Nanoparticles for Effective Combination Therapy of Cancer

Abstract

Cancer continues to remains a major healthcare problem across the world despite strong translational research efforts towards tackling the disease. Surgery, when possible, along with radiation and chemotherapy continue to remain the mainstay of cancer treatment. Novel targeted therapies or biologics and immunotherapies have recently been approved to improve treatment efficacies while reducing collateral damage to normal, non-cancerous tissues. Combination therapies have shown better results than individual monotherapies in the clinic but often the improvements in therapeutic indices remain marginal, at best. Several combinations treatments have been clinically approved for different types of cancer. Nanomedicine, the application of nanotechnology for medicine, has already made some positive impacts on the clinical care in this fight against cancer. Several nano-sized formulations of conventional chemotherapies have been clinically approved. Nanotechnology provides a novel way to deliver combination therapies with spatiotemporal control over drug release. This review explores the recent advances in nanotechnology-mediated combination treatments against cancer. Multifunctional nanomedicines for mechanism-based combination therapies are likely to deliver the right drugs to the right place at the right time for optimal treatment responses with reduced morbidity. No nanomedicine that combines two or more drugs in a single platform has been approved for clinical use yet. This is because several challenges still remain in the development of nano-combinations including but not limited to - the optimal drug ratios in these nanomedicines, control over these drug ratios over multiple batches, large scale, reproducible manufacturing of these nanomedicines and cost of these nano-combinations among others. These challenges need to be addressed soon using a multidisciplinary approach with collaborations between academia, the pharmaceutical industry and the regulatory bodies involved to ensure that nano-combination therapy delivers on its promise of better treatment outcomes while severely reducing morbidity thus improving the quality of life in cancer patients.

Keywords: Biomedical Nanotechnology; Biotherapeutics; Chemotherapy; Drug Delivery; Liposomes; Nanomedicine; Oncology; Photodynamic Therapy; Photothermal therapy; Targeted Treatments.

Figure 1

Targeted Nanomedicine- a cartoon showing a representative, targeted stealth nanoparticle as a drug delivery carrier with core-shell structure. A polyethylene glycol (PEG) coating on the nanoparticle surface has shown an improvement in colloidal and storage stability in vitro and circulation half life in vivo along with providing a spacer for the targeting ligand to bind to its cognate biomarker on the cancer cell.

Figure 2

Nanoparticle based combinations therapy. A) Monotherapy versus dual therapy, and sequential administration versus simultaneous administration. B) A schematic representation of cocktail and nanocarrier approaches for combination drug therapy (hypothetical case study shown). The in vitro and then in vivo fixed molar ratio (synergistic effect) can be translated from in vitro assay using nanoparticle approach strategy versus cocktail approach. C) Hypothetical results of a standard clinical trials of two treatments using dendrimers as nanocarrier. Images reproduced with permission from Mignani et. al. [21].

Figure 3

PPM-DD–optimized ND-drug combinations. (A) A schematic model of the PPM experimental framework. Doxorubicin; Bleomycin; Mitoxantrone; Paclitaxel. (B) PPM-derived optimal ND-drug combinations (NDC) outperform a random sampling of NDCs in effective therapeutic windows of treatment of cancer cells compared to control cells. Reprinted with permission from H. Wang et al. [24] Copyright 2014 American Chemical Society.

Figure 4

Gold Nanostars based theranostics for combined chemo- and photothermal therapy A) TEM Images showing the morphology of Gold Nanostar, before cRGD conjugation (i) and after cRGD conjugation (ii). B) Temperature of PBS, Au-MPA, Au-cRGD-MPA, Au-DOX, and Au-cRGDDOX upon light irradiation in vitro (i) and in vivo (ii). C) Intracellular uptake of DOX, Au-DOX, Au-cRGD-DOXMDA-MB-231 and MCF 12A cells after incubation for 1h. D) 3D fluorescence image of Au-cRGD-DOX internalized by MDA-MB-231 and transported to nuclei. E) Qualitative killing analysis of tumor activity in vitro of Au-NS, DOX, Au-DOX and Au-cRGD-DOX on MDA-MB-231. F) In vivo images of Au-cRGD-MPA in MDAMB- 231(positive αvβ3 receptor expression) (i) and MCF-7 (negative αvβ3 receptor expression) (ii). G) The ex vivo fluorescent images of individual organs. H) Tumor-to-normal tissue (T/N) ratios of Au-cRGD-DOX in MDA-MB-231 and MCF-7 tumor cell line. I) Comparison of the therapeutic efficacy of Au-NS +light, free DOX, Au-cRGD-DOX+light (intratumoral injection and Au-cRGD-DOX light (Tail vein injection) in S180 tumorbearing mice. Survival rates of mice (i), tumor growth of mice (ii), H&E stained tissue section for tail vein injection (iii). Images reproduced with permission from Chen, et al. [60].