Ultrasound contrast agents are typically microbubbles (MB) with a gas core that is stabilized by a shell made of lipids, proteins, or polymers. The high impedance mismatch between the gas core and an ...aqueous environment produces strong contrast in ultrasound (US). Poly(lactic acid) (PLA) MB, previously developed in our laboratory, have been shown to be highly echogenic both in vitro and in vivo. In recent years, MB have established their role in contrast enhanced medical imaging and bio-nanotechnology. We show that these microbubbles have potential in various applications including multimodal imaging and as a targeted drug delivery vehicle. Combining US with other imaging modalities such as fluorescence, magnetic resonance imaging (MRI), or computer tomography (CT) could improve the accuracy of many US applications and provide more comprehensive diagnostic information. Furthermore, our MB have the capacity to house a drug in the PLA shell and create drug-loaded nano fragments in situ when passing through an ultrasound beam. The nano-sized fragments can be taken up into the tumor via the enhanced permeability and retention (EPR) effect. To create multimodal contrast agents, we hypothesized that the polymer shell of our PLA MB platform could accommodate additional payloads. In this thesis, we therefore modified our current MB by encapsulating imaging-related nanoparticles including aqueous or organic quantum dots (QD), magnetic iron oxide nanoparticles (MNP), or gold nanoparticles (AuNP) to create bimodality platforms in a manner that minimally compromised the performance of each individual imaging technique. Controlled drug delivery system using microbubbles as vehicle in conjunction with ultrasound have been previously studied to reduce drug dosage, systemic toxicity, and side effects for treatment of cancer. To enhance more loading of drug on the MB for a more effective treatment, nanoparticles conjugated with drugs on the surface were used in the study. Nanopaticles are here used to take advantage of the increased surface area per volume ratio for the cancer drug to conjugate on the surface. These drug conjugated nanoaprticles have then been encapsulated inside the MB shell. AuNP and MNP were used in the study of drug delivery. The DOX-AuNP + DOX MB showed significantly higher loading than loading by the method that was previously developed in our lab, DOX-MB with drug payload (43.7 vs. 16.23 µg DOX / mg MB) and encpasulation effiency (48.5% vs. 22.1%). The agents achieved 19 dB of US contrast enhancement in vitro and are shown to provide visible contrast using clinical ultrasound machines. The agent also shown to be able to sustain release of DOX for more than period of 1 week, as well as to form nano polymer fragments (n-Sh) after being insonated for 20 minutes. In vitro therapeutics activity of these agents was shown with both a human breast cancer cell line (MDA-MB-231) and a hepatoma cancer cell line (Huh7). Using a model system for in situ nano-shard formation, we also demonstrated that DOX-AuNP + DOX MB can trigger cell death and caused cell lysis within 12 hours of treatment. This work brings together the advantages of multimodal imaging and drug delivery platforms to significant improve outcomes in cancer diagnostic and treatment.
Critical limb-threatening ischemia (CLTI) is a severe condition characterized by rest pain and ischemic tissue loss that affects 5% to 10% of people with peripheral artery disease. In the United ...States, there are few Food and Drug Administration-approved devices for the primary treatment of arteries below-the-knee (BTK). Unfortunately, all suffer from high restenosis rates due to intimal hyperplasia, elastic recoil, and untreated dissection because of a lack of scaffolding. The Esprit BTK system is a resorbable, drug-eluting scaffold device with the potential to address an unmet need in people suffering from CLTI because of infrapopliteal atherosclerosis. The LIFE-BTK (pivotaL Investigation of saFety and Efficacy of drug-eluting resorbable scaffold treatment-Below The Knee) randomized controlled trial (RCT) is a prospectively designed premarket evaluation of the Esprit BTK drug-eluting resorbable scaffold used in the treatment of those patients.
The LIFE-BTK trial enrolled 261 subjects with CLTI for the RCT and a further 7 subjects for a pharmacokinetic substudy. The objective of the RCT was to evaluate the safety and efficacy of the Esprit BTK scaffold compared to percutaneous transluminal angioplasty. The primary efficacy end point was a composite of limb salvage and primary patency at 12 months. The primary safety end point is freedom from major adverse limb events and peri-operative death at 6 months and 30 days, respectively. Clinical follow-up care is planned for 5 years.
Novel devices must be tested in RCTs to evaluate their safety and efficacy compared to the standard of care if we are to improve outcomes for this challenging group of patients.
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•Infrapopliteal interventions are still limited by durability because of restenosis and acute recoil.•Evidence suggests drug-eluting resorbable scaffolds may improve mid-long-term patency.•A randomized controlled trial comparing the Esprit scaffold to percutaneous angioplasty.•The trial design methodology is presented in detail.
Ultrasound Contrast Agents (UCA) are microencapsulated gas bubbles used to increase the overall contrast of the ultrasound (US) image. Novel multimodal polymeric UCA containing additional contrast ...agents that are active in multiple imaging modalities have been developed. Four platforms of loaded poly (lactic acid) (PLA) shelled UCA are presented. The first two platforms co-encapsulate aqueous or organic Quantum Dots (QD). The third platform contains magnetic iron oxide nanoparticles (MNP). The fourth platform contains gold nanoparticles (AuNP). All platforms showed that the properties of UCA are maintained as well as the properties of additional encapsulated contrast agent. This study explores the potential application for improving the screening of a subject using at least two different modalities.
Ultrasound Contrast Agents (UCA) are microencapsulated gas bubbles used to increase the overall contrast of the ultrasound (US) image. Novel multimodal polymeric UCA containing additional contrast ...agents that are active in multiple imaging modalities have been developed. Three platforms of loaded poly (lactic acid) (PLA) shelled UCA are presented. The first two platforms co-encapsulate aqueous or organic Quantum Dots (QD). The Third platform contains magnetic iron oxide nanoparticles (MNP). All platforms showed that the properties of UCA are maintained as well as the properties of additional encapsulated contrast agent. This study explores the potential application for improving the screening of a subject using at least two different modalities, e.g. ultrasound and magnetic resonance imaging.
