Light induced drug release from a folic acid-drug conjugate.

A major area of cancer research focuses on improving the specificity of therapeutic agents by engineering drug-delivery vehicles that target overexpressed receptors on tumor cells. One of the most commonly used approaches involves targeting of folate receptors using folic acid conjugated to a drug-containing macromolecular cargo. Once internalized via endocytosis, the drugs must be released from these constructs in order to avoid being trapped in the endosomes. Here, we describe the synthesis of a small-molecule conjugate that couples folic acid to doxorubicin via a photocleavable linker. Using HPLC we show that the doxorubicin can be released with light rapidly and with high efficiency. This approach has advantages over macromolecular systems due to its simplicity and efficiency.

Photoswitchable anticancer activity via trans-cis isomerization of a combretastatin A-4 analog.

Combretastatin A-4 (CA4) is highly potent anticancer drug that acts as an inhibitor of tubulin polymerization. The core of the CA4 structure contains a cis-stilbene, and it is known that the trans isomer is significantly less potent. We prepared an azobenzene analog of CA4 (Azo-CA4) that shows 13-35 fold enhancement in potency upon illumination. EC50 values in the light were in the mid nM range. Due to its ability to thermally revert to less toxic trans form, Azo-CA4 also has the ability to automatically turn its activity off with time. Azo-CA4 is less potent than CA-4 because it degrades in the presence of glutathione as evidenced by UV-Vis spectroscopy and ESI-MS. Nevertheless, Azo-CA4 represents a promising strategy for switchable potency for treatment of cancer.

Teaching evidence-based medicine skills can change practice in a community hospital.

OBJECTIVES: Several studies have evaluated whether evidence-based medicine (EBM) training courses can improve skills such as literature searching and critical appraisal but to date, few data exist on whether teaching EBM skills and providing evidence-based resources result in change in behavior or clinical outcomes. This study was conducted to evaluate whether a multifaceted EBM intervention consisting of teaching EBM skills and provision of electronic evidence resources changed clinical practice. DESIGN: Before/after study. SETTING: The medical inpatient units at a district general hospital. PARTICIPANTS: Thirty-five attending physicians and 12 medicine residents. INTERVENTION: A multicomponent EBM intervention was provided including an EBM training course of seven 1-hour sessions, an EBM syllabus and textbook, and provision of evidence-based resources on the hospital network. MEASUREMENTS AND MAIN RESULTS: The primary outcome of the study was the quality of evidence in support of therapies initiated for the primary diagnoses in 483 consecutive patients admitted during the month before and the month after the intervention. Patients admitted after implementation of the EBM intervention were significantly more likely to receive therapies proven to be beneficial in randomized controlled trials (62% vs 49%; P= .016). Of these trial-proven therapies, those offered after the EBM intervention were significantly more likely to be based on high-quality randomized controlled trials (95% vs 87%; P= .023). CONCLUSIONS: A multifaceted intervention designed to teach and support EBM significantly improved evidence-based practice patterns in a district general hospital.