Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

Abstract

We report a novel delivery platform for a highly potent anticancer drug, 7-(benzylamino)-3,4-dihydro-pyrrolo[4,3,2-de]quinolin-8(1H)-one (BA-TPQ), using pH- and redox-sensitive poly(methacrylic acid) (PMAA) hydrogel cubes of micrometer size as the encapsulating matrix. The hydrogels are obtained upon cross-linking PMAA with cystamine in PMAA/poly(N-vinylpyrrolidone) multilayers assembled within mesoporous sacrificial templates. The BA-TPQ-loaded hydrogels maintain their cubical shape and pH-sensitivity after lyophilization, which is advantageous for long-term storage. Conversely, the particles degrade in vitro in the presence of glutathione (5 mM) providing 80% drug release within 24 h. Encapsulating BA-TPQ into hydrogels significantly increases its transport via Caco-2 cell monolayers used as a model for oral delivery where the apparent permeability of BA-TPQ-hydrogel cubes was ~2-fold higher than that of BA-TPQ. BA-TPQ-hydrogel cubes exhibit better anticancer activity against HepG2 (IC50=0.52 μg/mL) and Huh7 (IC50=0.29 μg/mL) hepatoma cells with a 40% decrease in the IC50 compared to the non-encapsulated drug. Remarkably, non-malignant liver cells have a lower sensitivity to BA-TPQ-hydrogel cubes with 2-fold increased IC50 values compared to those of cancer cells. In addition, encapsulating BA-TPQ in the hydrogels amplifies the potency of the drug via down-regulation of MDM2 oncogenic protein and upregulation of p53 (a tumor suppressor) and p21 (cell proliferation suppressor) expression in HepG2 liver cancer cells. Moreover, enhanced inhibition of MDM2 protein expression by BA-TPQ-hydrogel cubes is independent of p53-status in Huh7 cells. This drug delivery platform of non-spherical shape provides a facile method for encapsulation of hydrophobic drugs and can facilitate the enhanced efficacy of BA-TPQ for liver cancer therapy.

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…Other types of MDM2 inhibitors, especially those that directly inhibit MDM2 itself, for example, SP141, JapA, and MA242, should be evaluated for their therapeutic efficacy and safety, as they may provide stronger activity by blocking both the p53‐dependent and p53‐independent functions of MDM2. Further evaluation and development of MDM2 inhibitors for cancer therapy are underway . These studies will provide proof‐of‐principle results to support the therapeutic value of this targeting strategy in drug discovery and may greatly contribute to the development of new therapeutics to treat noncancer diseases.…”

An Industry update: the Latest Developments in Therapeutic Delivery

“…In vitro experiments with the anticancer drug BA-TPQ (which is highly potent but with limited solubility, and hence has low bioavailability and toxicity) have demonstrated that drug-loaded hydrogel cubes are more potent against liver cancer cells than normal. Hydrogel cubes loaded with BA-TPQ can be delivered iv., as well as orally as experiments have shown [27].…”

Terphenyllin Suppresses Orthotopic Pancreatic Tumor Growth and Prevents Metastasis in Mice

“…Panc1 and HPAC cells were seeded in 6-cm dishes (3-5×10 5 cells/well) overnight and exposed to terphenyllin (20, 50, or 200 mM) or DMSO for 24 h. The treated cells were then lysed with RIPA buffer (Absin Bioscience Inc, Shanghai, China) containing protease inhibitors (Solarbio Science & Technology Co., Ltd., Beijing, China) and phosphatase inhibitors (Roche, Switzerland). The cell lysates were centrifuged and the supernatants were collected, quantified, separated by an SDS-PAGE gel, and transferred to a PVDF blotting membrane (GE Healthcare, USA) for Western blot analysis following the manufacturer's protocol (Xue et al, 2017;Qin et al, 2018). After blocking with 5% nonfat milk and incubation with primary and second antibodies, the blotting membranes were examined using ECL luminescence reagent (Absin, Shanghai, China), and the images were acquired on a FluorChem Q System (Alpha Innotech, Cell Bioscienes, USA).…”