Multi-functional nanocarriers to overcome tumor drug resistance

Abstract

The development of resistance to variety of chemotherapeutic agents is one of the major challenges in effective cancer treatment. Tumor cells are able to generate a multi-drug resistance (MDR) phenotype due to microenvironmental selection pressures. This review addresses the use of nanotechnology-based delivery systems to overcome MDR in solid tumors. Our own work along with evidence from the literature illustrates the development of various types of engineered nanocarriers specifically designed to enhance tumor-targeted delivery through passive and active targeting strategies. Additionally, multi-functional nanocarriers are developed to enhance drug delivery and overcome MDR by either simultaneous or sequential delivery of resistance modulators (e.g., with P-glycoprotein substrates), agents that regulate intracellular pH, agents that lower the apoptotic threshold (e.g., with ceramide), or in combination with energy delivery (e.g., sound, heat, and light) to enhance the effectiveness of anticancer agents in refractory tumors. In preclinical studies, the use of multi-functional nanocarriers has shown significant promise in enhancing cancer therapy, especially against MDR tumors.

Figure 1

Schematic illustration of the selection pressures in the tumor microenvironment that leads to development of multidrug resistance. Selection pressures such as hypoxia (A), genetic mutations in regulatory genes and altered regulation of apoptotic factors (D) can lead to cellular adaptation and aggressive MDR characteristics such as increased expression of growth factor receptors (E), increased expression of drug efflux pumps (F), reversion to anaerobic metabolism (G), decreased pH (H), and increased interstitial fluid pressure (H). The abnormal vasculature in the microenvironment of tumors (B and C) contributes to hypoxia (selection pressure) as well as to invasion and metastasis.

Figure 2

Mechanisms of multidrug resistance development in tumor cells. (Adapted from reference #5).

Figure 3

Different types of nanocarrier platforms used in tumor-targeted delivery.

Figure 4

Schematic illustration of multi-functional nanosystems.

Figure 5

Combination therapeutic strategies in overcoming tumor multi-drug resistance.

Figure 6

The importance of spatial distribution in combination therapy using a drug efflux inhibitor (G) and a chemotherapeutic drug (D). When separate PLN formulations are used to administer the agents (a) the inhibitor is ineffective in blocking drug efflux. The inhibitor is most effective when both the inhibitor and the drug are loaded into one PLN formulation (b). *Reprinted with permission from the Journal of Controlled Release 2006 Dec 1;116(3):275−84 © Elsevier [70].