Nanoencapsulation of MDM2 Inhibitor RG7388 and Class-I HDAC Inhibitor Entinostat Enhances their Therapeutic Potential Through Synergistic Antitumor Effects and Reduction of Systemic Toxicity.

Inhibitors of the p53-MDM2 interaction such as RG7388 have been developed to exploit latent tumor suppressive properties in p53 in 50% of tumors in which p53 is wild-type. However, these agents for the most part activate cell cycle arrest rather than death, and high doses in patients elicit on-target dose-limiting neutropenia. Recent work from our group indicates that combination of p53-MDM2 inhibitors with the class-I HDAC inhibitor Entinostat (which itself has dose-limiting toxicity issues) has the potential to significantly augment cell death in p53 wild-type colorectal cancer cells. We investigated whether coencapsulation of RG7388 and Entinostat within polymeric nanoparticles (NPs) could overcome efficacy and toxicity limitations of this drug combination. Combinations of RG7388 and Entinostat across a range of different molar ratios resulted in synergistic increases in cell death when delivered in both free drug and nanoencapsulated formats in all colorectal cell lines tested. Importantly, we also explored the in vivo impact of the drug combination on murine blood leukocytes, showing that the leukopenia induced by the free drugs could be significantly mitigated by nanoencapsulation. Taken together, this study demonstrates that formulating these agents within a single nanoparticle delivery platform may provide clinical utility beyond use as nonencapsulated agents.

Practices, perceptions and trust of the public regarding online drug purchasing: a web-based survey from Jordan.

OBJECTIVES: Online purchasing, including drugs, increased dramatically in the last decade especially through the COVID-19 pandemic. The aim of this study was to investigate the frequency and attitudes of consumers concerning online drug purchasing and assess their perceptions regarding the benefits and disadvantages. DESIGN: A web-based survey conducted through a self-administered questionnaire that was approved by the Institutional Review Board (IRB) committee, ethical approval number: IRB/Al-Ahliyya Amman University/3/13/2021-2022. Cronbach's alpha for the attributes of benefits and disadvantages was 0.608 and 0.744, respectively. Primary outcome measures were extent of trust of the public in online drug purchasing using Likert scale. Multivariate linear regression was used to assess predictors of the trust score. SETTINGS: Hashemite Kingdom of Jordan. PARTICIPANTS: Inclusion criteria; residents of the Hashemite Kingdom of Jordan 18 years or older. The questionnaire was distributed through snowball effect via different social media. RESULTS: A total of 428 participants filled the questionnaire, their average age was 29.7±11.2. Almost all participants, 419 (98.6%) use the internet daily but only 79 (18.6%) participants shop online regularly. Fifty participants (11.8%) purchased drugs online and they had higher benefits score of online purchasing compared with those who did not buy drugs online, 12.5±3.7 and 10.9±3.1, respectively, p=0.002. Participant who purchased drugs online had an increase in trust score of 0.847 compared with those who did not purchase drugs online, p<0.001. In the multivariate model, participants with education level of high school or higher than high school, compared with those with education lower than high school had an increase in trust score of 1.336 (p=0.026) and 1.137 (p=0.039), respectively. CONCLUSION: The public recognises the risks in buying drugs online. Awareness campaigns and regulations that control and monitor online drug purchasing should be implemented.

USP17 is required for peripheral trafficking of lysosomes.

Expression of the deubiquitinase USP17 is induced by multiple stimuli, including cytokines (IL-4/6), chemokines (IL-8, SDF1), and growth factors (EGF), and several studies indicate it is required for cell proliferation and migration. However, the mechanisms via which USP17 impacts upon these cellular functions are unclear. Here, we demonstrate that USP17 depletion prevents peripheral lysosome positioning, as well as trafficking of lysosomes to the cell periphery in response to EGF stimulation. Overexpression of USP17 also increases secretion of the lysosomal protease cathepsin D. In addition, USP17 depletion impairs plasma membrane repair in cells treated with the pore-forming toxin streptolysin O, further indicating that USP17 is required for lysosome trafficking to the plasma membrane. Finally, we demonstrate that USP17 can deubiquitinate p62, and we propose that USP17 can facilitate peripheral lysosome trafficking by opposing the E3 ligase RNF26 to untether lysosomes from the ER and facilitate lysosome peripheral trafficking, lysosome protease secretion, and plasma membrane repair.