Covalently Linking Poly(lactic-co-glycolic acid) Nanoparticles to Microbubbles Before Intravenous Injection Improves their Ultrasound-Targeted Delivery to Skeletal Muscle

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 7; no. 9; pp. 1227 - 1235
• Main Authors: Burke, Caitlin W., Hsiang, Yu-Han J., Alexander IV, Eben, Kilbanov, Alexander L., Price, Richard J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 09.05.2011; WILEY‐VCH Verlag
• Subjects: Animals; Injections, Intravenous - methods; Lactic Acid - chemistry; Mice; Mice, Inbred BALB C; Microbubbles; Muscle, Skeletal - metabolism; nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Polyglycolic Acid - chemistry; Polylactic Acid-Polyglycolic Acid Copolymer; skeletal muscle; targeted drug delivery; Ultrasonics; ultrasound
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.201001934

Intravenously injected nanoparticles can be delivered to skeletal muscle through capillary pores created by the activation of microbubbles with ultrasound; however, strategies that utilize coinjections of free microbubbles and nanoparticles are limited by nanoparticle dilution in the bloodstream. Here, improvement in the delivery of fluorescently labeled ≈150 nm poly(lactic‐co‐glycolic acid) nanoparticles to skeletal muscle is attempted by covalently linking them to albumin‐shelled microbubbles in a composite agent formulation. Studies are performed using an experimental model of peripheral arterial disease, wherein the right and left femoral arteries of BalbC mice are surgically ligated. Four days after arterial ligation, composite agents, coinjected microbubbles and nanoparticles, or nanoparticles alone are administered intravenously and 1 MHz pulsed ultrasound was applied to the left hindlimb. Nanoparticle delivery was assessed at 0, 1, 4, and 24 h post‐treatment by fluorescence‐mediated tomography. Within the coinjection group, both microbubbles and ultrasound are found to be required for nanoparticle delivery to skeletal muscle. Within the composite agent group, nanoparticle delivery is found to be enhanced 8‐ to 18‐fold over ‘no ultrasound’ controls, depending on the time of measurement. A maximum of 7.2% of the initial nanoparticle dose per gram of tissue was delivered at 1 hr in the composite agent group, which was significantly greater than in the coinjection group (3.6%). It is concluded that covalently linking 150 nm‐diameter poly(lactic‐co‐glycolic acid) nanoparticles to microbubbles before intravenous injection does improve their delivery to skeletal muscle. Composite drug‐delivery agents comprising 150 nm poly(lactide‐co‐glycolide) nanoparticles adhered to 2–4 μm dia­meter albumin‐shelled microbubbles are used to improve nanoparticle delivery to ultrasound‐targeted skeletal muscle.