Type I collagen–targeted PET probe for pulmonary fibrosis detection and staging in preclinical models by Pauline Désogère, Luis F. Tapias, Lida P. Hariri,

Slides:

Advertisements

Similar presentations

Molecular Therapy - Nucleic Acids

Advertisements

Circ Cardiovasc Imaging

Latency-Associated Peptide Prevents Skin Fibrosis in Murine Sclerodermatous Graft- Versus-Host Disease, a Model for Human Scleroderma Yan Zhang, Laura.

Volume 11, Issue 2, Pages (February 2005)

Fig. 5. Circulating PPi concentration does not correlate with severity of calcification phenotype in mice. Circulating PPi concentration does not correlate.

Fig. 3. Features of PH in KRasLA2 transgenic mice.

In vivo imaging of MMP-13 activity in the murine destabilised medial meniscus surgical model of osteoarthritis N.H. Lim, E. Meinjohanns, M. Meldal, G.

Volume 11, Issue 2, Pages (February 2005)

Fig. 5. Prophylactic treatment with GS-5734 reduces SARS-CoV disease.

Volume 140, Issue 5, Pages (May 2011)

Fig. 1. NASH and fibrosis develop late in mice fed an HFD.

Fig. 5. Pharmacological JAK2 inhibition in vivo abrogates tumor-initiating potential after chemotherapy. Pharmacological JAK2 inhibition in vivo abrogates.

IFN-γ activates the fibrinolytic system.

Fig. 7 Gel scaffold for inhibition of postsurgical recurrence of B16F10 tumors. Gel scaffold for inhibition of postsurgical recurrence of B16F10 tumors.

T. Kimura, T. Ozaki, K. Fujita, A. Yamashita, M. Morioka, K. Ozono, N

Fig. 4. Expression of HGF in liver ECs cooperates with NOX4 inhibition to enhance engraftment of regenerative hepatocytes. Expression of HGF in liver ECs.

NFATc2-deficient mice do not eliminate skin C. albicans infections.

The TGF-β pathway is activated in the skin after C

Fig. 5 Local gel scaffold for T cell memory response.

Cardiac Fibrosis at 18 Weeks Post TAC (A) Representative images (original magnification ×20) of Picrosirius red-stained cardiac tissue sections from HF +

Fig. 7 Improvement of clinical score and axon pathology by nasal IL-4 treatment during chronic EAE. Improvement of clinical score and axon pathology by.

Impaired ECM protein synthesis in infarcted area of S100a4cre+/− × Fstl1flox/flox mice Impaired ECM protein synthesis in infarcted area of S100a4cre+/−

Volume 14, Issue 1, Pages (July 2011)

Strong Promoters Are the Key to Highly Efficient, Noninflammatory and Noncytotoxic Adenoviral-Mediated Transgene Delivery into the Brain in Vivo Christian.

Volume 23, Issue 4, Pages (April 2015)

Scaffold degradation elevates the collagen content and dynamic compressive modulus in engineered articular cartilage K.W. Ng, Ph.D., L.E. Kugler, B.S.,

Volume 23, Issue 4, Pages (April 2015)

Fig. 4. Features of PH in LLC1 lung tumor mice.

Renal Fibrosis and Plasma Creatinine Levels at 18 Weeks Post TAC (A) Plasma creatinine levels. (B) Representative images (original magnification ×20) of.

Volume 19, Issue 6, Pages (June 2011)

Fig. 4. Acute lung injury in miR-223−/y mice.

Fig. 2 LAEs are characterized by vascular dysfunction, loss of endothelial perfusion and permeability, and perivascular hypoxia. LAEs are characterized.

Fig. 1 Neutrophils derived from patients with MPNs are associated with an increase in NET formation and a prothrombotic, NET-rich phenotype. Neutrophils.

Fig. 6 Combination therapy with LVSOD2 and LVshCTGF preserves flap volume and reduces fibrosis after RT. Combination therapy with LVSOD2 and LVshCTGF preserves.

Fig. 7 Correlation of NHP and human ISGs.

IFN-γ antagonizes TGF-β in vivo.

Biocompatibility evaluation in vivo with a mouse subcutaneous implant

Fig. 4 hiPSC-derived osteoblasts (Ad-hiPSCs) contribute to the healing of critical-sized bone defects through the formation of vascularized neobone tissue.

A: Total collagen content by Sirius red staining in cardiac tissue of control (SD) animals. A: Total collagen content by Sirius red staining in cardiac.

