Nanomedicine therapeutic approaches to overcome cancer drug resistance

Abstract

Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a complicated process that involves multiple mechanisms. Here we discuss the major forms of drug resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic profiles can be created making drug selection for personal patient treatment much more intensive and effective. This review aims to demonstrate the advantage of the young medical science field, nanomedicine, for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers, carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks promising and opens new horizons for cancer treatment.

Keywords: AML; CAM-DR; CCP; CLL; CNS; CSC; Drug delivery; EGFR; EPR; H(2)N-Leu-Leu-Leu-OH; HIF-1; IGF-1R; IL-2; LLL; MDR; MRP; NF-κB; NSCLC; Nanobiopolymers; Nanodrug; PDGFR-β; PEG; RES; SDF-1/CXCL12; TAT; TG2; TLR; TMZ; TNFα; TfR; Tumor multidrug resistance; acute myeloid leukemia; cancer stem cell; cell adhesion-mediated drug resistance; central nervous system; charge-conversion polymer; chronic lymphocytic leukemia; enhanced permeability and retention; epidermal growth factor receptor; hypoxia-inducible factor 1; insulin-like growth factor 1 receptor; interleukin-2; mAb; monoclonal antibody; multidrug resistance; multidrug-resistance-associated protein; non-small cell lung cancer; nuclear factor κB; platelet-derived growth factor receptor-β; polyethylene glycol; reticuloendothelial system; short interfering RNA; siRNA; stromal cell-derived factor 1; temozolomide; tissue transglutaminase; toll-like receptor; transactivator of transcription; transferrin receptor; tumor necrosis factor α.

Fig. 1

The number of references under the research topics of “nanomedicine,” “nanoscience,” and “nanotechnology” from 1996 to 2012. The number of publications peaked in 2011 with 7,279 and saw a slight decline in 2012 with 7,011 publications.

Fig. 2

An illustrative representation of different classes of third-generation multiple functional nanodrugs and their potential moieties for targeting, PEGylated for resistance and with imaging moieties.

Fig. 3

Upregulation of ABC transporters on cancer cell membranes effectively removes chemotherapeutic drugs and cytotoxic agents as a means of drug resistance.

Fig. 4

Two alternate drug resistance mechanisms. A. A heterogeneous population of cancer cells is shown in the top left. Following administration of treatment, Population 3 is completely eliminated while a subpopulation, Population 4, emerges as a dominant clone (bottom right). B. A heterogeneous population of cancer cells, including cancer stem cells, is shown in the top left. After administration of treatment, only the resistant cancer stem cells are seen (top right). After time, the cancer stem cells are able to repopulate the tumor with all previous cell populations present before treatment (bottom right).

Fig. 5

Representative example of the complexity of the tumor microenvironment and its interactions with tumor cells.

Fig. 6

The conjugation of TMZ on polymalic acid nanobiopolymer increases half-life and overcomes resistance in human glioma cell line T98G. A. Half-life of TMZ was increased from 1.8 to 7.4 hours (>4 times) after attachment to polymer. B. Attachment of TMZ to polymer resulted in overcoming the inherent resistance of T98G cells compared to TMZ alone. Reproduced from ref. [111].