Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, China 2.TOF-PET/CT/MR center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Department of Medicine, Division of Cardiology, Washington University School of Medicine, 4320 Forest Park Avenue, Saint Louis, MO 63108, USA.
Theranostics. 2018 Jan 1;8(2):563-574. doi: 10.7150/thno.21466. eCollection 2018.
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. This proof-of-concept study compared intratumoral localization of fluorescent paramagnetic (M) PFC NP in the Vx2 rabbit model using proton (H) and fluorine (F) magnetic resonance (MR) imaging (3T) following intratracheal (IT) or IV administration. MRI results were corroborated by fluorescence microscopy. Dynamic H-MR and F-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 H and F 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. IT delivery of PFC NP offered unique opportunity to locally deliver PFC NP in high concentrations into lung cancers with minimal extratumor systemic exposure.
80%的肺癌起源于支气管和肺泡的气道黏膜上皮层的微妙癌前变化，这些变化会逐渐深入到实质层。1966 年，全氟化碳（PFC）的液体通气首次在啮齿动物中得到证实，随后在 1996 年作为脂质包裹的 PFC 乳液应用于患有呼吸窘迫综合征的新生儿，以改善肺功能。随后，PFC 纳米颗粒（NP）作为静脉内（IV）血管受限的纳米技术，广泛用于诊断成像和靶向药物输送应用。这项概念验证研究比较了荧光顺磁（M）PFC NP 在 Vx2 兔模型中的肿瘤内定位，方法是使用质子（H）和氟（F）磁共振（MR）成像（3T），分别通过气管内（IT）或静脉内（IV）给药。MRI 结果通过荧光显微镜得到证实。在 IT 给药后 12 小时内，通过动态 H-MR 和 F-MR 图像（3T）获得的 72 小时结果显示，M-PFC NP 在原发性肺 Vx2 肿瘤中进行了显著且逐渐的积累。标记的 H 和 F MR 信号持续超过 72 小时。相比之下，IV M-PFC NP 在注射后最初 2 小时内产生了适度的短暂信号，与初始环形血池肿瘤增强一致。切除肿瘤的荧光显微镜观察结果与 MR 结果一致，并显示 IT 治疗后第 3 天出现大量肿瘤内 NP 沉积，但 IV 治疗后没有。与 PFC NP 表面活性剂结合的罗丹明磷脂在第 3 天广泛分布于肿瘤内，这与先前报道的基于半融合的接触药物输送机制一致。荧光显微镜还显示，在 IT 治疗转移性 Vx2 肺癌时，给予 IT 的 M-PFC NP 也具有相似的高浓度。在小鼠中的生物分布研究表明，IV 给予的 M-PFC NP 分布到网状内皮器官，而相同剂量的 IT 给予则基本上不在肺以外的部位检测到。IT 给予的 PFC NP 不会影响兔子的行为或损害呼吸功能。PFC NP 对培养细胞的影响可以忽略不计，当 IV 或 IT 给予时，兔子的血液学或血清临床化学参数均未发生变化。PFC NP 的 IT 给药为将 PFC NP 以高浓度局部递送至肺癌提供了独特的机会，同时最小化了肿瘤外的全身暴露。
