title: Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue.
abstract: Therapeutic nanoparticles (NPs) approved for clinical use in solid tumor therapy provide only modest improvements in patient survival, in part due to physiological barriers that limit delivery of the particles throughout the entire tumor. Here, we explore the thresholds for NP size and surface poly(ethylene glycol) (PEG) density for penetration within tumor tissue extracellular matrix (ECM). We found that NPs as large as 62nm, but less than 110nm in diameter, diffused rapidly within a tumor ECM preparation (Matrigel) and breast tumor xenograft slices ex vivo. Studies of PEG-density revealed that increasing PEG density enhanced NP diffusion and that PEG density below a critical value led to adhesion of NP to ECM. Non-specific binding of NPs to tumor ECM components was assessed by surface plasmon resonance (SPR), which revealed excellent correlation with the particle diffusion results. Intravital microscopy of NP spread in breast tumor tissue confirmed a significant difference in tumor tissue penetration between the 62 and 110nm PEG-coated NPs, as well as between PEG-coated and uncoated NPs. SPR assays also revealed that Abraxane, an FDA-approved non-PEGylated NP formulation used for cancer therapy, binds to tumor ECM. Our results establish limitations on the size and surface PEG density parameters required to achieve uniform and broad dispersion within tumor tissue and highlight the utility of SPR as a high throughput method to screen NPs for tumor penetration.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Jimena G
authors.initials: JG
authors.lastname: Dancy
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Aniket S
authors.initials: AS
authors.lastname: Wadajkar
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Schneider
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Joseph R H
authors.initials: JRH
authors.lastname: Mauban
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Olga G
authors.initials: OG
authors.lastname: Goloubeva
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Woodworth
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States. Electronic address: jwinkles@som.umaryland.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, United States; Center for Biomedical Engineering and Technology, University of Maryland School Medicine, Baltimore, MD 21201, United States. Electronic address: akim@smail.umaryland.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kim
mesh_terms: D000068196:Albumin-Bound Paclitaxel / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D004337:Drug Carriers / Q000032:analysis / Q000378:metabolism*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000032:analysis / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000032:analysis / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000032:analysis / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011509:Proteoglycans / Q000378:metabolism; D013499:Surface Properties
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000970:Antineoplastic Agents; D004337:Drug Carriers; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C506643:liposomal doxorubicin; C059485:matrigel; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003094:Collagen
keywords: Intravital microscopy; Multiple particle tracking (MPT); Nanoparticles; PEG density; Surface plasmon resonance (SPR); Tumor tissue penetration