Ultrasound-responsive Polymers for Controlled Drug Delivery

The project is focused on the preparation of new polymer materials able to selectively degrade upon ultrasound stimulation, with potential application in controlled drug delivery. In many diseases and clinical conditions, such as diabetes, osteoporosis, pain or inflammation, the control over the exact dose, precise timing and repeatable drug delivery is crucial. Such control over the drug release may be achieved by using drug carriers able to respond to an external or internal stimulus, such as change of temperature, pH, electromagnetic field, concentration of enzymes, etc. Ultrasound (US) represents one of the most promising external stimuli for the controlled delivery of drugs, due to its non-invasive nature, availability, low cost, and combination of both therapeutic and diagnostic abilities. Therefore, development of polymeric drug carriers that are able to respond to ultrasound is a hot topic in the current scientific scenario and may have a great impact on future therapeutic paradigms. However, the currently used US-responsive drug delivery systems often suffers by premature spontaneous release of encapsulated drug by diffusion. This spontaneous release not only hampers the long- term functionality of the drug delivery device, but also may be harmful for the patients. This project aims to reduce this spontaneous release, thus greatly enhancing the controllability of drug delivery, by two proposed approaches. The first approach involves the preparation of surface-attached polymer chains with incorporated US-responsive units. As US-responsive units, we will use weak bonds able to selectively break upon US stimulation. As polymers, we will use poly(2-oxazoline)s and polypeptoids, two polymers platforms currently intensively investigated as biomaterials due to their outstanding properties, synthetic variability and excellent biosafety. The model drug (fluorescent dye) will be covalently bound to the polymer chains. The second approach consists of the preparation of crosslinked thin films with the model drug attached to the network by US- responsive units. After the US-stimulation, the crosslinks will be broken and the model drug will be released. We will systematically study the US conditions, such as intensity, frequency and duration of the stimulation, in order to establish the fundamentals for the design of a safe and effective drug carrier.

The project entitled "Ultrasound-responsive polymer materials for drug delivery" is focused on the preparation of new polymer materials able to selectively degrade upon ultrasound stimulation, with potential application in controlled drug delivery. In many diseases and clinical conditions, such as diabetes, osteoporosis, pain or inflammation, the control over the exact dose, precise timing and repeatable drug delivery is crucial. Such control over the drug release may be achieved by using drug carriers able to respond to an external or internal stimulus, such as change of temperature, pH, electromagnetic field, concentration of enzymes, etc. Ultrasound (US) represents one of the most promising external stimuli for the controlled delivery of drugs, due to its non-invasive nature, availability, low cost, and combination of both therapeutic and diagnostic abilities. Therefore, development of polymeric drug carriers that are able to respond to ultrasound is a hot topic in the current scientific scenario and may have a great impact on future therapeutic paradigms. The aim of this project was to develop novel polymeric materials able to respond to ultrasound in an controlled manner. We selected poly(2-oxazoline)s as polymer platform currently intensively investigated as biomaterials due to their outstanding properties, synthetic variability and excellent biosafety. As US-responsive units, we used weak bonds able to selectively break upon US stimulation. More specifically, we selected coumarin, a compound which is also naturally occurring in tonka beans. Within the project, we synthesized a novel monomer, 2-oxazoline with coumarin unit in the side chain. This monomer was further used to prepare long polymers chains, poly(2-oxazoline)s containing coumarin units. Upon UV irradiation, coumarin units formed dimers, which led to the formation of soft hydrogel structures. To study the effect of ultrasonication on our soft hydrogels, we developed a special measurement device. We combined two different devices: a rheometer, the device for measurement of mechanical properties of hydrogels with an ultrasonic transducer, which changes electric signals to mechanical waves. With such enhanced rheometer, we were able to detect the changes in softness of our coumarin-containing hydrogels during ultrasonication. This special rheometer can, in the future, contribute to better understanding of interactions of ultrasonic waves with polymeric materials.