PEGylated dendrimers are attractive for biological applications due to their tunable pharmacokinetics and ability to carry multiple copies of bioactive molecules. The rapid and efficient synthesis of a robust and biodegradable PEGylated dendrimer based on a polyester-polyamide hybrid core is described. The architecture is designed to avoid destructive side-reactions during dendrimer preparation while maintaining biodegradability. Therefore, a dendrimer functionalized with doxorubicin (Dox) was prepared from commercial starting materials in nine, high-yielding linear steps. Both the dendrimer and Doxil™ were evaluated in parallel using equimolar dosage in the treatment of C26 murine colon carcinoma, leading to statistically equivalent results with most mice tumor-free at the end of the sixty day experiment. The attractive features of this dendritic drug carrier are its simple synthesis, biodegradability, and versatility for application to a variety of drug payloads with high drug loadings.

Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4CD8 (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORγT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)α selection. Strikingly, pharmacological inhibition of RORγ skews TCRα gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORγT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens. The analysis of RORγ inhibitors has allowed us to gain a broader perspective of the diverse function of RORγT and its impact on T cell biology.

Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]­pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]­pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.

For the past 40 years, liposomal and polymeric delivery vehicles have been studied as systems capable of modulating the cytotoxicity of small molecule chemotherapeutics, increasing tumor bearing animal survival times, and improving drug targeting. Although a number of macromolecular-drug conjugates have progressed to clinical trials, tuning drug release to maintain efficacy in conjunction with controlling drug toxicity has prevented the clinical adoption of many vehicles. In this article, we review the motivations for and approaches to polymer and liposomal delivery with regard to camptothecin and cisplatin delivery.