Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple-Negative Breast Cancer.

PURPOSE: Downregulation of miRNA-22 in triple-negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo. METHODS: To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations. RESULTS: Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs against TNBC, providing a basis for rational therapeutic combinations for improved response CONCLUSIONS: The present study highlights the translational potential of miRNA-22 nanotherapy for TNBC in combination with standard-of-care drugs.

A Multiscale Model to Identify Limiting Factors in Nanoparticle-Based miRNA Delivery for Tumor Inhibition.

MicroRNA-based gene therapy for cancer treatment via nanoparticles (NPs) requires navigation of multiple physical and physiological barriers in order to efficiently deliver the miRNAs to the cancer cell cytoplasm. We here present a mathematical model to investigate the variability associated with tumor, NP, and miRNA characteristics, and identify the limiting factors in miRNA delivery to tumors. Through global parameter analysis, the miRNA release rate from NPs and NP degradability were found to have the most significant impact on cytosolic accumulation of miRNAs. These NP properties can be fine-tuned in order to optimize the delivery system for enhancing the efficacy of miRNA-based therapy.Clinical Relevance-Understanding the effect of nanoparticle, tumor, and miRNA characteristics in governing the efficacy of miRNA-based cancer therapy will support its clinical translation.

A Mathematical Model to Estimate Chemotherapy Concentration at the Tumor-Site and Predict Therapy Response in Colorectal Cancer Patients with Liver Metastases.

Chemotherapy remains a primary treatment for metastatic cancer, with tumor response being the benchmark outcome marker. However, therapeutic response in cancer is unpredictable due to heterogeneity in drug delivery from systemic circulation to solid tumors. In this proof-of-concept study, we evaluated chemotherapy concentration at the tumor-site and its association with therapy response by applying a mathematical model. By using pre-treatment imaging, clinical and biologic variables, and chemotherapy regimen to inform the model, we estimated tumor-site chemotherapy concentration in patients with colorectal cancer liver metastases, who received treatment prior to surgical hepatic resection with curative-intent. The differential response to therapy in resected specimens, measured with the gold-standard Tumor Regression Grade (TRG; from 1, complete response to 5, no response) was examined, relative to the model predicted systemic and tumor-site chemotherapy concentrations. We found that the average calculated plasma concentration of the cytotoxic drug was essentially equivalent across patients exhibiting different TRGs, while the estimated tumor-site chemotherapeutic concentration (eTSCC) showed a quadratic decline from TRG = 1 to TRG = 5 (p < 0.001). The eTSCC was significantly lower than the observed plasma concentration and dropped by a factor of ~5 between patients with complete response (TRG = 1) and those with no response (TRG = 5), while the plasma concentration remained stable across TRG groups. TRG variations were driven and predicted by differences in tumor perfusion and eTSCC. If confirmed in carefully planned prospective studies, these findings will form the basis of a paradigm shift in the care of patients with potentially curable colorectal cancer and liver metastases.

Investigating the Effect of Aging on the Pharmacokinetics and Tumor Delivery of Nanomaterials using Mathematical Modeling.

The application of nanomedicine for diagnosis and treatment of cancer has immense potential, but has witnessed only limited clinical success, in part due to insufficient understanding of the role of nanomaterial properties and physiological variables in governing nanoparticle (NP) pharmacology. Here, we present a multiscale mathematical model to examine the effects of physiological changes associated with patient age on the pharmacokinetics and tumor delivery efficiency of NPs. We show that physiological changes due to aging prolong the residence of NPs in the systemic circulation, thereby improving passive accumulation of NPs in tumors.Clinical Relevance - Understanding the effect of inter-individual variability on the pharmacological behavior of nanomaterials will improve their clinical translatability.