title: Effect of particle size on the biodistribution, toxicity, and efficacy of drug-loaded polymeric nanoparticles in chemoradiotherapy.
abstract: Nanoparticle (NP) chemotherapeutics can improve the therapeutic index of chemoradiotherapy (CRT). However, the effect of NP physical properties, such particle size, on CRT is unknown. To address this, we examined the effects of NP size on biodistribution, efficacy and toxicity in CRT. PEG-PLGA NPs (50, 100, 150 nm mean diameters) encapsulating wotrmannin (wtmn) or KU50019 were formulated. These NP formulations were potent radiosensitizers in vitro in HT29, SW480, and lovo rectal cancer lines. In vivo, the smallest particles avoided hepatic and splenic accumulation while more homogeneously penetrating tumor xenografts than larger particles. However, smaller particles were no more effective in vivo. Instead, there was a trend toward enhanced efficacy with medium sized NPs. The smallest KU60019 particles caused more small bowel toxicity than larger particles. Our results showed that particle size significantly affects nanotherapeutics' biodistrubtion and toxicity but does not support the conclusion that smaller particles are better for this clinical application.
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: jcaster@unch.unc.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Caster
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Yu
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Artish N
authors.initials: AN
authors.lastname: Patel
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Newman
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Lee
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Warner
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Wagner
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Roche
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Tian
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Yuanzeng
authors.initials: Y
authors.lastname: Min
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Andrew Z
authors.initials: AZ
authors.lastname: Wang
mesh_terms: D000730:Androstadienes / Q000493:pharmacokinetics; D000818:Animals; D059248:Chemoradiotherapy; D064593:Heterografts; D006801:Humans; D051379:Mice; D053758:Nanoparticles; D010316:Particle Size; D011108:Polymers; D012004:Rectal Neoplasms; D014018:Tissue Distribution; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D011108:Polymers; D000077191:Wortmannin
keywords: Chemoradiotherapy; KU60019; Nanoparticle; Nanoparticle radiosensitization; Wortmannin