Thin-Shelled PEGylated Perfluorooctyl Bromide Nanocapsules for Tumor-Targeted Ultrasound Contrast Agent.

Arifudin Achmad,Yoshito Tsushima,Hirofumi Hanaoka,Aiko Yamaguchi

doi:10.1155/2018/1725323

Abstract

Shell thickness determines the acoustic response of polymer-based perfluorooctyl bromide (PFOB) nanocapsule ultrasound contrast agents. PEGylation provides stealth property and arms for targeting moieties. We investigated a modulation in the polymer formulation of carboxy-terminated poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l-lactide-co-glycolide)-block-polyethylene glycol (PLGA-b-PEG) to produce thin-shelled PFOB nanocapsules while keeping its echogenicity, stealth property, and active targeting potential. Polymer formulation contains 40% PLGA-PEG that yields the PEGylated PFOB nanocapsules of approximately 150 nm size with average thickness-to-radius ratio down to 0.15, which adequately hindered phagocytosis. Functionalization with antibody enables in vitro tumor-specific targeting. Despite the acoustic response improvement, the in vivo tumor accumulation was inadequate to generate an observable acoustic response to the ultrasound power at the clinical level. The use of PLGA and PLGA-PEG polymer blend allows the production of thin-shelled PFOB nanocapsules with echogenicity improvement while maintaining its potential for specific targeting.

Highlights

Gas-lipid microbubbles as ultrasound contrast agents (UCAs) enable microvasculature visualization but are incapable of tumor molecular evaluation due to their inability to extravasate and poor stability
We evaluated whether the blends of carboxyterminated PLGA and PLGA-polyethylene glycol (PEG) can produce thin-shelled PEGylated PFOB nanocapsules for tumor-targeting UCAs
PFOB encapsulation was maintained in all nanocapsules formulation regardless the PLGA-PEG percentage (Supplementary Figure S1)

Summary

Introduction

Gas-lipid microbubbles as ultrasound contrast agents (UCAs) enable microvasculature visualization but are incapable of tumor molecular evaluation due to their inability to extravasate and poor stability. Nanometric UCAs may directly reach molecular targets in tumor cells by the enhanced permeation and retention (EPR) e ect if they are stable and have targeting capability [1] Regarding their nanoscale design, a precise balance has to be made between material selection and physicochemical properties, including morphology, stability, and acoustic response [2]. Reduction of PLGA amount relative to PFOB in the polymer formulation lowered thicknessto-radius (T/R) ratio and raised acoustic response of plain PFOB nanocapsules made by the emulsion evaporation method [4, 5]. This reduction strategy may not apply to every polymer [13,14,15]. E varying amount of PLGA-PEG within the formulation was assessed to achieve optimum hindrance from phagocytosis. e functionalization of the PEG chains with monoclonal antibody cetuximab was tested for active targeting of epidermal growth factor receptor- (EGFR-) positive tumor

Materials and Methods

Results

Evaluation of Nanocapsule EGFR-Targeting Property

Conclusions