Longitudinal Investigation of Permeability and Distribution of Macromolecules in Mouse Malignant Transformation Using PET

Abstract

Purpose: We apply positron emission tomography (PET) to elucidate changes in nanocarrier extravasation during the transition from premalignant to malignant cancer, providing insight into the use of imaging to characterize early cancerous lesions and the utility of nanoparticles in early disease.Experimental Design: Albumin and liposomes were labeled with 64 Cu (half-life 12.7 hours), and longitudinal PET and CT imaging studies were conducted in a mouse model of ductal carcinoma in situ. A pharmacokinetic model was applied to estimate the tumor vascular volume and permeability.Results: From early time points characterized by disseminated hyperproliferation, the enhanced vascular permeability facilitated lesion detection. During disease progression, the vascular volume fraction increased 1.6-fold and the apparent vascular permeability to albumin and liposomes increased $2.5-fold to 6.6 Â 10 À8 and 1.3 Â 10 À8 cm/s, respectively, with the accumulation of albumin increasing earlier in the disease process. In the malignant tumor, both tracers reached similar mean intratumoral concentrations of $6% ID/cc but the distribution of liposomes was more heterogeneous, ranging from 1% to 18% ID/cc compared with 1% to 9% ID/cc for albumin. The tumor-to-muscle ratio was 17.9 AE 8.1 and 7.1 AE 0.5 for liposomes and albumin, respectively, indicating a more specific delivery of liposomes than with albumin. Conclusions: PET imaging of radiolabeled particles, validated by confocal imaging and histology, detected the transition from premalignant to malignant lesions and effectively quantified the associated changes in vascular permeability.

Dynamic contrast enhanced MRI detects changes in vascular transport rate constants following treatment with thermally-sensitive liposomal doxorubicin

“…The IRDye 800CW-to-albumin ratio ([A 780 /ε dye ]/[(A 280 -(0.03 × A 780 ))/ε Albumin ], ε dye = 270,000 M -1 cm -1 , ε Albumin = 43,824 M -1 cm -1 ) was calculated to be 0.91. The resulting IRDye 800 CW-labeled albumin has a similar circulation profile as that reported previously [38, 45], retaining 8% ID/cc (injected dose per cubic centimeter of blood) at 18-24 h post injection.…”

“…In addition, fluorescence imaging of conjugates, such as albumin bound to a fluorescent dye, can be applied to image the extravasation and accumulation of larger molecules [35]. Albumin is typically retained within the vasculature to maintain osmotic pressure, thus its extravasation is a widely-used measure of alterations in permeability [36-38]. …”

The pharmacokinetics of Zr-89 labeled liposomes over extended periods in a murine tumor model

“…Because of our interest in looking at lymphatics as well as the trafficking of macrophages, a syngeneic, orthotopic model was appropriate. As we have previously observed for 64 Cu-lipsosomal uptake in mouse mammary intraepithelial neoplasia outgrowth (MIN-Os) tumors 42 and MET-1 mammary carcinoma 43 , the accumulation of 89 Zr liposomes was primarily concentrated in the peripheral region of the tumor, reflecting the angiogenic status of the tumor periphery.…”

Spatial and temporal mapping of heterogeneity in liposome uptake and microvascular distribution in an orthotopic tumor xenograft model

“…Karathanasis et al effectively correlate tumor accumulation of iodinated liposomes to markers of blood vessel permeability (i.e., VEGF and VEGF receptor-2) [58], as well as therapeutic efficacy of doxorubicin-loaded liposomes in a separate report [15]. Other studies have demonstrated the impact of nanosystems, tumor properties, and modulating interventions on assessing the status and exploitation of the EPR effect at the whole-tumor level [14,[59][60][61]. Beyond the goal of achieving maximum tumor accumulation macroscopically -for which the direct impact on antitumor efficacy remains elusive -achievement of a favorable underlying micro-accumulation of nanomedicines may contribute significantly to an overall anti-tumor response.…”