Quantitative SPECT imaging and biodistribution point to molecular weight independent tumor uptake for some long-circulating polymer nanocarriers
Polymeric nanocarriers are promising entities for cancer diagnosis and therapy. The aim of such nanocarriers is to selectively accumulate in cancerous tissue that is difficult to visualize or treat. The passive accumulation of a nanocarrier in a tumor through extravasation is often attributed to the enhanced permeation and retention (EPR) effect and the size and shape of the nanocarrier. However, the tumor microenvironment is very heterogeneous and the intratumoral pressure is usually high, leading to different opinions about how the EPR of nanocarriers through the irregular vasculature of a tumor leads to accumulation. In order to investigate this topic, we studied methods for the determination of pharmacokinetic parameters, biodistribution and the tumor uptake of nanocarriers. More specifically, we used non-invasive quantitative Single-Photon Emission Computed Tomography/Computed Tomography (qSPECT/CT) imaging of hyperbranched polyglycerols (HPGs) to explore the specific biodistribution and tumor uptake of six model nanocarriers in Rag2m mice. We were interested to see if a distinct molecular weight (MW) of nanocarriers (HPG 25, 50, 100, 200, 300, 500 kDa) is favoured by the tumor. To trace the model nanocarriers, HPGs were covalently linked to the strong chelator desferrioxamine (DFO), and radiolabeled with the gamma emitter 67Ga (EC = 100%, Eγ = 185 keV (21.4%), 300 keV (16.6%), half-life = 3.26 d). Without the need for blood collection, but instead using qSPECT/CT imaging inside the heart, the blood circulation half-lives of the 67Ga labeled HPGs were determined and increased from 9.9 ± 2.9 to 47.8 ± 7.9 hours with increasing polymer MW. Total tumor accumulation correlated positively with the circulation time of the HPGs. Comparing the tumor-to-blood ratio dynamically revealed how blood and tumor concentrations of the nanocarrier change over time and when equilibrium is reached. The time of equilibrium is size-dependent and increases with molecular weight. Furthermore, the data indicate that for larger MWs, nanocarrier uptake and retention by the tumor is size independent. Further studies are necessary to advance our understanding of the interplay between MW and nanoparticle accumulation in tumors.