CB07

Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The β-cyclodextrin (β-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by β-CD, due to the low binding constant between PX and β-CD (∼100 M^-1). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between β-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (C_max) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile.

Glioblastoma multiforme (GBM) is one of the most common primary intracranial tumors in the central nervous system with poor prognosis, high invasiveness, risk of recurrence and low survival rate. Thus, it is urgent and vital to develop drug effective delivery systems that efficiently to traverse the blood-brain barrier and targeted transport therapeutic agents into the GBM tumor site for the treatment of brain tumors. Recently, amphiphilic cucurbit[7]uril-polyethylene glycol-hydrophobic Chlorin e6 (CB[7]-PEG-Ce6) polymer was designed, prepared, and self-assembled into micells (CPC) in an aqueous solution, and chemo drug methyl-triazeno-imidazole-carboxamide (MTIC), loaded into the cavity of CB[7] was subsequently coated with hybrid membrane mUMH (HMC3 membrane: macrophage membrane: U87MG membrane = 1:1:2) to afford mUMH@CPC@MTIC. The surface hybrid membrane mUMH potentially enhance the targeted delivery of CPC@MTIC to GBM tissue. Bioactive MTIC was released from the cavity of CB[7] in response to the high spermine level in GBM tumor microenvironments for effective tumor chemotherapy. The biomimetic mUMH@CPC@MTIC exhibited superior antitumor efficacy against GBM in mice. These findings provide new strategies for the design of biomimetic nanoparticle-based drug delivery systems and promising therapy of GBM.