title: Development of nanodroplets for histotripsy-mediated cell ablation.
abstract: This report describes the synthesis of amphiphilic copolymers (ABC-1 and ABC-2) composed of a hydrophilic poly(ethylene glycol) (PEG) block, a central poly(acrylic acid) (PAA) block, and a random copolymer of heptadecafluorodecyl methacrylate (HDFMA) and methyl methacrylate (MMA) forming the hydrophobic block, which are used to form nanodroplets for ultrasound-mediated cell ablation. Specifically, the effect of molecular weight of PEG and P(HDFMA-co-MMA) blocks on polymer's ability to self-assemble around a variable amount (0%, 1%, and 2% v/v) of perfluoropentane (PFP) forming nanodroplets is investigated. The ability of different nanodroplets formulations embedded with a monolayer of red blood cells (RBCs) in tissue-mimicking agarose phantoms to initiate and sustain a bubble cloud in response to ultrasound treatments with different acoustic pressures and the associated ablation of RBCs were also investigated. Results show that ABC-1 polymer composed of a 2 kDa PEG block and a 6.7 kDa P(HDFMA-co-MMA) block better encapsulate the PFP core compared to ABC-2 polymer composed of a 5 kDa PEG block and 11.4 kDa P(HDFMA-co-MMA) block. Further, the ablative capacity indicated by the damage area in the RBCs monolayer increased with the increase in PFP content and reached its maximum with the nanodroplets formulated using ABC-1 polymer and encapsulating 2% v/v PFP. The nanodroplets formulated using ABC-1 polymer and loaded with 2% PFP produced the cavitation cloud and exhibited their ablative effect at an acoustic pressure that is 2.5-fold lower than the acoustic pressure needed to generate the same effect using a histotripsy (ultrasound) pulse alone, which indicates the ability of these nanodroplets to achieve targeted and self-limiting fractionation of disease cells while sparing neighboring healthy ones. Results also show that effective nanodroplets maintained their size and concentration upon incubation with bovine serum albumin at 37 °C for 24 h, which indicates their stability in physiologic conditions and their promise for in vivo cancer cell ablation.
authors.affiliation: Department of Biomedical Engineering, College of Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Yuksel Durmaz
authors.forename: Eli
authors.initials: E
authors.lastname: Vlaisavljevich
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Mohamed
authors.initials: M
authors.lastname: ElSayed
mesh_terms: D000818:Animals; D002417:Cattle; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D004912:Erythrocytes; D005466:Fluorocarbons / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D010420:Pentanes
chemical_list: D004337:Drug Carriers; D005466:Fluorocarbons; D011092:Polyethylene Glycols; D011108:Polymers; C008806:perfluoropentane; D010420:Pentanes
keywords: amphiphilic polymer; cell ablation; nanodroplets; perfluorocarbon; therapeutic ultrasound