Hybrid (Bovine Serum Albumin)/Poly(N-vinyl-2-pyrrolidone-co-acrylic acid)-Shelled Microbubbles as Advanced Ultrasound Contrast Agents

Abstract

Microbubbles are routinely used ultrasound contrast agents in the clinic. While a soft protein shell is commercially preferable for imaging purposes, a rigid polymer shell demonstrates prolonged agent stability. Hence, combining polymers and proteins in one shell composition can advance microbubble properties. We formulated the hybrid “protein–copolymer” microbubble shell with a complex of bovine serum albumin and an amphiphilic copolymer of N-vinyl-2-pyrrolidone and acrylic acid. The resulting microbubbles demonstrated advanced physicochemical and acoustic properties, preserving in vitro biocompatibility. Adjusting the mass ratio between protein and copolymer allowed fine tuning of the microbubble properties of concentration (by two orders, up to 1010 MBs/mL), mean size (from 0.8 to 5 μm), and shell thickness (from 28 to 50 nm). In addition, the minimum air–liquid surface tension for the “protein–copolymer” solution enabled the highest bubble concentration. At the same time, a higher copolymer amount in the bubble shell increased the bubble size and tuned duration and intensity of the contrast during an ultrasound procedure. Demonstrated results exemplify the potential of the hybrid “protein–polymer” microbubble shell, allowing tailoring of microbubble properties for image-guided applications, combining advances of each material involved in the formulation.

Hybrid ultrasound and photoacoustic contrast agent designs combining metal phthalocyanines and PBCA microbubbles

“…This is important, since variations in MB size and shell characteristics may alter (or even hamper) the MB acoustic properties. 35,48…”

Nanoaggregates of Biphilic Carboxyl-Containing Copolymers as Carriers for Ionically Bound Doxorubicin

“…It was previously shown by the 1 H NMR, 13 C NMR, IR and MALDI-TOF spectroscopy methods that the radical copolymerization of N-vinyl-2-pyrrolidone and acrylic acid initiated by AIBN in the presence of n-octadecyl-mercaptan yields amphiphilic copolymers ( Scheme 1 ) capable of forming nanosized aggregates in aqueous solutions [ 50 , 55 ].…”

“…The number-average molecular weight of the random copolymers was determined by end group analysis [ 55 ], which was about 6500 ± 500 regardless of the N-vinyl-2-pyrrolidone/(acrylic acid) ratio in the initial reaction mixture.…”

Toxicity Evaluation and Controlled-Release of Curcumin-Loaded Amphiphilic Poly-N-vinylpyrrolidone Nanoparticles: In Vitro and In Vivo Models

“…The reaction was carried out at 70°C for 3 h. The resulting solution was dialyzed against water, frozen and freeze-dried. Molecular weight was determined by reverse iodometric titration according to the method described by the authors in [ 44 ] and it was 6 kDa. The absence of solvent residues was determined by thermogravimetric analysis.…”