Abstract
Targeted delivery of nanomedicine/nanoparticles (NM/NPs) to the site of disease (e.g., the tumor or lung injury) is of vital importance for improved therapeutic efficacy. Multimodal imaging platforms provide powerful tools for monitoring delivery and tissue distribution of drugs and NM/NPs. This study introduces a preclinical imaging platform combining X-ray (two modes) and fluorescence imaging (three modes) techniques for time-resolved in vivo and spatially resolved ex vivo visualization of mouse lungs during pulmonary NP delivery. Liquid mixtures of iodine (contrast agent for X-ray) and/or (nano)particles (X-ray absorbing and/or fluorescent) are delivered to different regions of the lung via intratracheal instillation, nasal aspiration, and ventilator-assisted aerosol inhalation. It is demonstrated that in vivo propagation-based phase-contrast X-ray imaging elucidates the dynamic process of pulmonary NP delivery, while ex vivo fluorescence imaging (e.g., tissue-cleared light sheet fluorescence microscopy) reveals the quantitative 3D drug/particle distribution throughout the entire lung with cellular resolution. The novel and complementary information from this imaging platform unveils the dynamics and mechanisms of pulmonary NM/NP delivery and deposition for each of the delivery routes, which provides guidance on optimizing pulmonary delivery techniques and novel-designed NM for targeting and efficacy.
Highlights
Lung diseases are among the leading causes of deaths worldwide
Building on our previously published in vivo Propagationbased phase-contrast X-ray imaging (PB-PCXI) studies in murine lungs,[18,24] the present study demonstrates that combined in vivo PB-PCXI and ex vivo fluorescence imaging can provide complementary information, which enhances the understanding of complex processes such as NM/NP delivery to the lung in a quantitative way on various scales
Encapsulated or conjugated hybrid particles consisting of one fluorescent and one X-rayabsorbing material, such as iodinated polymers or liposomes with fluorescent dyes that have been widely used for bimodal imaging of NP accumulation in tumors,[10,32,33,53] could be useful in future pulmonary studies. In this proof-of-concept study, we introduced and validated a multimodal imaging approach for comprehensive understanding of the mechanisms of pulmonary NP delivery in the context of dynamics of the delivery process, deposited dose, regional distribution, and cellular localization of NP in the whole murine lung
Summary
According to the World Health Organization[1] the chronic obstructive pulmonary disease (COPD) and lung cancer have even been rising from the fourth and ninth in 2000 to the third and sixth of most deadly disease in 2016, respectively. For treatment of lung diseases, direct application of the drug to the lung via aerosol inhalation is widely used due to its high therapeutic index, i.e., high efficacy at the site of disease and low side effects in secondary organs. Inhalation therapy is a cornerstone for the treatment of pulmonary infections, asthma, COPD, and cystic fibrosis, and treatment of lung cancer or even nonpulmonary disease such as diabetes is within reach.[2,3] nanotechnology enabled drugs (nanomedicines (NMs)) offer new diagnostic and therapeutic options for cancer and other diseases leveraging their unique features for controlled release, reduced drug toxicity, prolonged.
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