A carrier free delivery system of a MAGL inhibitor is effective on ovarian cancer.

Monoacylglycerol lipase (MAGL) is a promising target for cancer therapy due to its involvement in lipid metabolism and its impact on cancer hallmarks like cell proliferation, migration, and tumor progression. A potent reversible MAGL inhibitor, MAGL23, has been recently developed by our group, demonstrating promising anticancer activities. To enhance its pharmacological properties, a nanoformulation using nanocrystals coated with albumin was prepared (MAGL23AF). In a previous work, the formulated inhibitor showed to maintain its potency in ovarian and colon cancer cell lines in terms of IC50, and the formulation was tested on mice in order to assess its biocompatibility, organs biodistribution and toxicity. In the present work, we expanded the investigation to assess the potential in vivo application of MAGL23AF. Stability assays in serum and in human derived microsomes showed a good structural stability in physiological conditions of MAGL23AF. Antitumor efficacy tested on mice bearing ovarian cancer tumor highlighted that MAGL23AF has a more potent antitumor efficacy compared to non-formulated drug and leads to a necrosis-driven cancer cell death. In vivo studies revealed that albumin-complexed nanocrystals improved the therapeutic window of MAGL23, exhibiting a favorable biodistribution with slightly increased accumulation in the tumor. In conclusion, the MAGL23AF showed increased in vitro stability in conditions mirroring the bloodstream environment and hepatic metabolism coupled with an optimal antitumor efficacy in vivo. These results not only validates the efficacy of our formulation but also positions it as a promising strategy for addressing challenges related to the solubility of drugs in body fluids.

Microfluidic production of amiodarone loaded nanoparticles and application in drug repositioning in ovarian cancer.

Amiodarone repositioning in cancer treatment is promising, however toxicity limits seem to arise, constraining its exploitability. Notably, amiodarone has been investigated for the treatment of ovarian cancer, a tumour known for metastasizing within the peritoneal cavity. This is associated with an increase of fatty acid oxidation, which strongly depends on CPT1A, a transport protein which has been found overexpressed in ovarian cancer. Amiodarone is an inhibitor of CPT1A but its role still has to be explored. Therefore, in the present study, amiodarone was tested on ovarian cancer cell lines with a focus on lipid alteration, confirming its activity. Moreover, considering that drug delivery systems could lower drug side effects, microfluidics was employed for the development of drug delivery systems of amiodarone obtaining simultaneously liposomes with a high payload and amiodarone particles. Prior to amiodarone loading, microfluidics production was optimized in term of temperature and flow rate ratio. Moreover, stability over time of particles was evaluated. In vitro tests confirmed the efficacy of the drug delivery systems.

A carrier free delivery system of a monoacylglycerol lipase hydrophobic inhibitor.

Monoacylglycerol lipase (MAGL) is an emerging therapeutic target for cancer. It is involved in lipid metabolism and its inhibition impairs many hallmarks of cancer including cell proliferation, migration/invasion and tumor growth. For these reasons, our group has recently developed a potent reversible MAGL inhibitor (MAGL23), which showed promising anticancer activities. Here in, to improve its pharmacological properties, a nanoformulation based on nanocrystals coated with albumin was prepared for therapeutic applications. MAGL23 was solubilized by a nanocrystallization method with Pluronic F-127 as surfactant into an organic solvent and was recovered as nanocrystals in water after solvent evaporation. Finally, the solubilized nanocrystals were stabilized by human serum albumin to create a smart delivery carrier. An in-silico prediction (lipophilicity, structure at different pH and solubility in water), as well as experimental studies (solubility), have been performed to check the chemical properties of the inhibitor and nanocrystals. The solubility in water increases from less than 0.01 mg/mL (0.0008 mg/mL, predicted) up to 0.82 mg/mL in water. The formulated inhibitor maintained its potency in ovarian and colon cancer cell lines as the free drug. Furthermore, the system was thoroughly observed at each step of the solubilization process till the final formulation stage by different spectroscopic techniques and a comparative study was performed to check the effects of Pluronic F-127 and CTAB as surfactants. The formulated system is favorable to release the drug at physiological pH conditions (at pH 7.4, after 24 h, less than 20% of compound is released). In vivo studies have shown that albumin-complexed nanocrystals increase the therapeutic window of MAGL23 along with a favorable biodistribution. As per our knowledge, we are reporting the first ever nanoformulation of a MAGL inhibitor, which is promising as a therapeutic system where the MAGL enzyme is involved, especially for cancer therapeutic applications.

Microfluidic Organoids-on-a-Chip: Quantum Leap in Cancer Research.

Organ-like cell clusters, so-called organoids, which exhibit self-organized and similar organ functionality as the tissue of origin, have provided a whole new level of bioinspiration for ex vivo systems. Microfluidic organoid or organs-on-a-chip platforms are a new group of micro-engineered promising models that recapitulate 3D tissue structure and physiology and combines several advantages of current in vivo and in vitro models. Microfluidics technology is used in numerous applications since it allows us to control and manipulate fluid flows with a high degree of accuracy. This system is an emerging tool for understanding disease development and progression, especially for personalized therapeutic strategies for cancer treatment, which provide well-grounded, cost-effective, powerful, fast, and reproducible results. In this review, we highlight how the organoid-on-a-chip models have improved the potential of efficiency and reproducibility of organoid cultures. More widely, we discuss current challenges and development on organoid culture systems together with microfluidic approaches and their limitations. Finally, we describe the recent progress and potential utilization in the organs-on-a-chip practice.