title: Nanoparticle drug loading as a design parameter to improve docetaxel pharmacokinetics and efficacy.
abstract: Nanoparticle (NP) drug loading is one of the key defining characteristics of an NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT(®)), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel.
authors.affiliation: Department of Pharmaceutical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Chu
authors.forename: Allison N
authors.initials: AN
authors.lastname: Schorzman
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Finniss
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Bowerman
authors.forename: Lei
authors.initials: L
authors.lastname: Peng
authors.forename: James C
authors.initials: JC
authors.lastname: Luft
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Madden
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Wang
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: Joseph M
authors.initials: JM
authors.lastname: DeSimone
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D000077143:Docetaxel; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D011091:Polyesters; D011108:Polymers / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D043823:Taxoids / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D011091:Polyesters; D011108:Polymers; D043823:Taxoids; D000077143:Docetaxel; D019344:Lactic Acid; C033616:poly(lactide)
keywords: Docetaxel; Drug loading; Pharmacokinetics; Polylactic acid; Soft-lithography
references.citation: Clin Cancer Res. 2012 May 1;18(9):2591-602
references.pmid: 22392910
references.citation: Cancer Res. 2002 Dec 1;62(23):6831-6
references.pmid: 12460895
references.citation: Nanomedicine. 2013 Jul;9(5):686-93
references.pmid: 23219874
references.citation: Nat Nanotechnol. 2011 Oct 23;6(12):815-23
references.pmid: 22020122
references.citation: Biochim Biophys Acta. 1991 Sep 30;1068(2):133-41
references.pmid: 1911826
references.citation: Biochim Biophys Acta. 1986 Sep 19;888(2):184-90
references.pmid: 3741891
references.citation: Nano Lett. 2012 Jul 11;12(7):3369-77
references.pmid: 22650417
references.citation: Cancer Res. 2009 May 1;69(9):3918-26
references.pmid: 19383919
references.citation: Nanomedicine. 2014 Oct;10(7):1497-506
references.pmid: 24709328
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1317-24
references.pmid: 16489089
references.citation: J Pharm Sci. 2013 Mar;102(3):1054-62
references.pmid: 23280512
references.citation: Int J Pharm. 2001 Jun 19;221(1-2):143-52
references.pmid: 11397575
references.citation: J Control Release. 2001 May 14;72(1-3):191-202
references.pmid: 11389998
references.citation: ACS Nano. 2012 May 22;6(5):3954-66
references.pmid: 22494403
references.citation: Int J Pharm. 2010 May 31;391(1-2):248-59
references.pmid: 20156541
references.citation: J Drug Target. 2002 Nov;10(7):539-48
references.pmid: 12683721
references.citation: Biomaterials. 2007 Feb;28(5):869-76
references.pmid: 17055572
references.citation: Sci Transl Med. 2012 Apr 4;4(128):128ra39
references.pmid: 22491949
references.citation: Biochim Biophys Acta. 1981 May 18;674(3):354-71
references.pmid: 6165399
references.citation: Anticancer Drugs. 2008 Oct;19(9):899-909
references.pmid: 18766004
references.citation: Biochim Biophys Acta. 1983 Dec 13;761(2):142-51
references.pmid: 6652107
references.citation: Biochim Biophys Acta. 2007 Mar;1768(3):678-87
references.pmid: 17208196
references.citation: Nano Lett. 2011 Feb 9;11(2):808-13
references.pmid: 21265552
references.citation: Angew Chem Int Ed Engl. 2011 Nov 25;50(48):11417-20
references.pmid: 22113800