title: Tumor-penetrating microparticles for intraperitoneal therapy of ovarian cancer.
abstract: Intraperitoneal chemotherapy prolongs survival of ovarian cancer patients, but its utility is limited by treatment-related complications and inadequate drug penetration in larger tumors. Previous intraperitoneal therapy used the paclitaxel/Cremophor EL (polyethoxylated castor oil) formulation designed for intravenous use. The present report describes the development of paclitaxel-loaded microparticles designed for intraperitoneal treatment (referred to as tumor-penetrating microparticles or TPM). Evaluation of TPM was performed using intraperitoneal metastatic, human ovarian SKOV3 xenograft tumor models in mice. TPM were retained in the peritoneal cavity and adhered to tumor surface. TPM consisted of two biocompatible and biodegradable polymeric components with different drug release rates; one component released the drug load rapidly to induce tumor priming, whereas the second component provided sustained drug release. Tumor priming, by expanding interstitial space, promoted transport and penetration of particulates in tumors. These combined features resulted in the following advantages over paclitaxel/Cremophor EL: greater tumor targeting (16-times higher and more sustained concentration in omental tumors), lower toxicity to intestinal crypts and less body weight loss, greater therapeutic efficacy (longer survival and higher cure rate), and greater convenience (less frequent dosing). TPM may overcome the toxicities and compliance-related problems that have limited the utility of intraperitoneal therapy.
authors.affiliation: Optimum Therapeutics, LLC, Columbus, Ohio, USA.
authors.forename: Ze
authors.initials: Z
authors.lastname: Lu
authors.forename: Max
authors.initials: M
authors.lastname: Tsai
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: M Guillaume
authors.initials: MG
authors.lastname: Wientjes
authors.forename: Jessie L-S
authors.initials: JL
authors.lastname: Au
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000633:toxicity; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007700:Kinetics; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000633:toxicity; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D017239:Paclitaxel
references.citation: Cancer Res. 1987 Mar 15;47(6):1712-6
references.pmid: 3815369
references.citation: J Pharmacol Exp Ther. 2001 Mar;296(3):1035-42
references.pmid: 11181938
references.citation: N Engl J Med. 2006 Apr 13;354(15):1641-3; author reply 1641-3
references.pmid: 16611959
references.citation: Cancer Res. 1988 Oct 15;48(20):5874-7
references.pmid: 3167842
references.citation: Acta Cytol. 1996 May-Jun;40(3):429-36
references.pmid: 8669174
references.citation: Cancer Surv. 1993;17:105-22
references.pmid: 8137338
references.citation: Cancer Res. 1991 Apr 15;51(8):2041-6
references.pmid: 2009523
references.citation: J Clin Oncol. 1998 Aug;16(8):2620-4
references.pmid: 9704711
references.citation: AAPS PharmSci. 2001;3(2):E15
references.pmid: 11741266
references.citation: J Biomed Mater Res A. 2006 May;77(2):351-61
references.pmid: 16425240
references.citation: Pharm Res. 2002 Apr;19(4):411-7
references.pmid: 12033372
references.citation: Tumori. 1985 Feb 28;71(1):63-8
references.pmid: 3984048
references.citation: Adv Drug Deliv Rev. 1997 Oct 13;28(1):5-24
references.pmid: 10837562
references.citation: Semin Oncol. 1988 Jun;15(3 Suppl 4):27-31
references.pmid: 3134695
references.citation: Ann Intern Med. 1984 Jul;101(1):14-8
references.pmid: 6732077
references.citation: Clin Cancer Res. 2003 Dec 1;9(16 Pt 1):5896-901
references.pmid: 14676112
references.citation: Invest New Drugs. 2001 May;19(2):113-23
references.pmid: 11392446
references.citation: Surg Oncol Clin N Am. 2003 Jul;12(3):755-69, xiv
references.pmid: 14567029
references.citation: J Clin Oncol. 2006 Feb 20;24(6):988-94
references.pmid: 16461779
references.citation: J Pharmacol Exp Ther. 2007 Jul;322(1):80-8
references.pmid: 17420296
references.citation: Gynecol Oncol. 2000 Feb;76(2):157-62
references.pmid: 10637064
references.citation: Gynecol Oncol. 2006 Nov;103(2):391-6
references.pmid: 16626792
references.citation: N Engl J Med. 1996 Dec 26;335(26):1950-5
references.pmid: 8960474
references.citation: J Biomed Mater Res. 1985 Mar;19(3):349-65
references.pmid: 4077887
references.citation: Anticancer Drug Des. 1990 Nov;5(4):359-69
references.pmid: 2127181
references.citation: J Clin Oncol. 2001 Feb 15;19(4):1001-7
references.pmid: 11181662
references.citation: Cancer Res. 1996 May 1;56(9):2086-93
references.pmid: 8616855
references.citation: J Chromatogr B Biomed Appl. 1995 Jan 20;663(2):337-44
references.pmid: 7735481
references.citation: Pharm Res. 2007 Sep;24(9):1691-701
references.pmid: 17447121
references.citation: Cancer Chemother Pharmacol. 1990;25(6):389-94
references.pmid: 2311166
references.citation: J Pharmacol Exp Ther. 1999 Aug;290(2):871-80
references.pmid: 10411604
references.citation: Cancer Chemother Pharmacol. 1991;28(3):159-65
references.pmid: 1855272
references.citation: Clin Cancer Res. 1998 Feb;4(2):277-82
references.pmid: 9516911
references.citation: Eur J Gynaecol Oncol. 1998;19(3):265-70
references.pmid: 9641228
references.citation: J Clin Oncol. 2007 Feb 1;25(4):437-43
references.pmid: 17264340
references.citation: J Clin Oncol. 1992 Sep;10(9):1485-91
references.pmid: 1355523
references.citation: Gynecol Oncol. 1993 Jul;50(1):100-4
references.pmid: 8349150
references.citation: Cancer Res. 1999 Aug 1;59(15):3776-82
references.pmid: 10446995
references.citation: N Engl J Med. 2006 Jan 5;354(1):34-43
references.pmid: 16394300