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: Yasemin Yuksel Durmaz, Eli Vlaisavljevich, Zhen Xu, Mohamed ElSayed
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 11 Issue 10 Pg. 3684-95 (Oct 06 2014) ISSN: 1543-8392 [Electronic] United States
• PMID: 25137434 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Carriers
• Fluorocarbons
• Polymers
• Polyethylene Glycols
• perfluoropentane

Topics

• Animals
• Cattle
• Drug Carriers (chemistry)
• Drug Delivery Systems (methods)
• Erythrocytes
• Fluorocarbons (chemistry)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Polyethylene Glycols (chemistry)
• Polymers (chemistry)