Harnessing the Power of Nanocarriers to Exploit the Tumor Microenvironment for Enhanced Cancer Therapy

Abstract

The tumor microenvironment (TME) has a major role in malignancy and its complex nature can mediate tumor survival, metastasis, immune evasion, and drug resistance. Thus, reprogramming or regulating the immunosuppressive TME has a significant contribution to make in cancer therapy. Targeting TME with nanocarriers (NCs) has been widely used to directly deliver anticancer drugs to control TME, which has revealed auspicious outcomes. TME can be reprogrammed by using a range of NCs to regulate immunosuppressive factors and activate immunostimulatory cells. Moreover, TME can be ameliorated via regulating the redox environment, oxygen content, and pH value of the tumor site. NCs have the capacity to provide site-specific delivery of therapeutic agents, controlled release, enhanced solubility and stability, decreased toxicities, and enhanced pharmacokinetics as well as biodistribution. Numerous NCs have demonstrated their potential by inducing distinct anticancer mechanisms by delivering a range of anticancer drugs in various preclinical studies, including metal NCs, liposomal NCs, solid lipid NCs, micelles, nanoemulsions, polymer-based NCs, dendrimers, nanoclays, nanocrystals, and many more. Some of them have already received US Food and Drug Administration approval, and some have entered different clinical phases. However, there are several challenges in NC-mediated TME targeting, including scale-up of NC-based cancer therapy, rapid clearance of NCs by the mononuclear phagocyte system, and TME heterogeneity. In order to harness the full potential of NCs in tumor treatment, there are several factors that need to be carefully studied, including optimization of drug loading into NCs, NC-associated immunogenicity, and biocompatibility for the successful translation of NC-based anticancer therapies into clinical practice. In this review, a range of NCs and their applications in drug delivery to remodel TME for cancer therapy are extensively discussed. Moreover, findings from numerous preclinical and clinical studies with these NCs are also highlighted.

Keywords: TME remodeling; drug resistance; enhanced pharmacokinetics; nanocarriers; tumor microenvironment.

Figure 1

The role of tumor microenvironment (TME) components in the regulation of tumor growth and metastasis. Reproduced with permission from Elsevier, Reference [7]. TME involves a range of cell types, including microglia, fibroblasts, endothelial cells, pericytes, immune cells, and various other tissue-resident cell types. Interactions between the structural and cellular components of TME mediate cancer cells becoming invasive and spreading beyond the place where a tumor started to distant regions of the body, via a multi-stage and complex metastatic pathway. Growth-mediating and immunosuppressive properties are exhibited by tumor-associated macrophages (TAMs), exosomes that elevate the migratory capacity of cancer cells are generated by mesenchymal stem cells, and cancer-associated fibroblasts rearrange TME that enables metastasis of cancer cells. In addition, hypoxia at the primary tumor triggers cancer cells to genetically and/or epigenetically acclimatize to endure as well as metastasize. Cancer cells in the circulation encounter cytokines, immune cells, and platelets in the blood TME that mediate their transit and survival [7,60].

Figure 2

Potential nanocarriers to modulate the tumor microenvironment for enhanced cancer therapy.

Figure 3

Synthesis of camptothecin (CPT)-loaded folic acid-conjugated chitosan oligosaccharides assembled magnetic halloysite nanotubes (FA-COS/MHNTs). Reproduced with permission from Elsevier, Reference [124]. Abbreviations: FA, folic acid; COS, chitosan oligosaccharide; CPT, camptothecin; MHNTs, magnetic halloysite nanotubes; EDC/NHS, N-(3-dimethylaminopropyl)-N/-ethylcarbodiimide/N-hydroxysuccinimide.