title: Bimodal tumor-targeting from microenvironment responsive hyaluronan layer-by-layer (LbL) nanoparticles.
abstract: Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful strategy for tumor-specific cancer diagnostics and therapy that can be accomplished using a single bilayer of polyamine and hyaluronan that, when assembled, produce a dynamic and responsive cell-particle interface.
authors.affiliation: Koch Institute for Integrative Cancer Research, ‡Department of Chemical Engineering, and §Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology , 500 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Dreaden
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Morton
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Shopsowitz
authors.forename: Jae-Hyeok
authors.initials: JH
authors.lastname: Choi
authors.forename: Zhou J
authors.initials: ZJ
authors.lastname: Deng
authors.forename: Nam-Joon
authors.initials: NJ
authors.lastname: Cho
authors.forename: Paula T
authors.initials: PT
authors.lastname: Hammond
mesh_terms: D000818:Animals; D001692:Biological Transport; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D053758:Nanoparticles; D011107:Polylysine / Q000737:chemistry; D059016:Tumor Microenvironment
chemical_list: D004337:Drug Carriers; D018960:Hyaluronan Receptors; D011107:Polylysine; D006820:Hyaluronic Acid
keywords: controlled delivery; nanomaterials; nanomedicine; polymer engineering; self-assembly
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