Local Intratracheal Delivery of Perfluorocarbon Nanoparticles to Lung Cancer Demonstrated with Magnetic Resonance Multimodal Imaging

Abstract

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.

Folate receptor‐targeted 19F MR molecular imaging and proliferation evaluation of lung cancer

“…First, only two kinds of lung cancer subcutaneous tumor models were included; future study should include a variety of different kinds of cancers to study the relationship between FR expression and tumor proliferation. Second, as PFC has excellent respiratory gas carrying ability, some other cancer models and delivery methods are needed for further lung cancer study, such as the orthotopic lung cancer model with intratracheal delivery of PFC in the Wu et al study . Finally, we did not perform folate‐competing experiments in 19 F MRI in vivo, because of the short blood clearance time of folate.…”

“…Second, as PFC has excellent respiratory gas carrying ability, some other cancer models and delivery methods are needed for further lung cancer study, such as the orthotopic lung cancer model with intratracheal delivery of PFC in the Wu et al study. 20 Finally, we did not perform folate-competing experiments in 19 F MRI in vivo, because of the short blood clearance time of folate.…”

“…Perfluorocarbon nanoparticles were formulated as previously described . Briefly, the PFC emulsion is comprised of 20% (v/v) perfluoro‐15‐crown‐5‐ether (PFCE).…”

“…Perfluorocarbon nanoparticles were formulated as previously described. 20 Briefly, the PFC emulsion is comprised of 20% (v/v) perfluoro-15-crown-5-ether (PFCE). PFC nanoparticles can be used as 19 F MRI tracers because they contain very high concentrations of 19 F. They also carry a payload of 5 mol% 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic acid (gadolinium salt) (Gd-DTPA-DPPE) as a T 1 -weighted MRI constituent, and 0.1 mol% 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (ammonium salt) (16:0 Liss Rhod PE) as a fluorescent part.…”

Fluorinated MRI Contrast Agents and Their Versatile Applications in the Biomedical Field

“…Wu et al [133] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 should also be developed more thoroughly way since the fluorine signal can be registered with a good sensibility in a relatively short acquisition time. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58…”