Abstract
A synergistic combination of paclitaxel (PTX) and everolimus (EVER) can allow for lower drug doses, reducing the toxicities associated with PTX, while maintaining therapeutic efficacy. Polymeric nanoparticles (NPs) of high stability provide opportunities to modify the toxicity profile of the drugs by ensuring their delivery to the tumor site at the synergistic ratio while limiting systemic drug exposure and the toxicities that result. The goal of the current study is to evaluate the in vivo fate of human epidermal factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) dual-targeted PTX+EVER-loaded NPs (Dual-NPs) in an MDA-MB-231-H2N breast cancer (BC) tumor-bearing mouse model. The pharmacokinetic parameters, plasma area under the curve (AUC) and half-life (t1/2z) were found to be 20-fold and 3 to 4-fold higher, respectively, for the drugs when administered in the Dual-NPs in comparison to the free-drug combination (i.e., PTX+EVER) at an equivalent dose of PTX. While maintaining anti-tumor efficacy, the levels of body weight loss were significantly lower (p < 0.0001) and the overall degree of neurotoxicity was reduced with Dual-NPs treatment in comparison to the free-drug combination when administered at an equivalent dose of PTX. This study suggests that Dual-NPs present a promising platform for the delivery of the PTX and EVER combination with the potential to reduce severe PTX-induced toxicities and in turn, improve quality of life for patients with BC.
Highlights
Paclitaxel (PTX)-induced toxicities continue to be one of the main challenges associated with the use of this agent
This study demonstrates that Dual-NPs have high stability in vivo and, subsequently, result in significant improvements with regard to safety compared to the free-drug combination in the MDA-MB-231-H2N breast cancer (BC) tumor-bearing mouse model
PTX and EVER encapsulated in Dual-NPs exhibited slower clearance from the plasma compared to the free-drug combination
Summary
Paclitaxel (PTX)-induced toxicities continue to be one of the main challenges associated with the use of this agent. The commercial formulation of PTX (Taxol) has been associated with severe hypersensitivity reactions, mainly caused by the excipients used for drug solubilization (i.e., ethanol and Cremophor EL) [1]. We can take advantage of the synergistic effects of drug-combinations with the administration of doses that are much lower than the maximum tolerated doses (MTDs) of the drugs. This can lead to a reduction in systemic toxicity, while improving or at least maintaining the desired therapeutic effect [2,3,4,5]
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