title: The effects of particle size and molecular targeting on the intratumoral and subcellular distribution of polymeric nanoparticles.
abstract: The current study describes the impact of particle size and/or molecular targeting (epidermal growth factor, EGF) on the in vivo transport of block copolymer micelles (BCMs) in athymic mice bearing human breast cancer xenografts that express differential levels of EGF receptors (EGFR). BCMs with diameters of 25 nm (BCM-25) and 60 nm (BCM-60) were labeled with indium-111 ((111)In) or a fluorescent probe to provide a quantitative and qualitative means of evaluating their whole body, intratumoral, and subcellular distributions. BCM-25 was found to clear rapidly from the plasma compared to BCM-60, leading to an almost 2-fold decrease in their total tumor accumulation. However, the tumoral clearance of BCM-25 was delayed through EGF functionalization, enabling the targeted BCM-25 (T-BCM-25) to achieve a comparable level of total tumor deposition as the nontargeted BCM-60 (NT-BCM-60). Confocal fluorescence microscopy combined with MATLAB analyses revealed that NT-BCM-25 diffuses further away from the blood vessels (D(mean) = 42 +/- 9 microm) following extravasation, compared to NT-BCM-60 which mainly remains in the perivascular regions (D(mean) = 23 +/- 4 microm). The introduction of molecular targeting imposes the "binding site barrier" effect, which retards the tumor penetration of T-BCM-25 (D(mean) = 29 +/- 7 microm, p < 0.05). The intrinsic nuclear translocation property of EGF/EGFR leads to a significant increase in the nuclear uptake of T-BCM-25 in vitro and in vivo via active transport. Overall, these results highlight the need to consider multiple design parameters in the development of nanosystems for delivery of anticancer agents.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Division of Nuclear Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Lee
authors.forename: Humphrey
authors.initials: H
authors.lastname: Fonge
authors.forename: Bryan
authors.initials: B
authors.lastname: Hoang
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004815:Epidermal Growth Factor / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D011108:Polymers; D004815:Epidermal Growth Factor; D066246:ErbB Receptors