Enhancement of gemcitabine and paclitaxel uptake and retention in metastatic cancer cells: A novel targeted combination delivery approach to eliminate breast cancer in blood and lymph

Abstract

The best current breast cancer treatments are limited by a lifelong concern for tumor recurrence. The inability of therapies to eliminate residual cancer cells after surgery leads to disease progression and metastasis. Gemcitabine (G) and paclitaxel (T) is an effective combination chemotherapy for metastatic breast cancer. However, the inability to synchronize GT in plasma and cancer cells by IV infusion limits its therapeutic potential. Off-target toxicity from diverging distribution of GT is also harmful to patients. If GT can be localized preferentially and retained together in cancer cells, the treatment impact will be enhanced with lower toxicity. Due to disparate physicochemical properties of GT, these drugs are challenging to formulate together for co-delivery to cancer cells. To overcome this gap, this dissertation describes the discovery of a novel technology that brings together water soluble G and insoluble T to form a novel GT drug combination nanoparticle (GT DcNP). This enabling technology allows GT to form a multi-drug-motif (MDM) structure in the presence of lipid excipients. When suspended in aqueous buffer, it produces an injectable GT DcNP dosage form. After IV injection, GT DcNPs (compared to free drug controls) increase the plasma exposure of G by 61-fold and T by 4-fold. GT DcNPs are able to target GT to breast cancer cells with a 5-fold higher lung-to-plasma ratio of G in tumor bearing lungs compared to healthy lung tissue. The maintenance of the originally dosed ratio of G-to-T in tumor burdened tissue, suggests that the DcNPs are stable and able to synchronize delivery into cancer cells. A single intravenous dose of GT in DcNP can completely eliminate invading breast cancer cells with a therapeutic index of 15.8. In mammary tumors, subcutaneous dosing of GT DcNPs causes cancer regression and recovery of the mammary tissue. These data show that the coordinated delivery of GT by DcNPs overcome the limitations of current free drug infusions and achieves greater anti-tumor effects. The MDM structure in DcNPs enables the transformation of short acting combination therapies to long acting injectables and can extend to other cancers, infections or chronic diseases that target the blood or lymph.