Phytoestrogen-derived multifunctional ligands for targeted therapy of breast cancer

Nano-targeted delivery systems have been widely used for breast tumor drug delivery.Estrogen receptors are considered to be significant drug delivery target receptors due to their overexpression in a variety of tumor cells.However,targeted ligands have a significant impact on the safety and effectiveness of active delivery systems,limiting the clinical transformation of nanoparticles.Phytoestrogens have shown good biosafety characteristics and some affinity with the estrogen receptor.In the present study,molecular docking was used to select tanshinone IIA(Tan IIA)among phytoestrogens as a target ligand to be used in nanodelivery systems with somemodifications.Modified Tan IIA(Tan-NH2)showed a good biosafety profile and demonstrated tumor-targeting,anti-tumor and anti-tumor metastasis effects.Moreover,the ligand was utilized with the anti-tumor drug Dox-loaded mesoporous silica nanoparticles via chemical modification to generate a nanocomposite Tan-Dox-MSN.Tan-Dox-MSN had a uniform particle size,good dispersibility and high drug loading capacity.Validation experiments in vivo and in vitro showed that it also had a better targeting ability,anti-tumor effect and lower toxicity in normal organs.These results supported the idea that phytoestrogens with high affinity for the estrogen receptor could improve the therapeutic efficacy of nano-targeted delivery systems in breast tumors.

Honeycomb-Like Hydrogel Microspheres for 3D Bulk Construction of Tumor Models

A two-dimensional(2D)cell culture-based model is widely applied to study tumorigenic mechanisms and drug screening.However,it cannot authentically simulate the threedimensional(3D)microenvironment of solid tumors and provide reliable and predictable data in response to in vivo,thus leading to the research ilusionis and failure of drug screening.In this study,honeycomb-like gelatin methacryloyl(GelMA)hydrogel microspheres are developed by synchronous photocrosslinking microluidic technique to construct a 3D model of osteosarcoma.The in vitro study shows that ostcosarcoma cells(K7M2)culured in 3D GelMA microspheres have stronger tumorous stemness。proliferation and migration abilitics,more osteoclastogenetic ability,and reistance to chemotherapeutic drugs(DOX)than that of cells in 2D cultures.More imporantly,the 3D-cultured K7M2 cells show more tumorigenicity in immunologically sound mice,characterized by shorter tumorigenesis time,larger tumor volumc,severe bone destruction,and higher mortality.In conclusion,honeycomb like porous microsphere scaffolds are constructed with uniform structure by micofluidic technology to massively produce tumor cells with original phenotypes.Those microspheres could recapitulate the physiology microenvironment of tumors.maintain ell-cell and cell-extracellular matrix interactions,and thus provide an efective and convenient strategy for tumor pathogenesis and drug screening research.

Piezo1-targeted aerosol inhalation nanoparticles for acute lung injury

Inhaled drug-containing nanocarriers have been well applied as an important strategy in pulmonary dis-eases.Acute lung injury(ALI)is characterized by abnormal lung tension and complex pathogenesis,with high mortality because of the limitations of targeted intervention.Accordingly,in the present study,we first identified that the mechanosensitive ion channel Piezo1 participated in the ALI-associated processes induced by lipopolysaccharide(LPS)in vitro and in vivo.Then,chitosan-stabilized bovine serum albu-min nanoparticles(NCs)emulsified with the Piezo1 inhibitor GsMTx4(NC-GsMTx4)were generated and exhibited excellent biocompatibility and biological function.Through aerosol inhalation,NC-GsMTx4 im-proved lung injury and inhibited cell apoptosis in LPS-stressed ALI mice and alleviated pulmonary fibrosis during the later stage of ALI.Mechanistically,GsMTx4 could regulate inflammation and apoptosis in lung epithelial cells via NF-κB and ERK1/2 signaling.In summary,our findings provide new insights into the pathological mechanisms of Piezo1 in ALI progression,and nebulized inhalation of NC-GsMTx4 offers a prospective platform for targeting Piezo1 to treat ALI efficiently and conveniently.