Multicellular biology, as well as new cell based therapies, are dependent on the control of cell-cell interactions. Herein, we detail the use of a multivalent lipidated scaffold for the rapid...

Numerous approaches have targeted the Epidermal Growth Factor Receptor (EGFR) for the development of anti-cancer therapeutics, since it is over-expressed on a variety of cancers. Recently, EGFR chimeric antigen receptor (CAR)-T cells have shown potential promise for the immunological control of tumors.Our laboratory has recently demonstrated that bispecific chemically self-assembled nanorings (CSANs) can modify T cell surfaces and function as prosthetic antigen receptors (PARs). This technology allows selective targeting of tumor antigens due to high avidity of the multimeric rings, while incorporating a mechanism to dissociate the rings to prevent further T cell stimulation. Previously, PARs with singlechain variable fragments (scFvs) have been successful in vitro and in vivo, activating T cells selectively at the tumor site. Alternatively, here we report fibronectin (FN3)-based PARs with improved properties such as increased protein yield, rapid protein production, increased protein stability and predicted low immunogenicity due to the human origin of fibronectins. We examined the cytotoxicity of EGFRtargeting PARs in vitro in which the affinities of the EGFR fibronectins, the EGFR/CD3 valency of the CSANs and the antigen expression levels were varied. Based on these selective in vitro cytotoxicity results, we conducted an in vivo study of FN3-PARs using an orthotopic breast cancer model. The FN3-PARs demonstrated potent tumor growth suppression with no adverse effects. Furthermore, these results demonstrated that FN3-PARs modulated the tumor microenvironment by downregulating EGFR signaling resulting in decreased PD-L1 expression. In addition, the expression of PD-1 was also found to be reduced. Collectively, these results demonstrate that FN3-PARs have the potential to direct selective T cell targeted tumor killing and that EGFR FN3-PARs may enhance anti-tumor T cell efficacy by modulating the tumor microenvironment.

Inspired by the natural intercellular material-transfer process of trans-endocytosis or trogocytosis, we proposed that targeted farnesylated chemically self-assembled nanorings (f-CSANs) could serve as a biomimetic trogocytosis vehicle for engineering directional cargo transfer between cells, thus allowing cell–cell interactions to be monitored and facilitating cell–cell communications. The membranes of sender cells were stably modified by hydrophobic insertion with the targeted f-CSANs, which were efficiently transferred to receiver cells expressing the appropriate receptors by endocytosis. CSAN-assisted cell–cell cargo transfer (C4T) was demonstrated to be receptor specific and dependent on direct cell–cell interactions, the rate of receptor internalization, and the level of receptor expression. In addition, C4T was shown to facilitate cell-to-cell delivery of an apoptosis inducing drug, as wells as antisense oligonucleotides. Taken together, the C4T approach is a potentially versatile biomimetic trogocytosis platform that can be deployed as a macro-chemical biological tool for monitoring cell–cell interactions and engineering cell–cell communications.

The training of new medicinal chemists is vital to the future of the field, and as graduate students at this critical stage, we are uniquely positioned to comment on our training. Herein, we discuss the perspectives from graduate researchers before, during, and after graduate school by utilizing survey data obtained from five medicinal chemistry programs in the Midwest and recent alumni of the University of Minnesota. We also reflect on the female perspective within the field of medicinal chemistry. Finally, we offer recommendations to both students and faculty in the hopes of helping future generations succeed in the field.

With the recent success of cell-based therapies, there has been a rapidly emerging interest in the engineering of cell-cell interactions and communications. Inspired by the natural intercellular material transfer process of trans-endocytosis or trogocytosis, we proposed that targeted farnesylated chemically self-assembled nanorings (farnesyl-CSANs) could serve as a biomimetic trogocytosis vehicle for engineering directional cargo transfer between cells; thus, allowing cell-cell interactions to be monitored, as well as facilitating communication between the cells by delivery of bioactive species. The membranes of sender cells were stably modified by hydrophobic insertion with the targeted farnesyl-CSANs and to be efficiently transferred to receiver cells expressing the appropriate receptor by endocytosis. CSAN-assisted cell-cell cargo transfer (C4T) was demonstrated to be receptor-specific and dependent on direct cell-cell interactions, the rate of receptor internalization and the amount of receptor expression. In addition, C4T was shown to facilitate cell-to-cell delivery of an apoptosis inducing drug, as wells as antisense oligonucleotides (ASO). Taken together, the C4T approach is a potentially versatile biomimetic trogocytosis platform that can be used to monitor cell-cell interactions, as well as the engineering of cell-cell communications, such as cell-based drug delivery.