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To develop computed tomography (CT)-based models to increase the prediction accuracy of spread through air spaces (STAS) in clinical-stage T1N0 lung adenocarcinoma.

Fabry disease is a lysosomal storage disorder caused by the deficiency of α-galactosidase A. Enzyme deficiency results in a progressive decline in renal and cardiac function, leading to cardiomyopathy and end-stage renal disease. Current treatments available, including enzyme replacement therapies, have provided significant benefit to patients; however, unmet medical needs remain. mRNA therapy, with drug-like properties, has the unique ability to produce therapeutic proteins endogenously. Here we describe the sustained delivery of therapeutic human α-galactosidase protein in vivovia nanoparticle-formulated mRNA in mouse and non-human primate, with a demonstration of efficacy through clinically relevant biomarker reduction in a mouse Fabry disease model. Multi-component nanoparticles formulated with lipids and lipid-like materials were developed for the delivery of mRNA encoding human α-galactosidase protein. Upon delivery of human GLA mRNA to mice, serum GLA protein levels reached as high as ∼1,330-fold over normal physiological values.

Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.

It is a commonly held belief that most treatments for disseminated cancers are only moderately effective because the agents lack cell-killing mechanisms that act specifically on cancer cells. In antibody–drug conjugates, such nonspecific cytotoxic agents are combined with exquisitely specific monoclonal antibodies that bind to tumour-associated antigens and, thus, get endowed with new pharmacological characteristics. Not only is their activity newly targeted towards tumours and tumour cells, which hopefully renders them more tumour-specific, but they also acquire much of the pharmacokinetic behaviour of the monoclonal antibody component. With the structural composition of a macromolecular protein (the antibody), a small chemical cytotoxic agent and a linker to chemically connect these two molecules, antibody–drug conjugates are some of the most complex pharmacological agents ever developed. Their development over the last 20 years or so owes much to sophisticated in vitro and in vivo preclinical testing. This review attempts to summarise and exemplify many of the factors that had to be considered during the development, with special emphasis on the in vivo pharmacology of these agents.