Fig. 1 ZIKV RNA in blood and tissues.

Fig. 1. MSCs undergo in vivo apoptosis after infusion without affecting immunosuppression. MSCs undergo in vivo apoptosis after infusion without affecting.

Fig. 3. Features of PH in KRasLA2 transgenic mice.

Fig. 2 Box plots of water use with lateral lengths.

Fig. 6. Nontaxane chemotherapies induce TMEM-dependent prometastatic changes in the breast cancer microenvironment. Nontaxane chemotherapies induce TMEM-dependent.

Fig. 3 Exercise training enhances neuronal activity in vivo.

Genetic EGFR ablation in K-RAS–mutated lung AC reduces tumor growth

Fig. 3 Implantation of the battery-free optofluidic nerve cuff system and its impact on animal behavior and nerve health. Implantation of the battery-free.

Fig. 5. Vitamin B12 supplementation in the host altered the transcriptome of P. acnes in the skin microbiota. Vitamin B12 supplementation in the host altered.

A: Representative sections from the LV of sham and diabetic Ntg and IGF-1R mice. A: Representative sections from the LV of sham and diabetic Ntg and IGF-1R.

Fig. 5 Treatment with BMS (PO BID) protects from wasting and colitis in two SCID mouse models. Treatment with BMS (PO BID) protects from.

Fig. 3 Treating vaccinated mice with OVA-releasing scaffolds enhances angiogenesis and muscle regeneration following ischemic injury. Treating vaccinated.

Fig. 4 PSMA PET/CT enables visualization of CD19-tPSMA(N9del) CAR T cell infiltration into local and metastatic tumors. PSMA PET/CT enables visualization.

Effects of DPM treatment on tumor volume, tumor mass, and pulmonary metastasis at experimental end point. Effects of DPM treatment on tumor volume, tumor.

Fig. 1. Matrix stiffness sensitizes myofibroblasts to apoptosis induced by inhibition of their mechanotransduction pathways. Matrix stiffness sensitizes.

Representative CT and PET/CT images of three patients with NSCLCs

LTB4 production is elevated in preclinical and clinical lymphedema

Representative macrophage staining images only from the knee joints of CAIA mice injected s.c. with GalNAc–MASP-3–siRNA duplex 2 or GalNAc–luciferase–siRNA.

Fig. 3. Human liver tissue seed graft function.

Targeting p53-dependent stem cell loss for intestinal chemoprotection

SY-1425 induces maturation in RARA-high AML

Chronic Treg reduction results in dermal fibrosis.

Fig. 6 Antitumor effect on tumor growth and pulmonary metastasis of CSSD-9 in vivo. Antitumor effect on tumor growth and pulmonary metastasis of CSSD-9.

Fig. 2 In vitro and preclinical study with 18F-MPG.

Effects of ZOL treatment on pulmonary metastases.

Fig. 4 In vivo evaluation of insulin complex for type 1 diabetic mice treatment. In vivo evaluation of insulin complex for type 1 diabetic mice treatment.

Fig. 3. Paclitaxel promotes TMEM-dependent vascular permeability, cancer cell dissemination, and metastasis in breast cancer. Paclitaxel promotes TMEM-dependent.

Fig. 2. Col IV–Ac2-26 NPs increase subendothelial collagen in Ldlr−/− mice with established atherosclerosis. Col IV–Ac2-26 NPs increase subendothelial.

Fig. 1. APP/PS1;C3 KO mice show improved cognitive flexibility (reversal) compared to APP/PS1 mice at 16 months of age. APP/PS1;C3 KO mice show improved.

In vivo function of MeTro sealants using rat incision model of lungs

Fig. 2. SUS reduces Aβ plaques in an AD mouse model.

Presentation transcript:

Type I collagen–targeted PET probe for pulmonary fibrosis detection and staging in preclinical models by Pauline Désogère, Luis F. Tapias, Lida P. Hariri, Nicholas J. Rotile, Tyson A. Rietz, Clemens K. Probst, Francesco Blasi, Helen Day, Mari Mino-Kenudson, Paul Weinreb, Shelia M. Violette, Bryan C. Fuchs, Andrew M. Tager, Michael Lanuti, and Peter Caravan Sci Transl Med Volume 9(384):eaaf4696 April 5, 2017 Copyright © 2017, American Association for the Advancement of Science

