Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Here we report the first novel nanoformulations of PARP inhibitors NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.</jats:p>
<jats:p>Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.</jats:p>
<jats:p>Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.</jats:p>
<jats:p>NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.</jats:p>
<jats:p>In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.</jats:p>
<jats:p>Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.</jats:p>
<jats:p>This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.</jats:p>
<jats:p>Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.</jats:p>