Targeted Drug Delivery by MMAE Farnesyl-Bioconjugated Multivalent Chemically Self-Assembled Nanorings Induces Potent Receptor-Dependent Immunogenic Cell Death.

Antibody-drug conjugates, nanoparticles, and liposomes have been used for anticancer drug delivery. The success of targeted killing of cancer cells relies heavily on the selectivity of the drug delivery systems. In most systems, antibodies or their fragments were used as targeting ligands. In this study, we have investigated the potential for protein-based octomeric chemically self-assembled nanorings (CSANs) to be used for anticancer drug delivery. The CSANs are composed of a DHFR-DHFR fusion protein incorporating an EGFR-targeting fibronectin and the anticancer drug MMAE conjugated through a C-terminal farnesyl azide. The anti-EGFR-MMAE CSANs were shown to undergo rapid internalization and have potent cytotoxicity to cancer cells across a 9000-fold difference in EGFR expression. In addition, anti-EGFR-MMAE CSANs were shown to induce immunological cell death. Thus, multivalent and modular CSANs are a potential alternative anticancer drug delivery platform with the capability of targeting tumor cells with heterogeneous antigen expression while activating the anticancer immune response.

Comparison of the effectiveness and safety of the "endoscope-assisted polypropylene mesh lift" and "gliding brow lift" techniques for the treatment of lateral brow ptosis.

BACKGROUND: There are many techniques used to treat lateral brow ptosis. This study compared two techniques that are used for lateral brow rejuvenation in terms of effectiveness and safety-namely, endoscope-assisted polypropylene mesh lift (EAML) and gliding brow lift (GBL). METHOD: Eighty-six patients who underwent brow lift surgery between March 2018 and June 2020 were included in this retrospective study. Forty-four patients were operated on using the EAML technique, whereas 42 patients were operated on using the GBL technique. The measurement of defined distances in photographs was carried out using a software, and the Brow Positioning Grading Scale (BPGS) and Global Aesthetic Improvement Scale (GAIS) were applied in the pre and postoperative periods. RESULTS: The measurement results obtained in the postoperative period were better than those obtained in the preoperative period for both the techniques, whereas the results obtained at postoperative month 3 were found to be better than those obtained at month 12 (p < 0.05). The results were similar between the measurements at postoperative months 3 and 12 for both the techniques. The loss of brow height from postoperative months 3-12 was greater in the GBL group (p < 0.05). The postoperative scores on the BPGS were found to be better in both techniques than the preoperative scores (p < 0.05). The GAIS score at postoperative month 12 was found to be better in the EAML group. The two groups had similar rates of complications. CONCLUSION: The two techniques were found to have similar effectiveness and safety profiles for brow rejuvenation.

Anti-EGFR Fibronectin Bispecific Chemically Self-Assembling Nanorings (CSANs) Induce Potent T Cell-Mediated Antitumor Responses and Downregulation of EGFR Signaling and PD-1/PD-L1 Expression.

Overexpression of the epidermal growth factor receptor (EGFR) on various cancers makes it an important target for cancer immunotherapy. We recently demonstrated that single-chain variable fragment-based bispecific chemically self-assembled nanorings (CSANs) can successfully modify T cell surfaces and function as prosthetic antigen receptors (PARs) allowing selective targeting of tumor antigens while incorporating a dissociation mechanism of the rings. Here, we report the generation of anti-EGFR fibronectin (FN3)-based PARs with high yield, rapid protein production, predicted low immunogenicity, and increased protein stability. We demonstrated the cytotoxicity of FN3-PARs successfully while evaluating FN3 affinities, CSAN valencies, and antigen expression levels. Using an orthotopic breast cancer model, we showed that FN3-PARs can suppress tumor growth with no adverse effects and FN3-PARs reduced immunosuppressive programmed cell death ligand-1 (PD-L1) expression by downregulating EGFR signaling. These results demonstrate the potential of FN3-PARs to direct selective T cell-targeted tumor killing and to enhance antitumor T cell efficacy by modulating the tumor microenvironment.