size, stability, and drug encapsulation. However, nanomedicines sometimes fail because their properties are not optimized to maximize drugs' MOA and bypass disease-specific barriers. Because PNP surface polyethylene glycol (PEG) chains partially control circulation and biodistribution, we examined the impact of 2kDa, 3kDa, 5kDa (lead), and 10kDa PEG on (1) In vitro cell viability, (2) microsomal stability, (3) NP-protein complexes, and (4) hemolysis/hemagglutination.
Results: 5kDa performed the best across all assays. In TCL cell lines, the IC50 of all formulations were comparable, yet 5kDa improved the microsomal stability of romidepsin by >20%. Immunoprecipitating NP-protein complexes with anti-PEG IgG yielded similar staining patterns compared to the isotype control, indicating non-specific weak binding of proteins to the 5kDa PEG, ensuring their long NP circulation. Less than 5% hemolysis and no hemagglutination was seen in 5kDa PEG, fulfilling the translational requirement of nanomedicines.
Conclusion: This data justifies expanding the scope of the PNP platform into new indications. By improving our understanding of how PNP properties impact the pharmacologic features of drugs, we can leverage PNPs to optimize drug MOAs, improve tumor accumulation, and bypass the biological barriers posed by each disease. A focus on the translational development of novel nanotherapeutics offers a unique opportunity to improve existing drugs and create novel drug entities.
