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Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-Deficient Breast Cancer Jodi E

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Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-Deficient Breast Cancer Jodi E Theranostics 2017, Vol. 7, Issue 17 4340 Ivyspring International Publisher Theranostics 2017; 7(17): 4340-4349. doi: 10.7150/thno.18563 Research Paper Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-deficient Breast Cancer Jodi E. Belz1, 2, Rajiv Kumar2, 3, Paige Baldwin1, 2, Noelle Castilla Ojo2, Ana S. Leal4, 5, Darlene B. Royce4, Di Zhang4, Anne L. van de Ven2, 3, Karen T. Liby4, 5, Srinivas Sridhar2, 3 1. Northeastern University, Department of Bioengineering, Boston, MA; 2. Nanomedicine Science and Technology Center, Northeastern University, Boston, MA; 3. Northeastern University, Department of Physics, Boston, MA; 4. Geisel School of Medicine at Dartmouth, Department of Pharmacology, Hanover, NH; 5. Michigan State University, Department of Pharmacology and Toxicology, East Lansing, MI. Corresponding author: Srinivas Sridhar [email protected] © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2016.11.30; Accepted: 2017.06.17; Published: 2017.09.26 Abstract Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors. Key words: Talazoparib, PARP inhibitor, BRCA-1, breast cancer, local therapy, sustained delivery. Introduction The breast cancer-associated gene 1 (BRCA1) is functions including DNA damage and repair, the most frequently mutated tumor suppressor gene homologous recombination, cell-cycle regulation, found in familial breast cancers. Women with this transcription, epigenetic modification and apoptosis. mutation have a 50-80% risk of developing breast Typically, BRCA1 is required for homologous cancer in their lifetime. As many as 75% of these cases recombination, a commonly utilized double-stranded are diagnosed as triple-negative breast cancer break DNA repair mechanism. In tumor cells which (TNBC), a subtype known for its poor prognosis [1–3]. have a loss of both BRCA1 genes, homologous Mutations of the BRCA1 gene modulate many cellular recombination is lost and cells must rely on http://www.thno.org Theranostics 2017, Vol. 7, Issue 17 4341 non-homologous end joining, a more error prone altered by adjusting the ratio of the two polymers pathway, for survival [4–7]. PLA and PGA, so that a wide variety of payloads can Poly-ADP-Ribose Polymerase (PARP) plays a be incorporated into nanoparticles, microspheres, or key role in the repair of single-stranded DNA breaks implants [30, 31]. PLGA as an implant has been used and is recruited to sites of DNA damage to initiate intratumorally to deliver molecules, magnetic repair [6, 8, 9]. PARP inhibition (PARPi) produces cell particles, nanoparticles, drugs, and imaging agents to death via synthetic lethality in cancers with genetic improve the bioavailability at the tumor site and predispositions for impaired DNA repair or impaired minimize any leaking of particles from the tumor transcription, such as BRCA1 mutants [1, 10, 11]. [32–36]. Substantial research has been conducted that Drugs that inhibit PARP1 activity prevent the repair supports the use of biodegradable PLGA implants in of single-stranded DNA breaks, which propagate into the use of cancer treatment for prolonged drug double-stranded breaks after DNA replication. PARPi delivery with minimal systemic side effects. in cells deficient in homologous recombination results Here, we report a novel, biodegradable implant in genomic instability and ultimately cell death by for localized and sustained delivery of Talazoparib to forcing cells to repair double-stranded breaks using treat Brca1-deficient breast cancer with minimal lower fidelity methods such as non-homologous end treatment associated toxicities. The in vitro efficacy of joining [12–16]. PARP inhibitors have shown Talazoparib was compared to that of other PARP promising results in clinical trials for breast cancers, inhibitors Olaparib and Niraparib using two breast particularly those due to either inherited mutation or cancer cell lines derived from Brca1-deficient mice. somatic inactivation of BRCA1/2 genes which are For in vivo delivery, Talazoparib implants were present in ~15% of the patient population [17–19]. fabricated using poly(lactic-co-glycolic) acid (PLGA) These drugs are also expected to have wide with tuned release of drug over several weeks. applicability beyond BRCA mutations in breast Implants containing 25 or 50 µg Talazoparib were cancers that exhibit “BRCAness” such as sporadic administered intratumorally into tumors with homologous recombination defects Brca1Co/Co;MMTV-Cre;p53+/- mice and their treatment [20–22]. efficacy was compared to drug-free control implants Talazoparib (BMN-673) is known for high and Talazoparib treatment by oral gavage. Mice were PARP1 and PARP2 inhibition with potency at much monitored for signs of gross toxicity and lower concentrations than earlier generations of immunohistochemistry was performed to assess DNA PARP1/2 inhibitors like Olaparib or Veliparib [10, 23]. damage and cell proliferation in the tumors. The The cytotoxicity of Talazoparib at nanomolar results showed that localized delivery of Talazoparib concentrations is believed to be related to the trapping significantly delays tumor growth and prolongs of PARP-DNA complexes based on studies in survival time at sub-clinical doses. This new approach PARP1-/- mouse models [24–26]. However, the of localized treatment using Talazoparib implants is hydrophobic nature of Talazoparib, combined with its an attractive strategy to treat the 75% of TNBC oral delivery route, limits drug bioavailability (~50% patients and 33% of overall breast cancer patients after first-pass metabolism), necessitating the use of which would benefit from PARPi therapy [12, 37, 38]. high doses in patients and leading to off-site toxicity [10]. Thus, Talazoparib is an attractive drug candidate Materials and Methods for breast cancer patients with Brca1 mutations, but its All solvents used were HPLC grade and potency may limit long-term use [14, 27]. purchased from Sigma-Aldrich unless otherwise Local, sustained delivery of drugs has been stated. Talazoparib, Olaparib and Niraparib were achievable in the past few decades with the use of purchased from SelleckChem (Houston, TX). biodegradable polymers. Poly (lactic-co-glycolic) acid Poly(lactic-co-glycolic) acid (PLGA) (Mw 7-17 kDa) or PLGA is an FDA approved biodegradable and was purchased from Sigma-Aldrich. Syringes and biocompatible copolymer that has been widely silicon tubing (i.d. 0.8 mm) were purchased from studied for the use of drug delivery systems. PLGA Fisher Scientific. Unless otherwise stated, all cell has tunable mechanical and degradation properties culture products (nutrient media, trypsin, Penstrep, and is widely characterized for its extensive use in fetal bovine serum) were obtained from Life developing devices for controlled delivery and release Technologies and were used without further of many types of molecules, proteins, and drugs [28, purification. Antibodies were procured from Abcam 29]. Many groups have shown that PLGA can be and Calbiochem. For cell viability assay CellTiter 96® injected subcutaneously or intratumorally for AQueous One Solution Cell Proliferation Assay long-term controlled drug delivery without the need (MTS) reagent was procured from Promega. for surgery. The hydrophobicity of the polymer can be http://www.thno.org Theranostics 2017, Vol. 7, Issue 17 4342 Talazoparib Implant Fabrication kV. Talazoparib implants were fabricated using a Release Kinetics studies polymer extrusion method as reported previously by The release profile of Talazoparib from the our group with several modifications [36].
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