Self-assembled molecular structures as ultrasonically-responsive barrier membranes for pulsatile drug delivery

Abstract

Noninvasive ultrasound has been shown to increase the release rate on demand from drug delivery systems; however, such systems generally suffer from background drug leaching. To address this issue, a drug-containing polymeric monolith coated with a novel ultrasound-responsive coating was developed. A self-assembled molecular structure coating based on relatively impermeable, ordered methylene chains forms an ultrasound-activated on-off switch in controlling drug release on demand, while keeping the drug inside the polymer carrier in the absence of ultrasound. The orderly structure and molecular orientation of these C12 n-alkyl methylene chains on polymeric surfaces resemble self-assembled monolayers on gold. Their preparation and characterization have been published recently (Kwok et al. [Biomacromolecules 2000;1(1):139-148]). Ultrasound release studies showed that a copolymer of 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate (MW 400) coated with such an ultrasound-responsive membrane maintained sufficient insulin for multiple insulin delivery, compared with a substantial burst release during the first 2 h from uncoated samples. With appropriate surface coating coverage, the background leach rate can be precisely controlled. The biological activity of the insulin releasate was tested by assessing its ability to regulate [C14]-deoxyglucose uptake in 3T3-L1 adipocyte cells in a controlled cell culture environment. Uptake triggered by released insulin was comparable to that of the positive insulin control. The data demonstrate that the released insulin remains active even after the insulin had been exposed to matrix synthesis and the methylene chain coating process.

Ultrasonic drug delivery – a general review

“…Kwok et al studied insulin-loaded drug depots of poly(2-hydroxyethyl methacrylate) and poly(ethylene glycol) with a surface layer of C-18 alkyl chains [128]. In the absence of insonation, the alkyl chains appeared to form an organized and less permeable barrier to proteins; upon insonation, the surface organization was apparently disrupted and protein within the depot matrix escaped.…”

Switchable Materials Containing Polyzwitterion Moieties

“…The orthogonal solubility of some polyzwitterions to solvents could typically be used in the processing of organic semiconductors [123,124] and possibly of UCST, representing an open avenue for thermo-responsive and tunable platforms in organic electronic devices [122]. The external trigger as a mechanical force via ultrasonic stimuli as a component of a spatial and time-controlled switchable process represents a highly feasible approach, which was not previously reported [125,126].…”

The Use of Ultrasound and Micelles in Cancer Treatment

“…Thus US may increase even further the enhanced permeability of tumor capillaries which already allow passive targeting of tumors by drugs (26)(27)(28). Kwok et al demonstrated ultrasonic-activated release of insulin from a monolithic drug reservoir with an impermeable surface coating that is disrupted by the action of ultrasound (29). After insonation is stopped, the coating reforms and blocks further release of drug.…”