title: Enhanced performance of macrophage-encapsulated nanoparticle albumin-bound-paclitaxel in hypo-perfused cancer lesions.
abstract: Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.
authors.affiliation: Houston Methodist Research Institute, Department of Nanomedicine, R8-213, Houston, TX 77030, USA. bgodin@houstonmethodist.org bianagodinv@gmail.com.
authors.forename: Fransisca
authors.initials: F
authors.lastname: Leonard
authors.forename: Louis T
authors.initials: LT
authors.lastname: Curtis
authors.forename: Pooja
authors.initials: P
authors.lastname: Yesantharao
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tanei
authors.forename: Jenolyn F
authors.initials: JF
authors.lastname: Alexander
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: John
authors.initials: J
authors.lastname: Lowengrub
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.forename: Kenji
authors.initials: K
authors.lastname: Yokoi
authors.forename: Hermann B
authors.initials: HB
authors.lastname: Frieboes
authors.forename: Biana
authors.initials: B
authors.lastname: Godin
mesh_terms: D000068196:Albumin-Bound Paclitaxel / Q000008:administration & dosage*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D065546:Drug Liberation; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000068196:Albumin-Bound Paclitaxel
references.citation: Cancer Cell. 2008 Oct 7;14(4):299-311
references.pmid: 18835032
references.citation: Cancer Res. 2011 Apr 15;71(8):2826-37
references.pmid: 21363914
references.citation: Hum Pathol. 2009 Mar;40(3):381-9
references.pmid: 18992916
references.citation: Br J Cancer. 2004 Apr 5;90(7):1429-36
references.pmid: 15054467
references.citation: Nat Methods. 2007 Oct;4(10):855-60
references.pmid: 17767164
references.citation: Pharm Res. 2008 Aug;25(8):1815-21
references.pmid: 18373181
references.citation: Acc Chem Res. 2011 Oct 18;44(10):979-89
references.pmid: 21902173
references.citation: Cancer Immunol Immunother. 1986;23(3):214-6
references.pmid: 3024833
references.citation: J Physiol. 1973 Jan;228(2):279-84
references.pmid: 4687099
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1317-24
references.pmid: 16489089
references.citation: Gene Ther. 2000 Apr;7(8):707-13
references.pmid: 10800095
references.citation: Cancer Res. 1984 Jan;44(1):238-44
references.pmid: 6197161
references.citation: Mesoporous Biomater. 2014;1(1):
references.pmid: 25485265
references.citation: J Theor Biol. 2013 Mar 7;320:131-51
references.pmid: 23220211
references.citation: Nat Nanotechnol. 2008 Mar;3(3):151-7
references.pmid: 18654487
references.citation: Cancer Lett. 2013 Jul 1;334(2):319-27
references.pmid: 23000514
references.citation: Oncogene. 2009 Jan 22;28(3):461-8
references.pmid: 18978815
references.citation: Cancer Res. 2003 Nov 15;63(22):7853-60
references.pmid: 14633713
references.citation: J Theor Biol. 2014 Aug 21;355:194-207
references.pmid: 24751927
references.citation: Cancer Nanotechnol. 2012 Dec;3(1-6):47-54
references.pmid: 23205151
references.citation: Am J Pathol. 1997 Nov;151(5):1417-23
references.pmid: 9358768
references.citation: Biomaterials. 1998 Dec;19(24):2297-302
references.pmid: 9884043
references.citation: Br J Cancer. 2003 Jul 21;89(2):284-90
references.pmid: 12865918
references.citation: Liver Int. 2006 Dec;26(10):1175-86
references.pmid: 17105582
references.citation: Clin Exp Metastasis. 2002;19(2):119-25
references.pmid: 11964075
references.citation: Clin Cancer Res. 2005 Jun 1;11(11):4136-43
references.pmid: 15930349
references.citation: J Clin Oncol. 2005 Nov 1;23(31):7785-93
references.pmid: 16258082
references.citation: Cell. 2007 Aug 24;130(4):601-10
references.pmid: 17719539
references.citation: J Pain. 2013 Oct;14(10):1031-44
references.pmid: 23726937
references.citation: Ann Surg. 1985 Sep;202(3):384-93
references.pmid: 2931055
references.citation: J Biomed Mater Res A. 2010 Sep 15;94(4):1236-43
references.pmid: 20694990
references.citation: Small. 2009 May;5(10):1213-21
references.pmid: 19263430
references.citation: J Clin Oncol. 2005 Sep 1;23(25):6019-26
references.pmid: 16135470
references.citation: Cancer Res. 2013 Apr 1;73(7):2031-43
references.pmid: 23536564
references.citation: Cancer Res. 2016 Jan 15;76(2):429-39
references.pmid: 26744528
references.citation: World J Gastroenterol. 2003 Feb;9(2):193-200
references.pmid: 12532430
references.citation: Surgery. 2000 Apr;127(4):383-9
references.pmid: 10776428
references.citation: Biomaterials. 2012 Jun;33(16):4195-203
references.pmid: 22398206
references.citation: Folia Histochem Cytobiol. 2014;52(2):112-23
references.pmid: 25007179
references.citation: Nature. 2006 Aug 17;442(7104):736-8
references.pmid: 16915260
references.citation: Cancer Res. 1982 Feb;42(2):496-501
references.pmid: 7055801
references.citation: AIP Adv. 2012 Mar;2(1):11208
references.pmid: 22489278
references.citation: Invest New Drugs. 2006 Sep;24(5):455-6
references.pmid: 16505953
references.citation: Sci Rep. 2014 Oct 01;4:6468
references.pmid: 25270048
references.citation: Int J Pharm. 2010 Dec 15;402(1-2):190-7
references.pmid: 20883755
references.citation: J Math Biol. 2009 Apr;58(4-5):765-98
references.pmid: 18781303
references.citation: Adv Funct Mater. 2012 Oct 23;22(20):4225-4235
references.pmid: 23227000
references.citation: Br J Clin Pharmacol. 2003 Oct;56(4):433-40
references.pmid: 12968989