radiation-treatment-organotypic-cultures-from-submandibular-parotid

Radiation Treatment of Organotypic Cultures from Submandibular and Parotid Salivary Glands Models Key In Vivo Characteristics

Hyposalivation and xerostomia create chronic oral complications that decrease the quality of life in head and neck cancer patients who are treated with ...

University of Arizona

The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro studies revealed that the PNP was rapidly internalized into MiaPaCa-2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras. 

Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer.

A mathematical model of drug release that incorporates the simultaneous contributions of initial burst, nanoparticle degradation-relaxation and diffusion was developed and used to effectively describe the release of a kinase inhibitor and anticancer drug, PHT-427. The encapsulation of this drug into PLGA nanoparticles was performed by following the single emulsion-solvent evaporation technique and the release was determined in phosphate buffer pH 7.4 at 37 °C. The size of nanoparticles was obtained in a range of 162-254 nm. The experimental release profiles showed three well defined phases: an initial fast drug release, followed by a nanoparticle degradation-relaxation slower release and then a diffusion release phase. The effects of the controlled release most relevant parameters such as drug diffusivity, initial burst constant, nanoparticle degradation-relaxation constant, and the time to achieve a maximum rate of drug release were evaluated by a parametrical analysis. The theoretical release studies were corroborated experimentally by evaluating the cytotoxicity effectiveness of the inhibitor AKT/PDK1 loaded nanoparticles over BxPC-3 pancreatic cancer cells in vitro. These studies show that the encapsulated inhibitor AKT/PDK1 in the nanoparticles is more accessible and thus more effective when compared with the drug alone, indicating their potential use in chemotherapeutic applications.

Nanoparticle encapsulation and controlled release of a hydrophobic kinase inhibitor: Three stage mathematical modeling and parametric analysis.

The formulation and characterization of gentamicin-loaded microspheres as a delivery system targeting enterotoxigenic Escherichia coli K88 (E. coli K88) was investigated. Glycated albumin with lactose (BSA-glucose-β (4-1) galactose) was used as the microsphere matrix (MS-Lac) and gentamicin included as the transported antibiotic. The proposed target strategy was that exposed galactoses of MS-Lac could be specifically recognized by E. coli K88 adhesins, and the delivery of gentamicin would inhibit bacterial growth. Lactosylated microspheres (MS-Lac1, MS-Lac2 and MS-Lac3) were obtained using a water-in-oil emulsion, containing gentamicin, followed by crosslinking with different concentrations of glutaraldehyde. Electron microscopy displayed spherical particles with a mean size of 10-17 µm. In vitro release of gentamicin from MS-Lac was best fitted to a first order model, and the antibacterial activity of encapsulated and free gentamicin was comparable. MS-Lac treatments were recognized by plant galactose-specific lectins from Ricinus communis and Sophora japonica and by E. coli K88 adhesins. Results indicate MS-Lac1, produced with 4.2 mg/mL of crosslinker, as the best treatment and that lactosylated microsphere are promising platforms to obtain an active, targeted system against E. coli K88 infections. 

Article	Year
Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer. International journal of nanomedicine\| PubMed ID: 25516710	2014
Nanoparticle encapsulation and controlled release of a hydrophobic kinase inhibitor: Three stage mathematical modeling and parametric analysis. International journal of pharmaceutics\| PubMed ID: 26216413	2015
K88 Fimbrial Adhesin Targeting of Microspheres Containing Gentamicin Made with Albumin Glycated with Lactose. International journal of molecular sciences\| PubMed ID: 26389896	2015

Roberto Guzman

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