Subject(s)
Brain/metabolism , Consciousness/physiology , Death , Neurosciences , Spirituality , Humans , Philosophy, MedicalSubject(s)
Coma/psychology , Death , Mind-Body Relations, Metaphysical , Consciousness , Humans , MemoryABSTRACT
Nanoparticle (NP) drug delivery vehicles may eventually offer improved tumor treatments; however, NP delivery from the bloodstream to tumors can be hindered by poor convective and/or diffusive transport. We tested whether poly(lactic-co-glycolic acid) NP delivery can be improved by covalently linking them to ultrasound (US)-activated microbubbles in a "composite-agent" formulation and whether drug 5-fluorouracil (5FU)-loaded NPs delivered in this fashion inhibit the growth of tumors that are typically not responsive to intravenously administered 5FU. After intravenous composite-agent injection, C6 gliomas implanted on Rag-1(-/-) mice were exposed to pulsed 1 MHz US, resulting in the delivery of 16% of the initial NP dose per gram tissue. This represented a five- to 57-fold increase in NP delivery when compared to multiple control groups. 5FU-bearing NP delivery from the composite-agent formulation resulted in a 67% reduction in tumor volume at 7 days after treatment, and animal survival increased significantly when compared to intravenous soluble 5FU administration. We conclude that NP delivery from US-activated composite agents may improve tumor treatment by offering a combination of better targeting, enhanced payload delivery, and controlled local drug release.
Subject(s)
Fluorouracil/administration & dosage , Microbubbles , Nanoparticles , Administration, Intravenous , Animals , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Drug Delivery Systems/methods , Fluorouracil/chemistry , Mice , Nanoparticles/chemistry , Neoplasms/drug therapy , Neoplasms/mortality , Neoplasms/pathology , Rats , Tumor Burden/drug effectsABSTRACT
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.
