Exosome-based rare earth nanoparticles for targeted in situ and metastatic tumor imaging with chemo-assisted immunotherapy

In this research, a tumor exosome system DOX/2DG@E-RENPs with good biocompatibility, low immunogenicity, and high targeting effect was proposed for theranostics with high chemo-/starvation/immunotherapy efficiency. DOX and 2-deoxy-D-glucose (DOX/2DG) together...

Combined integrin αvβ3 and lactoferrin receptor targeted docetaxel liposomes enhance the brain targeting effect and anti-glioma effect

The integrin αvβ3 receptor and Lactoferrin receptor (LfR) are over-expressed in both cerebral microvascular endothelial cells and glioma cells. RGD tripeptide and Lf can specifically bind with integrin αvβ3 receptor and LfR, respectively. In our study, RGD and Lf dual-modified liposomes loaded with docetaxel (DTX) were designed to enhance the brain targeting effect and treatment of glioma. Our in vitro studies have shown that RGD-Lf-LP can significantly enhance the cellular uptake of U87 MG cells and human cerebral microvascular endothelial cells (hCMEC/D3) when compared to RGD modified liposomes (RGD-LP) and Lf modified liposomes (Lf-LP). Free RGD and Lf competitively reduced the cellular uptake of RGD-Lf-LP, in particular, free RGD played a main inhibitory effect on cellular uptake of RGD-Lf-LP in U87 MG cells, yet free Lf played a main inhibitory effect on cellular uptake of RGD-Lf-LP in hCMEC/D3 cells. RGD-Lf-LP can also significantly increase penetration of U87 MG tumor spheroids, and RGD modification plays a dominating role on promoting the penetration of U87 MG tumor spheroids. The results of in vitro BBB model were shown that RGD-Lf-LP-C6 obviously increased the transport of hCMEC/D3 cell monolayers, and Lf modification plays a dominating role on increasing the transport of hCMEC/D3 cell monolayers. In vivo imaging proved that RGD-Lf-LP shows stronger targeting effects for brain orthotopic gliomas than that of RGD-LP and Lf-LP. The result of tissue distribution confirmed that RGD-LF-LP-DTX could significantly increase brain targeting after intravenous injection. Furthermore, RGD-LF-LP-DTX (a dose of 5 mg kg−1 DTX) could significantly prolong the survival time of orthotopic glioma-bearing mice. In summary, RGD and LF dual modification are good combination for brain targeting delivery, RGD-Lf-LP-DTX could enhance brain targeting effects, and is thus a promising chemotherapeutic drug delivery system for treatment of glioma. Graphical abstract

Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance

Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.

Efficacy and Selectivity of FGF2-Saporin Cytosolically Delivered by PCI in Cells Overexpressing FGFR1

Fibroblast growth factor receptors (FGFRs) have become an attractive target in cancer research and therapy due to their implication in several cancers. Limitations of current treatment options require a need for additional, more specific and potent strategies to overcome cancers driven by FGFRs. Photochemical internalization (PCI) is a light-controlled method for cytosolic delivery of drugs that are entrapped in endosomes and lysosomes. We here evaluated the efficacy and selectivity of PCI of FGF2-saporin (FGF-SAP) in cells overexpressing FGFR1. FGF-SAP is a conjugate of FGF2 and the highly cytotoxic ribosome-inactivating protein (RIP) saporin, which is used as payload to eliminate cancer cells. Evaluation of the targeting effect of PCI of FGF-SAP was done by comparing the cytotoxic response in osteosarcoma cells with very low levels of FGFR1 (U2OS) to cells overexpressing FGFR1 (U2OS-R1). We demonstrate that PCI greatly enhances cytotoxicity of the drug showing efficient cell killing at pM concentrations of the drug in U2OS-R1 cells. However, U2OS cells were also sensitive to the toxin after PCI. Binding experiments using confocal microscopy and Western blotting techniques indicate that FGF-SAP is taken up by cells through heparan sulfate proteoglycans (HSPGs) in U2OS cells. We further show that the cytotoxicity of FGF-SAP in U2OS cells was reduced when cells were co-treated with heparin to compete out binding to HSPG, demonstrating that the cytotoxic effect was due to internalization by HSPGs. We conclude that to prevent off-target effects of FGF-based toxins, it will be necessary to circumvent binding to HSPGs, for example by mutating the binding site of FGF2 to HSPGs.

A core-shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity

Although inoculation of COVID-19 vaccines has rolled out globally, there is still a critical need for safe and effective vaccines to ensure fair and equitable supply for all countries. Here, we report on the development of a highly efficacious mRNA vaccine, SW0123 that is composed of sequence-modified mRNA encoding the full-length SARS-CoV-2 Spike protein packaged in core–shell structured lipopolyplex (LPP) nanoparticles. SW0123 is easy to produce using a large-scale microfluidics-based apparatus. The unique core–shell structured nanoparticle facilitates vaccine uptake and demonstrates a high colloidal stability, and a desirable biodistribution pattern with low liver targeting effect upon intramuscular administration. Extensive evaluations in mice and nonhuman primates revealed strong immunogenicity of SW0123, represented by induction of Th1-polarized T cell responses and high levels of antibodies that were capable of neutralizing not only the wild-type SARS-CoV-2, but also a panel of variants including D614G and N501Y variants. In addition, SW0123 conferred effective protection in both mice and non-human primates upon SARS-CoV-2 challenge. Taken together, SW0123 is a promising vaccine candidate that holds prospects for further evaluation in humans.