Delivering Combination Chemotherapies and Targeting Oncogenic Pathways via Polymeric Drug Delivery Systems

Abstract

The side-effects associated with chemotherapy necessitates better delivery of chemotherapeutics to the tumor. Nanoparticles can load higher amounts of drug and improve delivery to tumors, increasing the efficacy of treatment. Polymeric nanoparticles, in particular, have been used extensively for chemotherapeutic delivery. This review describes the efforts made to deliver combination chemotherapies and inhibit oncogenic pathways using polymeric drug delivery systems. Combinations of chemotherapeutics with other drugs or small interfering RNA (siRNA) combinations have been summarized. Special attention is given to the delivery of drug combinations that involve either paclitaxel or doxorubicin, two popular chemotherapeutics in clinic. Attempts to inhibit specific pathways for oncotherapy have also been described. These include inhibition of oncogenic pathways (including those involving HER2, EGFR, MAPK, PI3K/Akt, STAT3, and HIF-1α), augmentation of apoptosis by inhibiting anti-apoptosis proteins (Bcl-2, Bcl-xL, and survivin), and targeting dysregulated pathways such as Wnt/β-catenin and Hedgehog.

Keywords: Drug delivery; apoptosis; chemotherapy; copolymer; doxorubicin; nanoparticle; paclitaxel; pathway; polymer.

Figure 1

Schematic illustration of response by tumor cells following chemotherapy. Tumors are heterogeneous and consist of many subpopulations (here blue, red, and green) A and B. When cells are treated with a chemotherapeutic (A or B), the respective resistant subpopulations proliferate and eventually dominate. (C) Treatment with multiple drugs could eliminate this selectiveness and reduce the occurrence of resistance.

Figure 2

Treatment of proliferative cancer cells with either (A) therapeutics targeting oncogenic pathways or (B) therapeutics targeting antiapoptotic proteins can increase the probability of the cell undergoing apoptosis or undergoing quiescence.