Long-circulating doxorubicin and Schizandrin A liposome with drug-resistant liver cancer activity: in vitro and in vivo evaluation.

Co-loading doxorubicin (DOX) and Schizandrin A (SchA) long-circulating liposome (SchA-DOX-Lip) have been confirmed to have good antitumor activity in vitro. However, in vivo pharmacodynamics, targeting, safety, and mechanism of action of SchA-DOX-Lip still need to be further verified. We investigated the tumor inhibition effect, targeting, safety evaluation, and regulation of tumor apoptosis-related proteins of the SchA-DOX-Lip. MTT assay was used to investigate the inhibitory effect of SchA-DOX-Lip on CBRH7919 cells. The drug uptake of CBRH7919 cells was observed by inverted fluorescence microscope. The tumor-bearing nude mice models of CBRH7919 were established, and the anti-tumor effect of SchA-DOX-Lip in vivo was evaluated by tumor biological observation, H&E staining, and TUNEL staining. The distribution and targeting of SchA-DOX-Lip in nude mice models were investigated by small animal imaging and tissue distribution experiment of CBRH7919. The biosafety of SchA-DOX-Lip was evaluated by blood routine parameters, biochemical indexes, and H&E staining. The expression of tumor-associated apoptotic proteins (Bcl-2, Bax, and Caspase-3) was detected by immunohistochemistry anvd western blotting. The results showed that SchA-DOX-Lip had cytotoxicity to CBRH7919 cells which effectively inhibited the proliferation of CBRH7919 cells, improved the uptake of drugs by CBRH7919 cells and the targeting effect of drugs on tumor site. H&E staining and biochemical detection results showed that SchA-DOX-Lip had high biosafety and did not cause serious damage to normal tissues. Western-blotting and TUNEL staining results showed that SchA-DOX-Lip could improve the regulatory effect of drugs on tumor apoptosis proteins. It was demonstrated that SchA-DOX-Lip had high safety and strong tumor inhibition effects, providing a new method for the clinical treatment of hepatocellular carcinoma (HCC).

An artificial blood vessel implanted three-dimensional microsystem for modeling transvascular migration of tumor cells.

Reproducing a tumor microenvironment consisting of blood vessels and tumor cells for modeling tumor invasion in vitro is particularly challenging. Here, we report an artificial blood vessel implanted 3D microfluidic system for reproducing transvascular migration of tumor cells. The transparent, porous and elastic artificial blood vessels are obtained by constructing polysaccharide cellulose-based microtubes using a chitosan sacrificial template, and possess excellent cytocompatibility, permeability, and mechanical characteristics. The artificial blood vessels are then fully implanted into the collagen matrix to reconstruct the 3D microsystem for modeling transvascular migration of tumor cells. Well-defined simulated vascular lumens were obtained by proliferation of the human umbilical vein endothelial cells (HUVECs) lining the artificial blood vessels, which enables us to reproduce structures and functions of blood vessels and replicate various hemodynamic parameters. Based on this model, the adhesion and transvascular migration of tumor cells across the artificial blood vessel have been well reproduced.

Engineering interconnected 3D vascular networks in hydrogels using molded sodium alginate lattice as the sacrificial template.

Engineering 3D perfusable vascular networks in vitro and reproducing the physiological environment of blood vessels is very challenging for tissue engineering and investigation of blood vessel function. Here, we engineer interconnected 3D microfluidic vascular networks in hydrogels using molded sodium alginate lattice as sacrificial templates. The sacrificial templates are rapidly replicated in polydimethylsiloxane (PDMS) microfluidic chips via Ca⁺²-crosslinking and then fully encapsulated in hydrogels. Interconnected channels with well controlled size and morphology are obtained by dissolving the monolayer or multilayer templates with EDTA solution. The human umbilical vein endothelial cells (HUVECs) are cultured on the channel linings and proliferated to form vascular lumens. The strong cell adhesion capability and adaptive response to shear stress demonstrate the excellent cytocompatibility of both the template and template-sacrificing process. Furthermore, the barrier function of the endothelial layer is characterized and the results show that a confluent endothelial monolayer is fully developed. Taken together, we develop a facile and rapid approach to engineer a vascular model that could be potentially used in physiological studies of vascular functions and vascular tissue engineering.