Background: Nanoscale drug-delivery systems (DDSs) have great promise in tumor diagnosis and treatment. Platelet membrane (PLTM) biomimetic DDSs are expected to enhance retention in vivo and escape uptake by macrophages, as well as minimizing immunogenicity, attributing to the CD47 protein in PLTM sends “ don’t eat me ” signals to macrophages. In addition, P-selectin is overexpressed on the PLTM, which would allow a PLTM-biomimetic DDS to specifically bind to the CD44 receptors upregulated on the surface of cancer cells. Results: In this study, porous nanoparticles loaded with the anti-cancer drug bufalin (Bu) were prepared from a chitosan oligosaccharide (CS)-poly(lactic-co-glycolic acid) (PLGA) copolymer. These were subsequently coated with platelet membrane (PLTM) to form PLTM-CS-pPLGA/Bu NPs. The PLTM-CS-pPLGA/Bu NPs bear a particle size of ~ 192 nm, and present the same surface proteins as the PLTM. Confocal microscopy and flow cytometry results revealed a greater uptake of PLTM-CS-pPLGA/Bu NPs than uncoated CS-pPLGA/Bu NPs, as a result of the targeted binding of P-selectin on the surface of the PLTM to the CD44 receptors of H22 hepatoma cells. In vivo biodistribution studies in H22-tumor carrying mice revealed that the PLTM-CS-pPLGA NPs accumulated in the tumor, because of a combination of active targeting effect and the EPR effect. The PLTM-CS-pPLGA/Bu NPs led to more effective tumor growth inhibition over other bufalin formulations. Conclusions: Platelet membrane biomimetic nanoparticles played a promising targeted treatment of cancer with low side effect.

Vascular-targeted photodynamic therapy (PDT) is an important strategy for cancer therapy. 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. PDGFRβ is abundantly expressed in the pericytes of various tumors. In this experiment, a dimeric Z_PDGFRβ affibody with a 0.9 nM affinity for PDGFRβ was produced. The Z_PDGFRβ affibody showed PDGFRβ-dependent pericyte binding. Intravenously injected Z_PDGFRβ affibody was predominantly distributed on pericytes and thus accumulated in LS174T tumor grafts. The conjugate of the Z_PDGFRβ affibody and IR700 dye, i.e. Z_IR700, bound to PDGFRβ⁺ pericytes but not to PDGFRβ⁻ 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_PDGFRβ affibody-directed delivery of PS.

Background: Solid tumor hypoxic conditions prevent the generation of reactive oxygen species (ROS) and the formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, which ultimately contributes to radiotherapy (RT) resistance. Recently, there have been significant technical advances in nanomedicine to reduce hypoxia by facilitating in situ O₂ production, which in turn serves as a “radiosensitizer” to increase the sensitivity of tumor cells to ionizing radiation. However, off-target damage to the tumor-surrounding healthy tissue by high-energy radiation is often unavoidable, and tumor cells that are further away from the focal point of ionizing radiation may avoid damage. Therefore, there is an urgent need to develop an intelligent targeted nanoplatform to enable precise enhanced RT-induced DNA damage and combined therapy. Results: Human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (Z_Her2) mediated cisplatin-loaded mesoporous polydopamine/MnO₂/polydopamine nanoparticles (Pt@mPDA/MnO₂/PDA-Z_Her2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumors is reported. These NPs are biodegradable under a simulated tumor microenvironment, resulting in accelerated cisplatin release, as well as localized production of O₂. Z_Her2, produced using the E. coli expression system, endowed NPs with Her2-dependent binding ability in Her2-positive SKOV-3 cells. An in vivo MRI revealed obvious T₁ contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration via the efficient internalization and penetrability of Z_Her2. These NPs exhibited excellent inhibition of tumor growth with X-ray irradiation. An immunofluorescence assay showed that these NPs significantly reduced the expression of HIF-1α and improved ROS levels, resulting in radiosensitization. Conclusions: The nanocarriers described in the present study integrated Her2 targeting, diagnosis and RT sensitization into a single platform, thus providing a novel approach for translational tumor theranostics. Graphic

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 Z_PDGFRβ affibody showed high affinity (nM) for PDGFRβ and was predominantly distributed on tumor-associated PDGFRβ-positive pericytes. Co-administration with the Z_PDGFRβ affibody did not significantly enhance the antitumor effect of hTRAIL in mice bearing tumor xenografts. Fusion to the Z_PDGFRβ affibody endows hTRAIL with PDGFRβ-binding ability but does not interfere with its death receptor binding and activation. The fused Z_PDGFRβ 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 Z_PDGFRβ affibody initially accumulated on tumor-associated pericytes and then diffused to the tumor parenchyma over time. Fusion to the Z_PDGFRβ 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 Z_PDGFRβ affibody is an alternative strategy for tumor-targeted delivery of anticancer agents.