Lu (2017) PDGFRβ-specific affibody-directed delivery of a photosensitizer, IR700, is efficient for vascular-targeted photodynamic therapy of colorectal cancer, Drug Delivery, 24:1, 1818-1830, DOI: 10.1080/10717544.2017 Conventional vascular-targeted PDT has been achieved by passive photosensitizer (PS) delivery, which involves a high risk of adverse effects. Active PS delivery is urgently required for vascular-targeted PDT. Although endothelial cells and pericytes are major cellular components of tumor blood vessels, little attention has been paid to pericyte-targeted PDT for cancer therapy. PDGFRb is abundantly expressed in the pericytes of various tumors. In this experiment, a dimeric Z PDGFRb affibody with a 0.9 nM affinity for PDGFRb was produced. The Z PDGFRb affibody showed PDGFRb-dependent pericyte binding. Intravenously injected Z PDGFRb affibody was predominantly distributed on pericytes and thus accumulated in LS174T tumor grafts. The conjugate of the Z PDGFRb affibody and IR700 dye, i.e. Z IR700 , bound to PDGFRb þ pericytes but not to PDGFRb À LS174T tumor cells. Accordingly, Z IR700 -mediated PDT in vitro induced the death of pericytes but not of LS174T tumor cells. In mice bearing LS174T tumor grafts, Z IR700 -mediated PDT damaged tumor blood vessels, thus inducing tumor destruction by intensifying tissue hypoxia. The average mass of tumor grafts administered with Z IR700 -mediated PDT was approximately 20-30% of that of the control, indicating that pericyte-targeted PDT is efficient for cancer therapy. In addition, Z IR700 -mediated PDT increased the tumor uptake of TNF-related apoptosis-inducing ligand (TRAIL) injected post-illumination. Consequently, combination therapy of Z IR700 -mediated PDT and TRAIL showed greater tumor suppression than Z IR700 -mediated PDT-or TRAIL-based monotherapy. These results demonstrated that active vascular-targeted PDT could be achieved by using Z PDGFRb affibody-directed delivery of PS. ARTICLE HISTORY

Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) has exhibited superior in vitro cytotoxicity in a variety of tumor cells. However, hTRAIL showed a disappointing anticancer effect in clinical trials, although hTRAIL-based regimens were well tolerated. One important reason might be that hTRAIL was largely trapped by its decoy receptors, which are ubiquitously expressed on normal cells. Tumor-targeted delivery might improve the tumor uptake and thus enhance the antitumor effect of hTRAIL. Platelet-derived growth factor receptor β (PDGFRβ)-expressing pericytes are enriched in tumor tissues derived both from patients with colon cancer and from mice bearing colorectal tumor xenografts. A ZPDGFRβ affibody showed high affinity (nM) for PDGFRβ and was predominantly distributed on tumor-associated PDGFRβ-positive pericytes. Co-administration with the ZPDGFRβ affibody did not significantly enhance the antitumor effect of hTRAIL in mice bearing tumor xenografts. Fusion to the ZPDGFRβ affibody endows hTRAIL with PDGFRβ-binding ability but does not interfere with its death receptor binding and activation. The fused ZPDGFRβ affibody mediated PDGFRβ-dependent binding of hTRAIL to pericytes. In addition, hTRAIL bound on pericytes could kill tumor cells through juxtatropic activity or exhibit cytotoxicity in tumor cells after being released from pericytes. Intravenously injected hTRAIL fused to ZPDGFRβ affibody initially accumulated on tumor-associated pericytes and then diffused to the tumor parenchyma over time. Fusion to the ZPDGFRβ affibody increased the tumor uptake of hTRAIL, thus enhancing the antitumor effect of hTRAIL in mice bearing tumor xenografts. These results demonstrate that pericyte-targeted delivery mediated by a ZPDGFRβ affibody is an alternative strategy for tumor-targeted delivery of anticancer agents.

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BackgroundNanoparticles exhibit great promise for improving the solubility and tissue-specific distribution of chemotherapeutic agents; however, the passive and highly variable enhanced permeability and retention (EPR) effects observed in tumors frequently leads to insufficient delivery of nanodrugs into tumors. The tumor-penetrating peptide iRGD can actively enhance tumor-selective delivery of nanoparticles into tumors by binding to integrin and interacting with tissue-penetrating receptor neuropilin-1.Materials and methodsTo improve colorectal cancer treatment, in this study, we prepared a paclitaxel (PTX)-loaded PLGA nanoparticle (PLGA-PTX) and evaluated its tumor-targeting and antitumor activity by co-administration with iRGD.ResultsCompared to free PTX, encapsulated PTX retained preferential cytotoxicity toward various colorectal cancer cells while effectively sparing healthy cells. PLGA-PTX treatment resulted in cell cycle arrest at the G2/M phase and apoptosis, leading to inhibition of cancer cell migration and invasion. PLGA-PTX combined with iRGD displayed little enhancement of cytotoxicity in vitro. Despite this, iRGD receptors integrin and neuropilin-1 were found to be primarily overexpressed on abundant tumor vessels in mice bearing colorectal tumors. Consequently, co-administration of nanoparticles with iRGD promoted the selective delivery of nanoparticles into tumor tissues in vivo. Additionally, the combined regimen enhanced the antitumor effects compared to those of each individual reagent.ConclusionOur findings suggest that PLGA nanoparticles combined with the iRGD peptide provide a promising drug delivery strategy for facilitating active drug accumulation into tumors, given that iRGD receptors are overexpressed on tumor vessels. This co-administration system lacking covalent conjugation provides a more convenient means to combine various therapeutic agents with iRGD to achieve personalized nanotherapy.