In vivo fate tracking of degradable nanoparticles for lung gene transfer using PET and Ĉerenkov imaging

Abstract

Nanoparticles (NPs) play expanding roles in biomedical applications including imaging and therapy, however, their long-term fate and clearance profiles have yet to be fully characterized in vivo. NP delivery via the airway is particularly challenging, as the clearance may be inefficient and lung immune responses complex. Thus, specific material design is required for cargo delivery and quantitative, noninvasive methods are needed to characterize NP pharmacokinetics. Here, biocompatible poly(acrylamidoethylamine)-b-poly(DL-lactide) block copolymer-based degradable, cationic, shell-cross-linked knedel-like NPs (Dg-cSCKs) were employed to transfect plasmid DNA. Radioactive and optical beacons were attached to monitor biodistribution and imaging. The preferential release of cargo in acidic conditions provided enhanced transfection efficiency compared to non-degradable counterparts. In vivo gene transfer to the lung was correlated with NP pharmacokinetics by radiolabeling Dg-cSCKs and performing quantitative biodistribution with parallel positron emission tomography and Čerenkov imaging. Quantitation of imaging over 14 days corresponded with the pharmacokinetics of NP movement from the lung to gastrointestinal and renal routes, consistent with predicted degradation and excretion. This ability to noninvasively and accurately track NP fate highlights the advantage of incorporating multifunctionality into particle design.

Utilizing the power of Cerenkov light with nanotechnology

“…As liposomes such as Doxil and Caelyx are already approved by the US Food and Drug Administration for drug delivery, their use in imaging is attractive for clinical translation 44 . In another radioiodine nanosystem, biodegradable nanoparticles were used to transfect plasmid DNA into the lungs of mice with in vivo biodistribution followed serially using both PET and CLI, highlighting the increased prevalence of CL in biological studies 45 .…”

Radionuclide‐Activated Nanomaterials and Their Biomedical Applications

“…[54] As ac onsequence of its ability to bridge nuclear and optical imaging techniques,CRcould potentially support the translation of already approved radiotracers for optical imaging. [63] Even though the amount of light generated from CR emitters is still lower than that of bioluminescence and fluorescence,t he nondependencyo na nexternal light source is known to reduce tissue autofluorescence and can result in significantly improved signal-to-background ratios. [54] Since the role of nanoparticles in the imaging field is already established, it is no surprise that nanoparticles have been coupled with CL agents as as imple yet novel imaging modality to drive CRET and PDT.…”

“…Black et al [63] utilized PET imaging and Cerenkov luminescence to non-invasively determine the long-term pharmacokinetics of degradable positively charged polymeric nanoparticles following administration to lung airflow. 124 I-or 131 Ilabeled poly(acrylamidoethylamine)-b-poly(DL-lactide) block copolymer based degradable,c ationic,s hell-crosslinked knedel-like NPs (Dg-cSCKs) were administered to mice through intratracheal injection.…”

Multimodality Imaging Agents with PET as the Fundamental Pillar

“…As ar esult, PET/CL dualmodality imaging could be applied to track the in vivo fate of degradable NPs for lung gene transfer imaging,i nw hich CL could be acquired using as tandard IVIS system that expanded imaging accessibility and the possibilities for highthroughput screening. [41] However,C Li sm ore intense at higher frequencies (UV/blue), which can be easily attenuated by tissues.F ortunately,v arious NPs including QDs, [42] TiO 2 NPs, [43] Au NPs, [44] and rare-earth NPs, [45] can be excited by the UV/blue Cherenkov luminescence of labeled isotopes,a nd then in turn emit light of alonger wavelength that allows for much greater depth penetration (Figure 4c). This phenomenon is known as Cerenkov resonance energy transfer (CRET).…”