Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment

Paige Baldwin,1,* Anders W Ohman,2,* Shifalika Tangutoori,3 Daniela M Dinulescu,2,# Srinivas Sridhar1,3,4,#1Department of Bioengineering, Northeastern University, Boston, MA, USA; 2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3Department o...

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Autores principales:	Baldwin P, Ohman AW, Tangutoori S, Dinulescu DM, Sridhar S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	PARP inhibitor Olaparib intraperitoneal treatment nanoparticle DNA repair ovarian cancer Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/f0d5df12d696417d8ac41da069330628
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spelling	oai:doaj.org-article:f0d5df12d696417d8ac41da0693306282021-12-02T05:04:47ZIntraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment1178-2013https://doaj.org/article/f0d5df12d696417d8ac41da0693306282018-11-01T00:00:00Zhttps://www.dovepress.com/intraperitoneal-delivery-of-nanoolaparib-for-disseminated-late-stage-c-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Paige Baldwin,1,* Anders W Ohman,2,* Shifalika Tangutoori,3 Daniela M Dinulescu,2,# Srinivas Sridhar1,3,4,#1Department of Bioengineering, Northeastern University, Boston, MA, USA; 2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3Department of Physics, Northeastern University, Boston, MA, USA; 4Division of Radiation Oncology, Harvard Medical School, Boston, MA, USA*These authors contributed equally to this work#These senior co-authors contributed equally to this workBackground: PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy. Methods: The tumor cell line 404, which was derived from a Brca2-/-, Tp53-/-, Pten-/- genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration. Results: Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected. Conclusion: NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.Keywords: PARP inhibitor, Olaparib, intraperitoneal treatment, nanoparticle, DNA repair, ovarian cancerBaldwin POhman AWTangutoori SDinulescu DMSridhar SDove Medical PressarticlePARP inhibitorOlaparibintraperitoneal treatmentnanoparticleDNA repairovarian cancerMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 8063-8074 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	PARP inhibitor Olaparib intraperitoneal treatment nanoparticle DNA repair ovarian cancer Medicine (General) R5-920
spellingShingle	PARP inhibitor Olaparib intraperitoneal treatment nanoparticle DNA repair ovarian cancer Medicine (General) R5-920 Baldwin P Ohman AW Tangutoori S Dinulescu DM Sridhar S Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment
description	Paige Baldwin,1,* Anders W Ohman,2,* Shifalika Tangutoori,3 Daniela M Dinulescu,2,# Srinivas Sridhar1,3,4,#1Department of Bioengineering, Northeastern University, Boston, MA, USA; 2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 3Department of Physics, Northeastern University, Boston, MA, USA; 4Division of Radiation Oncology, Harvard Medical School, Boston, MA, USA*These authors contributed equally to this work#These senior co-authors contributed equally to this workBackground: PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy. Methods: The tumor cell line 404, which was derived from a Brca2-/-, Tp53-/-, Pten-/- genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration. Results: Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected. Conclusion: NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.Keywords: PARP inhibitor, Olaparib, intraperitoneal treatment, nanoparticle, DNA repair, ovarian cancer
format	article
author	Baldwin P Ohman AW Tangutoori S Dinulescu DM Sridhar S
author_facet	Baldwin P Ohman AW Tangutoori S Dinulescu DM Sridhar S
author_sort	Baldwin P
title	Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment
title_short	Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment
title_full	Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment
title_fullStr	Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment
title_full_unstemmed	Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment
title_sort	intraperitoneal delivery of nanoolaparib for disseminated late-stage cancer treatment
publisher	Dove Medical Press
publishDate	2018
url	https://doaj.org/article/f0d5df12d696417d8ac41da069330628
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Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment

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