title: Smart Superstructures with Ultrahigh pH-Sensitivity for Targeting Acidic Tumor Microenvironment: Instantaneous Size Switching and Improved Tumor Penetration.
abstract: The currently low delivery efficiency and limited tumor penetration of nanoparticles remain two major challenges of cancer nanomedicine. Here, we report a class of pH-responsive nanoparticle superstructures with ultrasensitive size switching in the acidic tumor microenvironment for improved tumor penetration and effective in vivo drug delivery. The superstructures were constructed from amphiphilic polymer directed assembly of platinum-prodrug conjugated polyamidoamine (PAMAM) dendrimers, in which the amphiphilic polymer contains ionizable tertiary amine groups for rapid pH-responsiveness. These superstructures had an initial size of ∼80 nm at neutral pH (e.g., in blood circulation), but once deposited in the slightly acidic tumor microenvironment (pH ∼6.5-7.0), they underwent a dramatic and sharp size transition within a very narrow range of acidity (less than 0.1-0.2 pH units) and dissociated instantaneously into the dendrimer building blocks (less than 10 nm in diameter). This rapid size-switching feature not only can facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention effect but also allows faster nanoparticle diffusion and more efficient tumor penetration. We have further carried out comparative studies of pH-sensitive and insensitive nanostructures with similar size, surface charge, and chemical composition in both multicellular spheroids and poorly permeable BxPC-3 pancreatic tumor models, whose results demonstrate that the pH-triggered size switching is a viable strategy for improving drug penetration and therapeutic efficacy.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, Emory University and Georgia Institute of Technology , Atlanta, Georgia 30322, United States.
authors.forename: Jin-Zhi
authors.initials: JZ
authors.lastname: Du
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Xiao-Jiao
authors.initials: XJ
authors.lastname: Du
authors.forename: Song
authors.initials: S
authors.lastname: Shen
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Zhu
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale , Hefei, Anhui 230027, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale , Hefei, Anhui 230027, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Biomedical Engineering, Emory University and Georgia Institute of Technology , Atlanta, Georgia 30322, United States.
authors.forename: Shuming
authors.initials: S
authors.lastname: Nie
authors.affiliation: Hefei National Laboratory for Physical Sciences at the Microscale , Hefei, Anhui 230027, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053758:Nanoparticles; D009369:Neoplasms; D059016:Tumor Microenvironment
chemical_list: D050091:Dendrimers
keywords: drug delivery; nanoparticle; pH-responsive; particle size; tumor microenvironment; tumor penetration