Background. Rodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed.Methods. In this work, we evaluated the plasma and

With the recent advances in the development of novel protein based therapeutics, controlled delivery of these biologics is an important area of research. Herein, we report the synthesis of microparticles from bovine serum albumin (BSA) as a model protein using Particle Replication in Non-wetting Templates (PRINT) with specific size and shape. These particles were functionalized at room temperature using multifunctional chlorosilane that cross-link the particles to render them to slowly-dissolving in aqueous media. Mass spectrometric study of the reaction products of diisopropyldichlorosilane with individual components of the particles revealed that they are capable of reacting and forming cross-links. Energy dispersive spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) were also used to confirm the functionalization of the particles. Cross sectional analysis using focused ion beam (FIB) and EDS proved that the functionalization occurs throughout the bulk of the particles and is not just limited to the surface. Circular dichroism data confirmed that the fraction of BSA molecules released from the particles retains its secondary structure thereby indicating that the system can be used for delivering protein based formulations while controlling the dissolution kinetics.

During efforts to stabilize metal oxide bound chromophores for photoelectrochemical applications, a novel photochemical reaction has been discovered. In the reaction, the bisphosphonate functional groups -C(PO(3)H(2))(2)(OH) in the metal complex [Ru(bpy)(2)(4,4'-(C(OH)(PO(3)H(2))(2)bpy)](2+) are converted into -COOH and H(3)PO(4). The reaction occurs by sensitized formation of (1)O(2) by the lowest metal-to-ligand charge transfer excited state(s) of [Ru(bpy)(2)(4,4'-(C(PO(3)H(2))(2)(OH))(2)(bpy))](2+)* followed by (1)O(2) oxidation of the bisphosphonate substituent. A related reaction occurs for the bisphosphonate-based drug, risedronic acid, in the presence of O(2), light, and a singlet oxygen sensitizer ([Ru(bpy)(3)](2+) or Rose Bengal).

Background: It is currently unclear what preclinical tumor model most accurately reflects the tumor disposition and antitumor response of an anticancer agent in patients with solid tumors. GEMMs of melanoma and other solid tumors may better predict drug distribution and antitumor response compared with flank tumor models by allowing for the development of tumor in situ which may more faithfully recapitulate human cancer. We compared the plasma and tumor disposition of carboplatin in a GEMM and murine models of melanoma and in patients with cutaneous melanoma. Methods: Carboplatin was administered at 50mg/kg IV x 1 via a tail vein to a GEMM of melanoma [tyrosinase-H-RasG12V Ink4a/Arf−/− (TRIA)] and mice bearing B16 murine melanoma. Plasma total and ultrafiltrate conc were obtained (n = 3 mice per time point) from 0 to 6 h after administration. Microdialysis studies evaluating carboplatin in tumor extracellular fluid (ECF) were performed (n = 6 mice) from 0 to 4 h after administration. Six patients with cutaneous metastatic melanoma were administered carboplatin at 400mg/m2 IV over 20 minutes. Plasma total and tumor ECF, collected by microdialysis, were obtained from 0 to 6 h after administration. Platinum (Pt) conc were measured by ICP-MS, FAAS and FAAS in the GEMM, B16 and patient studies, respectively. Areas under the plasma conc versus time curves from 0 to infinity (AUC) of standard and allometrically scaled data were calculated. Results: Results are in the table: UnitsHumanGEMMB16Standard / Unscaled    Plasma Total Pt AUCµg/mL·h26.028.540.5Plasma Ultrafiltrate Pt AUCµg/mL·h—25.427.9Tumor ECF Pt AUCµg/mL·h15.38.61.9Allometrically Scaled    Plasma Total Pt AUC(µg/mL)/(mg/kg)]·(h/kg)0.841.372.15Tumor ECF Pt AUC(µg/mL)/(mg/kg)]·(h/kg)0.490.410.10Ratio of Plasma Total pt AUC to Tumor ECF pt AUC 0.580.300.05 Conclusion: The tumor PK of carboplatin in GEMM models of melanoma more closely resembles the tumor disposition in patients with melanoma as compared with flank tumor models. GEMMs show promise in becoming an improved prediction model for drug PK and response in patient tumors. Studies are being conducted to determine the basis for differences in tumor drug delivery between GEMMs and transplanted tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4203.

No abstract