High endothelial venules (HEVs) are specialized blood vessels that support the migration of lymphocytes from the bloodstream into lymph nodes (LNs). They are also formed ectopically in mammalian ...organs affected by chronic inflammation and cancer. The recent arrival of immunotherapy at the forefront of many cancer treatment regimens could boost a crucial role for HEVs as gateways for the treatment of cancer. In this review, we describe the microanatomical and biochemical characteristics of HEVs, mechanisms of formation of newly made HEVs, immunotherapies potentially dependent on HEV-mediated T cell homing to tumors, and finally, how HEV-targeted therapies might be used as a complementary approach to potentially shape the therapeutic landscape for the treatment of cancer and immune-mediated diseases.
Certain drugs against cancers or immune-mediated diseases are marked by limited efficacy and off-target toxicity; however, targeting high endothelial venules for selective nanocarrier-based, active drug delivery harbors significant potential to solve this clinical problem.
High endothelial venules (HEVs) are specialized mammalian segments of vasculature that are specific to secondary lymphoid organs and hence represent potential targets for immunotherapeutics.Antibodies that bind selectively to HEVs provide efficient targeting tools for immunotherapeutics through conjugation or encapsulation inside HEV antibody-coated nanocarriers.HEVs can also develop in organ tissues in association with autoimmune and immune-mediated disorders, including transplant rejection; they are also often found in conjunction with tertiary lymphoid organs in humans and mice.Located proximal to primary tumors, tumor-draining lymph nodes, and metastatic lesions in humans and mice, tumor-associated HEVs provide a rationale for the development of potential HEV-targeted, drug-specific delivery to cancer patients.
Targeting immunosuppressive metastatic cancer cells is a key challenge in therapy. We recently have shown that a rigid‐rod aromatic, pBP−NBD, that responds to enzymes and kill immunosuppressive ...metastatic osteosarcoma (mOS) and castration resistant prostate cancer (CRPC) cells in mimetic bone microenvironment. However, pBP−NBD demonstrated moderate efficacy against CRPC cells. To enhance activity, we incorporated the unnatural amino acid L‐ or D‐4,4′‐biphenylalanine (L‐ or D−BiP) into pBP−NBD, drastically increasing cellular uptake and CRPC inhibition. Specifically, we inserted BiP into pBP−NBD to target mOS (Saos2 and SJSA1) and CRPC (VCaP and PC3) cells with overexpressed phosphatases. Our results show that the D‐peptide backbone with an aspartate methyl diester at the C‐terminal offers the highest activity against these immunosuppressive mOS and CRPC cells. Importantly, imaging shows that the peptide assemblies almost instantly enter the cells and accumulate primarily within the endoplasmic reticulum of Saos2, SJSA1, and PC3 cells and at the lysosomes of VCaP cells. By using BiP to boost cellular uptake and self‐assembly within cancer cells, this work illustrates an unnatural hydrophobic amino acid as a versatile and effective residue to boost endocytosis of synthetic peptides for intracellular self‐assembly.
This research demonstrates that the integration of unnatural amino acids (L‐ or D‐4,4′‐biphenylalanine) into peptide assemblies significantly accelerates their accumulation within prostate cancer cells, boosting their capacity to hinder cancer proliferation. This work paves a way for engineering supramolecular medicine, potentially heightening the efficacy of peptide‐based treatments for prostate cancer. It may lead to more effective therapeutic strategies for treating other cancers.
