Polymeric micelle nanocarriers for targeted epidermal delivery of the hedgehog pathway inhibitor vismodegib: formulation development and cutaneous biodistribution in human skin.

Background: The aim was to investigate cutaneous delivery and biodistribution of the hedgehog pathway inhibitor, vismodegib (VSD), indicated for basal cell carcinoma (BCC), from polymeric micelle formulations under infinite/finite dose conditions. Methods: VSD-loaded micelles were characterized for drug content, particle size, and shape; a micelle gel was characterized for its rheological behavior. Cutaneous deposition and biodistribution of VSD were determined using porcine and human skin in vitro with quantification by UHPLC-MS/MS. Results: The optimal micelle solution (Zav 20-30 nm) increased the aqueous solubility of VSD by >8000-fold; drug content was stable after 4 weeks at 4°C. Application of micelle solution and micelle gel (0.086% w/v) to human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.62 ± 0.11 and 0.67 ± 0.14 µg/cm2, respectively). Cutaneous biodistribution in human skin under infinite (micelle solution and gel) and finite (micelle gel) dose conditions showed that the VSD concentrations obtained in the basal epidermis, at depths of 120-200 µm, were ˃3800- and ˃2300-fold greater than the IC50 reported for hedgehog signaling pathway inhibition in vitro. Conclusion: Cutaneous delivery of VSD from micelle-based formulations might enable targeted, topical treatment of superficial BCC with minimal risk of systemic exposure.

Selective delivery of adapalene to the human hair follicle under finite dose conditions using polymeric micelle nanocarriers.

Drug delivery systems that target the pilosebaceous unit (PSU) selectively could improve the clinical management of diseases that originate in the hair follicle. The aims of this study were (i) to prepare polymeric micelles using d-α-tocopheryl polyethylene glycol succinate diblock copolymer that incorporated adapalene (ADA), a retinoid indicated for Acne vulgaris, and (ii) to investigate the feasibility of delivering ADA preferentially to the PSU under finite dose conditions - thereby better approximating actual conditions of use by patients. Incorporation of ADA into spherical micelles (dn <20 nm) increased aqueous solubility by ∼50 000-fold (from <4 ng mL-1 to 0.2 mg mL-1). Optimized micelle solution and gel formulations (0.02% ADA) were stable after storage for 4 weeks at 4 °C. Finite dose experiments using full-thickness porcine and human skin revealed that ADA delivery efficiency from micelle solution and gel formulations was equivalent and was >2- and 10-fold higher than that from Differin® gel and Differin® cream (products containing ADA at 0.1% (w/w)). Follicular delivery studies in human skin, using a punch biopsy technique to extract the intact PSU, demonstrated that the micelle solution and gel formulations did indeed enable preferential delivery of ADA to the PSU (4.5- and 3.3-fold higher, respectively, than that to PSU-free skin biopsies). Confocal laser scanning microscopy provided visual corroboration that ADA was uniformly distributed in the hair follicles. In conclusion, the results confirmed that polymeric micelle nanocarriers enabled selective, targeted drug delivery to the PSU under finite dose conditions and so might improve therapy of follicular diseases and decrease off-site side-effects.

Oxidative Dearomatization of Indoles via Pd-Catalyzed C-H Oxygenation: An Entry to C2-Quaternary Indolin-3-ones.

An oxidative dearomatization chemistry of 2-arylindole via a unique pathway involving Pd-catalyzed C-H peroxygenation is documented. Coupled with cascade transformation, it provides a new route to access indolin-3-ones bearing a C2-quaternary functionality, including a chiral center (indoxyls), a motif prevalent in indole alkaloids but synthetically underexplored. The method is chemo- and regioselective and compatible with versatile substrates. A mechanism has been outlined on the basis of results of control experiments, isolation/use of intermediates, and spectroscopic studies.

Structural elaboration of a natural product: identification of 3,3'-diindolylmethane aminophosphonate and urea derivatives as potent anticancer agents.

An approach involving rational structural elaboration of the biologically active natural product diindolylmethane (DIM) with the incorporation of aminophosphonate and urea moieties toward the discovery of potent anticancer agents was considered. A four-step approach for the synthesis of DIM aminophosphonate and urea derivatives was established. These novel compounds showed potent anticancer activities in two representative kidney and colon cancer cell lines, low toxicity to normal cells, higher potency than the parent natural product DIM and etoposide, and potent inhibition of cancer cell migration. Biophysical and immunological studies, including DAPI nuclear staining, western blot analysis with apoptotic protein markers, flow cytometry, immunocytochemistry, and comet assays of the two most potent compounds revealed good efficacies in apoptosis and DNA damage. It was found that down-regulation of nuclear factor κB (NF-κB p65) could be an important mode of action in apoptosis, and the two most potent derivatives were found to be more potent than parent compound DIM in the down-regulation of NF-κB. Our results show the importance of structural elaboration of DIM by rational incorporation of aminophosphonate and urea moieties to produce potent anticancer agents; they also suggest that this approach using other structurally simple bioactive natural products as scaffolds holds promise for future drug discovery and development.

Indenoindolone derivatives as topoisomerase II-inhibiting anticancer agents.

Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II-inhibiting anticancer agents. They are hydrazones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with suitable substitutions exhibited potent specific inhibition of human DNA TopoIIα while not showing inhibition of topoisomerase I and DNA intercalation, despite the fact that parent indenoindolones are known poor/moderate inhibitors of topoisomerase II. The potent topoisomerase II inhibitor indenoindolone derivatives exhibited good anticancer activities compared to etoposide and 5-fluorouracil, and relatively low toxicity to normal cells. These derivatizations of indenoindolones were found to result in enhancement of anticancer activities.

C-H bond functionalization under metalation-deprotonation process: regioselective direct arylation of 3-aminoimidazo[1,2-a]pyrazine.

Concerted metalation deprotonation (CMD) approach with appropriate proton shuttle precursor, base, and solvent (PivOH-K(2)CO(3)-toluene) has rendered a regioselective Pd-catalyzed C6-arylation of 3-aminoimidazo[1,2-a]pyrazine, a therapeutically relevant scaffold accessible by multicomponent reaction. The arylation of this heteroarene suffers from competing C5 and C2'-arylation reactions, while the developed process has virtually eliminated these competing arylations. Density functional calculations for CMD C-H activation at C6, C5, C8, and C2' sites imply that the energy barrier with distortion energy penalty as major contributing component influences the regioselectivity.