Many cancer treatment regimens routinely require the administration of multiple chemotherapeutic agents that usually differ with respect to their mechanism of action. This can allow for enhanced efficacy, a reduction in the required dose of each individual agent, and/or a delay in the onset of drug resistance (relative to single therapy administration).
A desirable outcome for a drug combination is a synergistic effect, wherein the sum of the clinical activity of a drug combination is greater than the added effect of each individual drug. Several publications by the Allen lab (and others) have shown that the synergistic effect can be dependent on the relative molar ratio of one drug to another. This presents a significant challenge when administering a drug combination in its free form due to the different properties of these drugs, leading to varying pharmacokinetic and biodistribution profiles. This makes the likelihood of a chemotherapeutic combination arriving at the tumour site at a specific synergistic ratio very small.
At the Allen Lab, we are designing novel nanoparticle formulations that encapsulate synergistic drug combinations in a single-vehicle. The ratio of these drugs is pre-determined by in vitro analysis using the Chou and Talalay combination index equation. Drug combinations are co-encapsulated to ensure that they arrive at the tumour site at the predetermined ratio to exert their synergistic effect. In addition to the potential for enhanced efficacy, the formulation of these drugs into a nanoparticle may also reduce the systemic toxicity commonly seen with chemotherapeutic agents (such as doxorubicin or paclitaxel).