Tumor Microenvironment Targeted Nanotherapy

Abstract

Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. While enhanced permeability and retention effect promotes nano-chemotherapeutics extravasation, the abnormal tumor vasculature, high interstitial pressure and dense stroma structure limit homogeneous intratumoral distribution of nano-chemotherapeutics and compromise their imaging and therapeutic effect. Moreover, heterogeneous distribution of nano-chemotherapeutics in non-tumor-stroma cells damages the non-tumor cells, and interferes with tumor-stroma crosstalk. This can lead not only to inhibition of tumor progression, but can also paradoxically induce acquired resistance and facilitate tumor cell proliferation and metastasis. Overall, the tumor microenvironment plays a vital role in regulating nano-chemotherapeutics distribution and their biological effects. In this review, the barriers in tumor microenvironment, its consequential effects on nano-chemotherapeutics, considerations to improve nano-chemotherapeutics delivery and combinatory strategies to overcome acquired resistance induced by tumor microenvironment have been summarized. The various strategies viz., nanotechnology based approach as well as ligand-mediated, redox-responsive, and enzyme-mediated based combinatorial nanoapproaches have been discussed in this review.

Tumor-penetrating peptide for systemic targeting of Tenascin-C

“…(2020) 10:5809 | https://doi.org/10.1038/s41598-020-62760-y www.nature.com/scientificreports www.nature.com/scientificreports/ Over the years, several preclinical and clinical-stage affinity ligands for TNC have been developed, such as a aptamers 33 , FHK peptide 7 , a bispecific PL1 peptide that in addition to TNC-C also targets fibronectin extra domain B 8 , TNC-C-targeting single-chain G11 antibody 34 , and TNC-C/D targeting monoclonal antibody 81C6 35 . These and other ECM-reactive affinity ligands have proven useful for tumor delivery of extracellularly-acting anticancer payloads such as cytokines/growth factors, or payloads with intrinsic internalizing ability, such as proapoptotic D (KLKLAK) 2 peptide nanoparticles, or cell-permeable cytotoxic compounds 3,32,36 . However, a challenge for these and other ECM-directed systemic compounds is that they can only reach extravascular tumor tissue passively, through the increased leakiness of aberrant tumor microvasculature, a phenomenon known as enhanced permeability and retention (EPR) effect 37 .…”

Ultrasound-Responsive Materials for Drug/Gene Delivery

“…Microbubbles with the size of 1-10 mm cannot generally extravasate from blood vessels to tumor tissues. However, "leaky" tumor vessels and obstructive lymphatic drainage make nanobubbles with the size of 10-780 nm extravasate through endothelial gaps and accumulate in tumor tissue via the EPR effect (Fernandes et al, 2018). Therefore, nanobubbles show great potential in drug/gene delivery for the diagnosis and therapy of cancer because they can accumulate in tumor tissues and interact with tumor cells directly.…”

Multifunctional Magnetic Nanowires: Design, Fabrication, and Future Prospects as Cancer Therapeutics

“…Tumor microenvironments play an important role in the biological impact of nanosystems as well their distribution [20]. For nanosystems to be efficacious for cancer therapeutics, it needs to attain a homogenous distribution intratumorally, however nanosystems need to overcome the tumor microenvironment's barriers, which are summarized by Fernandez and co-workers [21]. Although the enhanced permeability and retention effect promotes extravasation of nanosystems intratumorally, they must first overcome the high interstitial pressure, abnormal tumor vasculature, and dense stroma, so that they may be efficacious.…”