Fig. 1. Probe 68Ga-CBP8 monitors disease progression in the BM mouse model of pulmonary fibrosis. Probe 68Ga-CBP8 monitors disease progression in the BM mouse model of pulmonary fibrosis. (A) Representative images of lung tissue stained with hematoxylin and eosin (H&E) and Sirius Red (magnification, ×10; scale bar, 300 μm) for sham and BM-treated mice at days 7 and 14 after BM instillation; higher-magnification views are also displayed (×40; scale bar, 60 μm). (B to D) Disease progresses in a stepwise fashion as determined by histological Ashcroft scoring of lung fibrosis (B), by histological quantification of the area affected by disease (C), and by hydroxyproline analysis (D). (E) Ex vivo lung uptake of 68Ga-CBP8 increases with disease progression in the BM-treated mice: 5-fold higher in BM mice 14 days after instillation than in sham animals and 1.5-fold higher in BM mice 14 days after instillation than in BM mice 7 days after instillation. (F) Correlation of ex vivo 68Ga-CBP8 lung uptake and Ashcroft score. (G) Correlation between ex vivo lung uptake of 68Ga-CBP8 and lung hydroxyproline. Data were analyzed with one-way analysis of variance (ANOVA), followed by post hoc Tukey tests with two-tailed distribution. For (B) to (F), data are displayed as box plots, with the dark band inside the box representing the mean, the bottom and top of the box representing the first and third quartiles, and the whiskers representing the minimum and maximum values. For all of the experiments shown in this figure: n = 11 for sham, n = 4 for BM-treated mice at day 7, and n = 7 for BM-treated mice at day 14. Pauline Désogère et al., Sci Transl Med 2017;9:eaaf4696 Copyright © 2017, American Association for the Advancement of Science

Fig. 2. 68Ga-CBP8 is specifically taken up by fibrotic but not healthy lungs (BM model). 68Ga-CBP8 is specifically taken up by fibrotic but not healthy lungs (BM model). (A) Representative fused PET-CT images show specific accumulation of 68Ga-CBP8 (left images) in fibrotic but not in control lungs; 68Ga-CBP12 (right images) showed no preferential uptake in the lungs of BM-treated mice compared to control mice. Grayscale image shows CT image, and color scale image shows PET image from integrated data 50 to 80 min after probe injection. (B) Hydroxyproline level was significantly higher in fibrotic BM-treated than in sham-treated animals. (C) PET activity values for 68Ga-CBP8 and 68Ga-CBP12 in sham- and BM-treated mice (50 to 80 min after injection). Data are expressed as percent injected dose per cubic centimeter of tissue (% ID/cc). Data show significantly higher uptake in fibrotic lungs with 68Ga-CBP8. (D) Ex vivo uptake of 68Ga-CBP8 and 68Ga-CBP12 in lungs from sham- and BM-treated mice 150 min after injection expressed as % ID/lung. (E) Distribution of 68Ga-CBP8 and 68Ga-CBP12, expressed as percent injected dose per gram of tissue (% ID/g) (mean ± SE) in various organs, was similar except in fibrotic lungs. (Inset) Same data as in (E) expressed as % ID/lung. Data were analyzed using one-way ANOVA, followed by post hoc Tukey tests with two-tailed distribution. For all of the experiments shown in this figure: n = 4 for sham injected with 68Ga-CBP12, n = 4 for BM-treated mice injected with 68Ga-CBP12, n = 11 for sham injected with 68Ga-CBP8, and n = 7 for BM-treated mice injected with 68Ga-CBP8. For (B) to (D), data are displayed as box plots, with the dark band inside the box representing the mean, the bottom and top of the box representing the first and third quartiles, and the whiskers representing the minimum and maximum values. Pauline Désogère et al., Sci Transl Med 2017;9:eaaf4696 Copyright © 2017, American Association for the Advancement of Science

