Design and Optimization of Nanoformulations for Stability and Sustained Release of Therapeutic Compounds

Due to the complexity of physiological conditions inside the human body, therapeutic compounds often face challenges such as short half-life in plasma, fast enzymatic metabolism and degradation. Nanocarriers such as liposomes and polymeric nanoparticles offer solutions to improve the stability and sustain the release of therapeutic compounds. However, the development of such vehicles often requires careful optimization. We demonstrated that by using X-ray techniques integrated with the Langmuir trough, the liposomal development process can be shortened significantly through the understanding of the molecular interaction between our prodrug 5-FCPal, a capecitabine analogue, with our model lipids and the effects of 5-FCPal on the lipid packing structure at the air-liquid interface. Additionally, the X-ray techniques can be used as a new platform to predict the drug loading in liposomes by increasing the molar fraction of the prodrug in the monolayer and observing the changes in molecular interaction. It was revealed that 5-FCPal interacted strongly with cationic lipids through electrostatic interaction of the head groups and caused the molecular packing to be tighter while the prodrug exhibited weak interaction with neutral and anionic lipids. Proof-of-concept nanoformulations were prepared and found that cationic lipids were able to form 100 nm vesicles while neutral lipids formed large aggregates with 5-FCPal. Utilizing a unique flash nanoprecipitation (FNP) process, polymeric particles were optimized to sustain the release of pazopanib for the treatment of osteoarthritis (OA). The results showed that the release of pazopanib strongly depended on the degradation rate of the polymer matrix and pH conditions. In vivo efficacy evaluation found that after single injection, the pain reduction effect lasted up to 16 weeks in mice with partial medial meniscectomy (PMM)-induced knee. FNP was also optimized to produce PLGA polymeric nanoparticles encapsulating emricasan, a peptide compound with poor pharmacokinetics property. The nanoparticles stability in aqueous condition was tracked for 6 hours. Our results indicated that the nanoparticles were more stable with shorter sonication time and lower concentration of trehalose (added as cryoprotectant). These results lay the important groundwork for future direction of designing stable nanoparticles systems to improve emricasan pharmacokinetics and enhance its cancer treatment property.