Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy.

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvß3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

Study of vascular sclerosing agent based on the dual mechanism of vascular endothelial cell damage-plasmin system inhibition.

Venous malformations are a vascular disorder. Currently, the use of chemical sclerosing agents is a common clinical approach for the treatment of venous malformations. However, the effectiveness of existing sclerosing agents is unsatisfactory and often accompanied by severe side effects. In this study, we have developed a novel cationic surfactant-based sclerosing agent (POL-TA) by conjugating the plasmin inhibitor tranexamic acid (TA) with a nonionic surfactant polidocanol (POL) through an ester bond. POL-TA induces endothelial cell damage, triggering the coagulation cascade and thrombus formation. Moreover, it releases TA in vivo, which inhibits plasmin activity and the activation of matrix metalloproteinase (MMPs), thereby stabilizing the fibrin network of the thrombus and promoting vascular fibrosis. We have established a cell model using venous malformation endothelial cells and assessed the cellular damage and underlying mechanisms of POL-TA. The inhibitory effects of POL-TA on the plasmin-MMPs system were evaluated using MMP-9 activity assay kit. Additionally, the mice tail vein model was employed to investigate the vascular sclerosing effects and mechanisms of POL-TA.

Erythrocyte Membrane-Coated Invisible Acoustic-Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

Fabrication of human serum albumin-imprinted photothermal nanoparticles for enhanced immunotherapy.

Photothermal nanoparticles have been confirmed to induce an antitumor immune response and turn "cold tumor" into "hot tumor". However, their delivery efficacy to tumors is limited by the elimination from the reticalendothel system. Herein, human serum albumin (HSA)-imprinted polymer coated Fe3O4 nanoparticles (Fe3O4@MIPs) are fabricated by oxidative polymerization of dopamine in the presence of HSA on the polydopamine pre-modified Fe3O4 nanoparticle surface, followed by the removal of HSA. The Fe3O4@MIPs exhibit rapid and specific reabsorption toward HSA. The molecularly imprinted sites on the Fe3O4@MIPs endow it with an albumin-rich protein corona in the blood and result in less elimination from the reticalendothel system than non-albumin-imprinted particles (Fe3O4@NIPs). Moreover, the molecularly imprinted polymer, which consists of polydopamine, also improves the photothermal effect of Fe3O4 nanoparticles. In vivo, the albumin camouflage in Fe3O4@MIPs produces a 2.6-fold improvement in tumor accumulation in comparison to Fe3O4@NIPs, and more heat is produced upon 808 nm laser irradiation, which further triggers an efficient immunogenic cell death (ICD) progress. Thus, the combination of Fe3O4@MIPs and PD-L1 antibody can not only inhibit the growth of primary tumors but also eliminates lung metastasis by eliciting immunological effect.

Tumor Microenvironment Stimuli-Responsive Nanoparticles for Programmed Anticancer Drug Delivery.

It is well-known that large size nanoparticles stay for a long time in the circulation system, but show poor tissue penetration and low cellular uptake. In order to reconcile the conflicting needs for extended circulation time, extensive tumor tissue penetration, and enhanced cellular uptake for nanodrug delivery systems, we designed DOX-containing hypersensitive nanoparticles that responded to the tumor microenvironment for programmed DOX delivery. A supersensitive polymer material, poly(2-ethyl-2-oxazoline)-poly(methacryloyl sulfadimethoxine), was synthesized (PEOz-b-PSD, pKa = 6.96). At the physiological environment, PEOz-b-PSD and polyamidoamine/DOX (PAMAM/DOX) can form nanoparticles, PEOz-b-PSD/PAMAM/DOX (PEPSD/PAM/DOX), via electrostatic adsorption. The PEPSD/PAM/DOX has an intact structure, which can prolong circulation time. While in the tumor environment, the PEOz-b-PSD was rapidly protonated and showed charge reversal, leading the detachment of PEOz-b-PSD from the nanoparticles; then the large size nanoparticles with a negative charge (PEPSD/PAM/DOX) instantaneously turn into positively charged ultrafine nanoparticles. The sudden inversion of size and charge can effectively improve tumor accumulation and internal penetration. After entering tumor cells, nanoparticles can release drugs quickly through the action of a PAMAM proton sponge, resulting in enhanced tumor inhibition. Our results proved that the programmed nanoparticles could remarkably enhance the in vivo antitumor efficacy and reduce cardiotoxicity of DOX. This study designed ultrasensitive nanoparticles in the tumor microenvironment, which appear to be beneficial for enhancing the treatment efficacy of DOX in solid tumors.

[Application of maxillary wings guiding plate in rehabilitation of combined defects of maxilla and mandible].

PURPOSE: To evaluate the role of maxillary wings guiding plate in rehabilitation of combined defects of maxilla and mandible in convalescent stage. METHODS: Combined resection of maxilla and mandible without reconstruction were performed in 10 patients with oral cancers. The impressions were got in 2 patients preoperatively and 8 patients postoperatively because of preoperative limited mouth opening. The clasps were designed to provide the retentive force according to the remained teeth. The plastic palate baseboard with wings guiding plate was made. The patients wore the plate 1 week after surgery. RESULTS: All the patients get good velopharyngeal competence and occlusion without leakage from nose after using this prosthesis for 1 to 3 months. CONCLUSIONS: Palate baseboard combined with wings guiding plate can not only obstruct the nasal-oral fistula but also correct malocclusion. It's convenient for taking dental prosthesis in late stage and improving patient's quality of life. Supported by Research Fund of Science and Technology Commission of Shanghai Municipality(Grant No.08DZ2271100).