Fig. 3. 68Ga-CBP8 detects and stages disease in a mouse model of pulmonary fibrosis with enhanced vascular permeability. 68Ga-CBP8 detects and stages disease in a mouse model of pulmonary fibrosis with enhanced vascular permeability. (A) Treatment scheme for the LDBVL group, which was treated with a low dose of BM (0.1 U/kg) and the vascular leak agent FTY720. (B to F) Mice were treated with a very low dose of BM (LDB), the vascular leak agent FTY720 (FTY), or both, administered together (LDBVL). The LDBVL group, but not the LDB or FTY group, exhibited a fibrotic response as determined by histological Ashcroft scoring of lung fibrosis (B), by Sirius Red staining (% total area affected by disease) (C), and by hydroxyproline analysis (D). Data show significantly higher uptake of 68Ga-CBP8 in the lungs of LDBVL animals compared to FTY or LDB animals, as quantified by PET data (% ID/cc) (E) and by ex vivo uptake (% ID/lung) (F). (G and H) Correlations between hydroxyproline levels and % ID/cc (G) and % ID/lung (H). Data were analyzed using one-way ANOVA, followed by post hoc Tukey tests with two-tailed distribution. For all of the experiments shown in this figure: n = 6 for the FTY group, n = 4 for the LDB group, and n = 9 for the LDBVL group. For (B) to (F), data are displayed as box plots, with the dark band inside the box representing the mean, the bottom and top of the box representing the first and third quartiles, and the whiskers representing the minimum and maximum values. Pauline Désogère et al., Sci Transl Med 2017;9:eaaf4696 Copyright © 2017, American Association for the Advancement of Science

Fig. 4. 68Ga-CBP8 PET allows monitoring of the response to antifibrotic therapy in mice. 68Ga-CBP8 PET allows monitoring of the response to antifibrotic therapy in mice. (A) Representative images of lung tissue stained with H&E and Sirius Red (magnification, ×10; scale bar, 300 μm) for mice treated with 3G9 only (n = 5), for mice treated with a low dose of BM and FTY720 (LDBVL; n = 9), for LDBVL mice receiving 3G9 (LDBVL + 3G9; n = 11), and for LDBVL mice receiving 1E6 (LDBVL + 1E6; n = 11); higher-magnification views are also displayed (×40; scale bar, 60 μm). (B) Representative fused PET-CT images show specific accumulation of 68Ga-CBP8 in the lungs of mice from the LDBVL and LDBVL + 1E6 groups but low PET signal in the lungs of the control 3G9 or treated LDBVL + 3G9 groups. Grayscale image shows CT image, and color scale image shows PET image from integrated data 50 to 80 min after probe injection. (C) Hydroxyproline content was significantly higher in animals from the LDBVL and LDBVL + 1E6 groups than in those from the 3G9 and LDBVL + 3G9 groups. (D and E) Similar effects were seen for quantitative PET data (D) and ex vivo uptake in the lungs. Data were analyzed using one-way ANOVA, followed by post hoc Tukey tests with two-tailed distribution. For (C) to (E), data are displayed as box plots, with the dark band inside the box representing the mean, the bottom and top of the box representing the first and third quartiles, and the whiskers representing the minimum and maximum values. For all of the experiments shown in this figure: n = 5 for the 3G9 group, n = 9 for the LDBVL group, n = 11 for the LDBVL + 3G9 group, and n = 11 for the LDBVL + 1E6 group. Pauline Désogère et al., Sci Transl Med 2017;9:eaaf4696 Copyright © 2017, American Association for the Advancement of Science

Fig. 5. Probe 68Ga-CBP8 signal reflects changes in collagen concentration in human IPF lung tissues. Probe 68Ga-CBP8 signal reflects changes in collagen concentration in human IPF lung tissues. (A) Uptake of 68Ga-CBP8 in human lung samples taken from the upper, middle, and lower lobes of explanted lung of IPF patients. The uptake is defined as % ID/g lung tissue (mean ± SE). Data were analyzed using one-way ANOVA, followed by post hoc Tukey tests with two-tailed distribution. For patient 1, n = 5 (upper lobe), n = 5 (middle lobe), and n = 6 (lower lobe). For patient 2, n = 8 (upper lobe), n = 6 (middle lobe), and n = 6 (lower lobe). For patient 3, n = 5 (upper lobe), n = 5 (middle lobe), and n = 9 (lower lobe). (B) Representative images of Sirius Red staining of collagen showing early stage of IPF (left, lung section taken from the upper lobe of patient 2) characterized by thickening of the alveolar septa and knot-like formation and late stage of fibrosis (right, lung section taken from the lower lobe of patient 2) characterized by a denser deposition of collagen. (C) Correlation of 68Ga-CBP8 (n = 9) and 68Ga-CBP12 (n = 9) uptake in lung tissue samples from IPF patients with histological staining of collagen, as measured by quantification of % collagen staining (Sirius Red) in the area affected by disease (for 68Ga-CBP8, r2 = 0.94, P < 0.0001). Pauline Désogère et al., Sci Transl Med 2017;9:eaaf4696 Copyright © 2017, American Association for the Advancement of Science