Optimizing MYCi975 delivery using PLGA nanoparticles for triple negative breast cancer therapy: Characterization and in vitro evaluation

MYCi975 is an orally active small-molecule c-MYC (here after Myc) inhibitor that regulates Myc phosphorylation thereby leading to its degradation. It has a poor plasma half-life and low aqueous solubility. Localization of Myc protein in the nucleus presents an additional challenge. This study aimed to optimize the delivery of MYCi975 using PLGA nanoparticles to enhance its therapeutic efficacy against triple-negative breast cancer (TNBC) by evaluating its in vitro efficacy and assessing its potential synergistic effects when combined with doxorubicin (DOX). The DoE software was used to optimize the nanoparticles where a three-level, three-factorial Box-Behnken design was employed for optimisation. Particle size, PDI, zeta potential, shape, and release of the produced nanoparticles were assessed. MDA-MB-231 and MCF-7 cell lines were used for biological investigations, which included combination studies with DOX, cytotoxicity tests, and scratch wound tests. MYCi975 was successfully encapsulated in PLGA nanoparticles (PLGA 975 ). The TEM and SEM images confirmed their spherical morphology with a particle size of 120.7± 2.3 nm, PDI of 0.159±0.025, and zetapotential of -16.12±1.25 mV. The release of MYCi975 was higher in an acidic medium (pH 5.5) than in physiological condition (pH 7.4) in a sustained manner. An in vitro cytotoxicity assay and scratch wound assay on MDA-MB-231 and MCF-7 cells revealed that PLGA 975 showed improved anticancer activity against TNBC compared with non-TNBC. Combination treatment with DOX showed synergistic activity against TNBC. Optimized PLGA 975 showed excellent in vitro anticancer activity against TNBC in combination with DOX. • High metastasis and chemoresistance are characteristics of triple-negative breast cancer (TNBC) • Breast cancer development is significantly influenced by the transcription factor c-Myc, • MYCi975, an orally active small-molecule Myc inhibitor, regulates Myc protein by phosphorylating it, ultimately leading to its degradation • The lipophilicity of MYCi975 indicated by its log-P value of 8.4 presents challenges in developing suitable solutions for in vivo administration • In vitro cell culture studies indicated that the developed PLGA 975 nanoparticles exhibited more potent cytotoxicity through improved cellular penetration. • The combination of DOX and PLGA 975 nanoparticles exhibited synergistic activity in both cell lines.