Introduction: Current anticancer agents continue to face substantial challenges, including inherently narrow therapeutic indexes (TIs) as well as suboptimal therapeutic combinations stemming from mixtures of active pharmaceutical ingredients (APIs) with dissimilar properties. While nanomedicine-based platforms for drug delivery can potentially address these challenges, key questions remain such as i/ will synergies of free drug combinations translate to nanoparticles, or should synergies be screen in the context of nanoparticles?, and ii/ are multi-drug-laden nanoparticles better than mixtures of single-drug-laden nanoparticles?
Methods: To evaluate the efficacy of Btz monotherapy, a Btz-BPD was designed to enable a 25-fold increase in API dosing compared to Btz alone, while maintaining tolerable toxicity in mice. The Btz-BPD was tested in vivo using subcutaneous and orthotopic MM models, assessing tumor progression and survival outcomes. Furthermore, BPDs carrying Btz, Pom, and Dex were synthesized for combination therapies. In vitro studies were conducted to analyze the synergistic, additive, or antagonistic patterns of the BPD combination nanomedicines compared to their free drug counterparts. Mathematical modeling was employed to provide insights into the underlying mechanisms and explain the observed results.
Results: The Btz-BPD monotherapy demonstrated a significant reduction in tumor progression and improved survival in both subcutaneous and orthotopic MM models. Furthermore, BPDs carrying combinations of Btz, Pom, and Dex exhibited distinct in vitro patterns of synergy, additivity, or antagonism, differing from their free drug counterparts. Importantly, statistical mixtures of the three drugs in BPDs outperformed free drug combinations, single-drug BPD mixtures, and antagonistic 3-drug BPDs. Quantitative analysis using a mathematical model confirmed that statistical 3-drug BPDs were more likely to deliver a synergistic drug ratio to cells compared to mixtures of single-drug BPDs.
Conclusions: Our results address critical gaps in the field of nanomedicine and provides new design principles for combination nanomedicines. The BPD platform offers promising strategies for improving existing mono- and combination therapies for MM. By demonstrating the superiority of statistical 3-drug BPDs over other formulations, our findings open doors for more effective and rational approaches to combination therapy in MM. These results have broader implications for enhancing current cancer treatments and advancing the field of nanomedicine.
