Strategy for Traceless Codrug Delivery with Platinum(IV) Prodrug Complexes Using Self-Immolative Linkers.

A common challenge in Pt(IV) prodrug design is the limited repertoire of linkers available to connect the Pt(IV) scaffold with the bioactive payload. The commonly employed linkers are either too stable, leading to a linker artifact on the payload upon release, or too unstable, leading to premature release. In this study, we report the synthesis of a new class of Pt(IV) prodrugs using masked self-immolative 4-aminobenzyl linkers for controlled and traceless codrug delivery. Upon reduction of self-immolative Pt(IV) prodrugs, the detached axial ligands undergo decarboxylation and 1,6-elimination for payload release. Introduction of self-immolative linkers conferred good aqueous stability to the Pt(IV) codrug complex. Investigation revealed that efficient 1,6-elimination could be attributed to stabilization of the p-aza-quinone-methide intermediate. In particular, the self-immolative Pt(IV) prodrugs with cinnamate and coumarin derivatives were more potent than the coadministration of cisplatin with an unconjugated cinnamate or coumarin payload in vitro.

A Cisplatin-Selective Fluorescent Probe for Real-Time Monitoring of Mitochondrial Platinum Accumulation in Living Cells.

Mitochondria have emerged as important targets for cisplatin in cancer therapy. Apart from cisplatin, anticancer Pt complexes based on similar scaffolds have also been developed to target mitochondria. Yet cellular processing of cisplatin or these mitochondria-targeting Pt analogues remained unexplored, largely due to a lack of tools capable of probing these Pt drugs within an intracellular environment. We developed the first mitochondria-targeted fluorescent probe for real-time monitoring of Pt accumulation in mitochondria. We applied the probe to investigate mitochondria as cellular targets for Pt drug complexes and uncovered two distinct pathways whereby these Pt complexes could be delivered to mitochondria after cell entry.

Design and investigation of photoactivatable platinum(iv) prodrug complexes of cisplatin.

Platinum(iv) carboxylate scaffolds have garnered considerable research interest because they can be engineered to function as prodrugs of clinical platinum(ii) anticancer drugs. These platinum(iv) prodrug complexes are stable and tunable, and activated by reduction to release their cytotoxic platinum(ii) cargo. Here we propose new platinum(iv) prodrug complexes designed to release cisplatin via photoreduction upon UV irradiation. The central strategy is to utilise aryl carboxylate ligands on the axial positions of that platinum(iv) scaffold that confer significant UV absorption and would stabilise carboxyl radical formation, thus favouring homolytic Pt-O bond cleavage. We isolated and identified aryl carboxyl radicals via spin-trapping and showed that the photoreduced platinum species mirror cisplatin reactivity toward DNA bases, thereby validating the efficacy of this approach.

Bone Mass, Microstructure, and Strength Can Discriminate Vertebral Fracture in Patients on Long-Term Steroid Treatment.

Context: Measurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) was able to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric bone mineral density (vBMD), microarchitecture, and strength that may increase our understanding of fracture susceptibility. Objective: To ascertain whether vBMD, microarchitecture, and estimated bone strength derived from HR-pQCT can discriminate vertebral fractures in patients with glucocorticoid-induced osteoporosis (GIOP) independent of aBMD. Design: A cross-sectional case-control study. Setting: Seven regional hospitals in Hong Kong. Patients: A total of 110 patients on long-term glucocorticoids with vertebral fracture, determined radiographically, and 110 patients on long-term glucocorticoids without fracture. Main Outcome Measures: We assessed vBMD, microarchitecture, and bone strength; aBMD; and fracture risk assessment tool (FRAX). Results: Patients with vertebral fracture had lower total vBMD and a thinner cortex at the distal tibia after adjustment for age, sex, and aBMD or FRAX. In the antiresorptive treatment-naive subgroup, patients with vertebral fracture also had lower total vBMD at both the distal radius and the tibia after adjustment for covariates. Lower total vBMD and a thinner cortex were also noticed in the nonosteoporotic or FRAX score of <10% subgroups with vertebral fracture and were also associated with increasing prevalence of vertebral fracture. Conclusion: Patients with GIOP and vertebral fracture have a significant reduction in total vBMD and cortical thinning independent of aBMD and FRAX. These changes may help identify high-risk patients in the subgroups currently considered to have low fracture risk as assessed by DXA or FRAX.

Effect of Treat-to-target Strategies Aiming at Remission of Arterial Stiffness in Early Rheumatoid Arthritis: A Randomized Controlled Study.

OBJECTIVE: To determine the efficacy of 2 tight control treatment strategies aiming at Simplified Disease Activity Score (SDAI) remission (SDAI ≤ 3.3) compared to 28-joint count Disease Activity Score (DAS28) remission (DAS28 < 2.6) in the prevention of arterial stiffness in patients with early rheumatoid arthritis (RA). METHODS: This was an open-label study in which 120 patients with early RA were randomized to receive 1 year of tight control treatment. Group 1 (n = 60) aimed to achieve SDAI ≤ 3.3 and Group 2 (n = 60), DAS28 < 2.6. Pulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline and 12 months. A posthoc analysis was also performed to ascertain whether achieving sustained remission could prevent progression in arterial stiffness. RESULTS: The proportions of patients receiving methotrexate monotherapy were significantly lower in Group 1 throughout the study period. At 12 months, the proportions of patients achieving DAS28 and SDAI remission, and the change in PWV and AIx, were comparable between the 2 groups. In view of the lack of differences between the 2 groups, a posthoc analysis was performed at Month 12, including all 110 patients with PWV, to elucidate the independent predictors associated with the change in PWV. Multivariate analysis revealed that achieving sustained DAS28 remission at months 6, 9, and 12 and a shorter disease duration were independent explanatory variables associated with less progression of PWV. CONCLUSION: With limited access to biologic disease-modifying antirheumatic drugs, treatment efforts toward DAS28 and SDAI remission had similar effects in preventing the progression of arterial stiffness at 1 year. However, achieving sustained DAS28 remission was associated with a significantly greater improvement in PWV. [Clinical Trial registration: Clinicaltrial.gov NCT01768923.].

Boston Society's 11th Annual Applied Pharmaceutical Analysis conference.

Boston Society's 11th Annual Applied Pharmaceutical Analysis conference, Hyatt Regency Hotel, Cambridge, MA, USA, 14-16 September 2015 The Boston Society's 11th Annual Applied Pharmaceutical Analysis (APA) conference took place at the Hyatt Regency hotel in Cambridge, MA, on 14-16 September 2015. The 3-day conference affords pharmaceutical professionals, academic researchers and industry regulators the opportunity to collectively participate in meaningful and relevant discussions impacting the areas of pharmaceutical drug development. The APA conference was organized in three workshops encompassing the disciplines of regulated bioanalysis, discovery bioanalysis (encompassing new and emerging technologies) and biotransformation. The conference included a short course titled 'Bioanalytical considerations for the clinical development of antibody-drug conjugates (ADCs)', an engaging poster session, several panel and round table discussions and over 50 diverse talks from leading industry and academic scientists.