Replacing cholesterol with asiatic acid to prolong circulation and enhance anti-metastatic effects of non-PEGylated liposomes.

Cholesterol is an indispensable component of most liposomes, heavily influencing their physical and surface properties. In this study, cholesterol in non-PEGylated liposomes was replaced by its analog, asiatic acid (AA), to generate liposomes with an alternative composition. These AA liposomes are generally smaller and more rigid than conventional liposomes, circulate longer in the body, and accumulate more in primary tumors and lung metastases in vivo. On the other hand, as an active ingredient, AA can decrease TGF-ß secretion to inhibit the epithelial-mesenchymal transition (EMT) process, increase the sensitivity of tumor cells to doxorubicin (DOX), and synergize with DOX to enhance the immune response, thus improving their antitumor and anti-metastasis efficiency. Based on this rationale, DOX-loaded AA liposomes were fabricated and tested against triple-negative breast cancer (TNBC). Results showed that compared with conventional liposomes, the DOX-AALip provided approximately 28.4% higher tumor volume reduction with almost no metastatic nodules in the mouse model. Our data demonstrate that AA liposomes are safe, simple, and efficient, and thus in many situations may be used instead of conventional liposomes, having good potential for further clinical translational development.

Biopharmaceutical, preclinical pharmacokinetic and pharmaco-dynamic investigations of an orally administered novel 3-nbutylphthalide prodrug for ischemic stroke treatment.

Ischemic stroke (IS) has been contributing in leading causes of disability and death worldwide and the cases are still increasing. In China, naturally sourced compound 3-n-butylphthalide (NBP) is widely applied in clinical practice for IS treatment with established evidences of efficacy and safety. However, NBP is an oily liquid at room temperature and has no active brain targeting ability, quite limiting its broader application in clinical practice. Via intravenous injection (i.v.) a prodrug compound (DB1) we previously developed deriving from NBP had dramatically enhanced the pharmacological effects, where however, this i.v. route still discount future patient compliance. As druggability of DB1 in oral administration has yet to be elaborated, the current study intended to systemically investigate its biopharmaceutical properties, so as to further consider clinical applicability of DB1 oral preparations. Additionally, pharmacokinetics and pharmacodynamics of DB1 via oral administered route were also studied, illustrating broad potential of further DB1 medicine development. After the derivation, aqueous solubility of DB1 improved 3∼400 folds compared with NBP in various pH media, and n-octanol/water partition coefficient kept in the range of 0∼2. In situ single-pass intestinal perfusion on rats showed effective permeability coefficient of DB1 over 10-2 cm/s. In contrast to NBP, oral administration of DB1 could display significant enhanced bioavailability in rats and achieve increased accumulation in brain tissues. As expected, DB1 effectively alleviated oxidative stress damage and reduced infarct volume on ischemia/reperfusion (I/R) modeled rats, resulting in reduced mortality. Additionally, this new prodrug did not add any safety concerns based on NBP. Therefore, biopharmaceutical results and preclinical pharmacodynamic evidences support the conclusion that an oral administration of DB1 may have a good potential for clinical IS treatment.

Novel brain-targeting 3-n-butylphthalide prodrugs for ischemic stroke treatment.

Currently, ischemic stroke is the leading cause of disability and death worldwide, and the performance of corresponding drugs is often unsatisfactory owing to the complex pathological processes and the impediment of the blood-brain barrier (BBB). Here, we employed various tertiary amino groups, including different linear, cyclic, and bimolecular drug structures, to modify 3-n-butylphthalide (NBP), a natural product used for ischemic stroke treatment, which has poor bioavailability, to generate a series of six prodrugs. These prodrugs showed significantly improved solubility and cellular uptake, which were primarily driven by putative pyrilamine cationic transporters. They also displayed more efficient brain delivery in vivo, reaching as high as 21.5-fold brain accumulation increase compared with NBP, leading to much higher bioavailability and stronger therapeutic effects. The toxicity of these molecules is also lower or similar to that of unmodified NBP. We showed that the tertiary amino group-modified NBP prodrugs are effective and safe for treating ischemic stroke with significantly enhanced druggability; hence, they have potential for further clinical development.