Translational Nano-Medicines: Targeted Therapeutic Delivery for Cancer and Inflammatory Diseases

Abstract

With the advent of novel and personalized therapeutic approaches for cancer and inflammatory diseases, there is a growing demand for designing delivery systems that circumvent some of the limitation with the current therapeutic strategies. Nanoparticle-based delivery of drugs has provided means of overcoming some of these limitations by ensuring the drug payload is directed to the disease site and insuring reduced off-target activity. This review highlights the challenges posed by the solid tumor microenvironment and the systemic limitations for effective chemotherapy. It then assesses the basis of nanoparticle-based targeting to the tumor tissues, which helps to overcome some of the microenvironmental and systemic limitations to therapy. We have extensively focused on some of the tumor multidrug resistance mechanisms (e.g., hypoxia and aerobic glycolysis) that contribute to the development of multidrug resistance and how targeted nano-approaches can be adopted to overcome drug resistance. Finally, we assess the combinatorial approach and how this platform has been used to develop multifunctional delivery systems for cancer therapy. The review article also focuses on inflammatory diseases, the biological therapies available for its treatment, and the concept of macrophage repolarization for the treatment of inflammatory diseases.

Fig. 1

a Tumor MDR mechanisms including hypoxia, aerobic glycolysis, and strategies to overcome resistance using targeted nanoparticle-based delivery. b MDA-MB-231 estrogen-negative human breast tumor xenograft was established orthotopically in the mammary fat pad of female athymic (nu/nu) mice using cells cultured under normoxic and hypoxic conditions. At the time of excision, the tumor size was the same ∼100 mm³. c EGFR-targeted nanoparticles showing preferential accumulation in tumor tissue and d the mean weight and volumes of tumors upon treatment with different formulations on day 28 drug post-administration. The dose of paclitaxel (PTX) was 20 mg/kg and lonidamine (LON) was 80 mg/kg administered in MDA-MB-231 human breast cancer-bearing female athymic (nu/nu) mice. Reprinted from Milane et al., Therapeutic Efficacy and Safety of Paclitaxel/Lonidamine Loaded EGFR-Targeted Nanoparticles for the Treatment of Multidrug-Resistant Cancer. Plos One. (2011). DOI: 10.1371/journal.pone.0024075

Fig. 2

a Combinatorial-designed nano-assemblies enabling selection of delivery components to achieve optimal encapsulation efficiency, minimal toxicity, and desired in vitro and in vivo activity. b Qualitative biodistribution analysis of indocyanine green encapsulated HA-PEI/HA-PEG nanoparticles in human non-small cell lung cancer A549 and A549DDP (a) and small cell lung cancer H69 and H69AR cells (b) tumor bearing mice. Free indocyanine green dye was injected as control to see the clearance of dye from the circulation in mice (c). The images have been acquired using IVIS live imaging station. Reprinted from Ganesh et al., 2013 (c) In vivo Survivin and Bcl-2 Gene Silencing Efficacy in Mice Bearing A549^DDP Cisplatin-Resistant NSCLC Xenografts (d) In vivo antitumor efficacy following combination Gene Silencing and Cisplatin Efficacy in Mice Bearing A549^DDP NSCLC Xenografts

Fig. 3

Disease progression in rheumatoid arthritis (RA). a Induction phase: initial activation of the immune system leads to an inflammatory cascade. b Inflammation phase: self-antigen presentation leads to activation of T cells and B cells. c Self-perpetuation: cartilage autoantigens activate the immune system against cartilage tissue with infiltration of pannus into the joints resulting in tissue destruction. d Destruction phase: synovial fibroblasts and osteoclasts are activated by pro-inflammatory cytokines such as TNF and IL-6. Abbreviations: APC, antigen-presenting cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; TEFF, effector T cell; TH, helper T (cell); TH1, type 1 helper T cell; TH17, type 17 helper T cell; TREG, regulatory T cell. Reprinted from Burmester et al., 2014 with permission from NPG

Fig. 4

Macrophage polarization upon exposure to different stimuli. M1 macrophages are induced in response to IFN-γ, which can be produced by T helper 1 (TH1) cells or natural killer (NK) cells, and tumor necrosis factor (TNF), which is produced by antigen-presenting cells (APCs). M2a macrophages arise in response to interleukin-4 (IL-4), which can be produced by TH2 cells or granulocytes. M2c macrophages are generated in response to various stimuli, including immune complexes, prostaglandins, G-protein coupled receptor (GPCR) ligands, glucocorticoids, apoptotic cells, or IL-10. TLR Toll-like receptor. Reprinted from Mosser and Edwards, 2008 with permission from NPG