Impact of Hydrogel Nanoparticle Size and Functionalization on In Vivo Behavior for Lung Imaging and Therapeutics

Abstract

Polymer chemistry offers the possibility of synthesizing multifunctional nanoparticles which incorporate moieties that enhance diagnostic and therapeutic targeting of cargo delivery to the lung. However, since rules for predicting particle behavior following modification are not well defined, it is essential that probes for tracking fate in vivo are also included. Accordingly, we designed polyacrylamide-based hydrogel particles of differing sizes, functionalized with a nona-arginine cell-penetrating peptide (Arg9), and labeled with imaging components to assess lung retention and cellular uptake after intratracheal administration. Radiolabeled microparticles (1–5 µm diameter) and nanoparticles (20–40 nm diameter) without and with Arg9 showed diffuse airspace distribution by positron emission tomography imaging. Biodistribution studies revealed that particle clearance and extrapulmonary distribution was, in part, size dependent. Microparticles were rapidly cleared by mucociliary routes but unexpectedly, also through the circulation. In contrast, nanoparticles had prolonged lung retention enhanced by Arg9 and were significantly restricted to the lung. For all particle types, uptake was predominant in alveolar macrophages, and, to a lesser extent, lung epithelial cells. In general, particles did not induce local inflammatory responses, with the exception of microparticles bearing Arg9. Whereas microparticles may be advantageous for short-term applications, nano-sized particles constitute an efficient high-retention and non-inflammatory vehicle for the delivery of diagnostic imaging agents and therapeutics to lung airspaces and alveolar macrophages that can be enhanced by Arg9. Importantly, our results show that minor particle modifications may significantly impact in vivo behavior within the complex environments of the lung, underscoring the need for animal modeling.

Antisense peptide nucleic acid-functionalized cationic nanocomplex for in vivo mRNA detection

“…As expected, for non-specific uptake of the nanocomplexes of antisense and mismatched PNAs and non-specific clearance from uninduced cells, the biodistribution in the non-targeted organs showed similar profiles at both 4 and 24 h. Accumulation of radioactivity in the thyroid, liver and kidney is likely due to transit from the air space through the alveolar epithelium-capillary endothelial barrier [54], which was also confirmed by measurable activity in the blood at 4 and 24 h p.i. Similar to the reported extra pulmonary fate of nanoparticles, following intratracheal instillation [51,55], significant amounts of gastrointestinal tract clearance were observed for both nanocomplexes, likely due to mucociliary clearance. Recently, a report showed that the translocation of nanoparticles from the lung airspace to the body was sizedependent, irrespective of chemical composition, shape and conformational flexibility.…”

Adenosine monophosphate is elevated in the bronchoalveolar lavage fluid of mice with acute respiratory toxicity induced by nanoparticles with high surface hydrophobicity

“…Most of the studies of low-toxicity nanomaterials have been conducted using rigid, crystalline, insoluble materials, whereas there has been less research on the response of the respiratory system to the administration of organic nanomaterials (Beyerle et al, 2011;Dailey et al, 2006;Harush-Frenkel et al, 2010;Liu et al, 2009;Nassimi et al, 2009), sometimes referred to as soft nanomaterials (Nalwa, 2009). Organic nanomaterials are increasingly being developed as inhaled nanomedicines or components of aerosol-based consumer products, e.g.…”

Radio‐Labeled Nanoparticles for Biomedical Imaging

“…7.3). These studies indicate the potential of microparticles for short-term applications as well as the benefits of nanoparticles for serial imaging or therapy of a persistent lung injury [131]. In contrast, a study of acute lung injury used latex nanoparticles coated with antiintercellular adhesion molecule-1(ICAm-1) antibody and labeled with 64 Cu for targeting the pulmonary endothelium.…”