Eighty percent of lung cancers originate as subtle premalignant changes in the airway mucosal epithelial layer of bronchi and alveoli, which evolve and penetrate deeper into the parenchyma. Liquid-ventilation, with perfluorocarbons (PFC) was first demonstrated in rodents in 1966 then subsequently applied as lipid-encapsulated PFC emulsions to improve pulmonary function in neonatal infants suffering with respiratory distress syndrome in 1996. Subsequently, PFC nanoparticles (NP) were extensively studied as intravenous (IV) vascular-constrained nanotechnologies for diagnostic imaging and targeted drug delivery applications.Methods: This proof-of-concept study compared intratumoral localization of fluorescent paramagnetic (M) PFC NP in the Vx2 rabbit model using proton (1H) and fluorine (19F) magnetic resonance (MR) imaging (3T) following intratracheal (IT) or IV administration. MRI results were corroborated by fluorescence microscopy.Results: Dynamic 1H-MR and 19F-MR images (3T) obtained over 72 h demonstrated marked and progressive accumulation of M-PFC NP within primary lung Vx2 tumors during the first 12 h post IT administration. Marked 1H and 19F MR signal persisted for over 72 h. In contradistinction, IV M-PFC NP produced a modest transient signal during the initial 2 h post-injection that was consistent circumferential blood pool tumor enhancement. Fluorescence microscopy of excised tumors corroborated the MR results and revealed enormous intratumor NP deposition on day 3 after IT but not IV treatment. Rhodamine-phospholipid incorporated into the PFC nanoparticle surfactant was distributed widely within the tumor on day 3, which is consistent with a hemifusion-based contact drug delivery mechanism previously reported. Fluorescence microscopy also revealed similar high concentrations of M-PFC NP given IT for metastatic Vx2 lung tumors. Biodistribution studies in mice revealed that M-PFC NP given IV distributed into the reticuloendothelial organs, whereas, the same dosage given IT was basically not detected beyond the lung itself. PFC NP given IT did not impact rabbit behavior or impair respiratory function. PFC NP effects on cells in culture were negligible and when given IV or IT no changes in rabbit hematology nor serum clinical chemistry parameters were measured.Conclusion: IT delivery of PFC NP offered unique opportunity to locally deliver PFC NP in high concentrations into lung cancers with minimal extratumor systemic exposure.

Microbubbles are widely used as ultrasound contrast agents owing to their excellent echoing characteristics under ultrasound radiation. However, their short sonographic duration and wide size distribution still hinder their application. Herein, we present a hard-template approach to produce perfluoropropane-loaded cerasomal microbubbles (PLCMs) with uniform size and long sonographic duration. The preparation of PLCMs includes deposition of Si-lipids onto functionalized CaCO3 microspheres, removal of their CaCO3 cores and mild infusion of perfluoropropane. In vitro and in vivo experiments showed that PLCMs had excellent echoing characteristics under different ultrasound conditions. More importantly, PLCMs could be imaged for much longer than SonoVue (commercially used microbubbles) under the same ultrasound parameters and concentrations. Our results demonstrated that PLCMs have great potential for use as a novel contrast agent in ultrasound imaging.

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Various nanoformulations of perfluorocarbon have been developed thus far, to achieve ultrasound imaging of tumors and tumor-targeted therapy. However, their application has been greatly limited by their short sonographic duration and large size distribution. A novel theranostic agent was constructed based on gold nanoshell cerasome-encapsulated L-menthol (GNC-LM). Owing to the sustained and controllable generation of L-menthol bubbles under near-infrared laser irradiation, GNC-LM showed good performance in contrast enhancement of ultrasound imaging in vivo. GNC-LM could be imaged for 30 min, which is much longer than the imaging time of SonoVue (commercially used microbubbles). Moreover, photothermal therapy (PTT) based on the light-to-heat conversion of the nanosystem effectively ablated the tumor. Our study demonstrated the promising potential of the obtained GNC-LM to serve as a therapeutic nanoprobe for ultrasound contrast imaging and PTT of tumors.