scholarly journals Proof of Concept Study for Increasing Tenascin-C-Targeted Drug Delivery to Tumors Previously Subjected to Therapy: X-Irradiation Increases Tumor Uptake

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3652
Author(s):  
Aya Sugyo ◽  
Atsushi B. Tsuji ◽  
Hitomi Sudo ◽  
Kanako Takano ◽  
Moriaki Kusakabe ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Drug Delivery ◽  
Tissue Injury ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Tumor Uptake ◽  
Tenascin C ◽  
Biodistribution Studies ◽  
Tumor Tissues ◽  
X Irradiation

In treatment-refractory cancers, tumor tissues damaged by therapy initiate the repair response; therefore, tumor tissues must be exposed to an additional burden before successful repair. We hypothesized that an agent recognizing a molecule that responds to anticancer treatment-induced tissue injury could deliver an additional antitumor agent including a radionuclide to damaged cancer tissues during repair. We selected the extracellular matrix glycoprotein tenascin-C (TNC) as such a molecule, and three antibodies recognizing human and murine TNC were employed to evaluate X-irradiation-induced changes in TNC uptake by subcutaneous tumors. TNC expression was assessed by immunohistochemical staining of BxPC-3 tumors treated with or without X-irradiation (30 Gy) for 7 days. Antibodies against TNC (3–6, 12–2–7, TDEAR) and a control antibody were radiolabeled with 111In and injected into nude mice having BxPC-3 tumors 7 days after X-irradiation, and temporal uptake was monitored for an additional 4 days by biodistribution and single-photon emission computed tomography with computed tomography (SPECT/CT) studies. Intratumoral distribution was analyzed by autoradiography. The immunohistochemical signal for TNC expression was faint in nontreated tumors but increased and expanded with time until day 7 after X-irradiation. Biodistribution studies revealed increased tumor uptake of all three 111In-labeled antibodies and the control antibody. However, a statistically significant increase in uptake was evident only for 111In-labeled 3–6 (35% injected dose (ID)/g for 30 Gy vs. 15% ID/g for 0 Gy at day 1, p < 0.01), whereas limited changes in 111In-labeled TDEAR2, 12–2–27, and control antibody were observed (several % ID/g for 0 and 30 Gy). Serial SPECT/CT imaging with 111In-labeled 3–6 or control antibody provided consistent results. Autoradiography revealed noticeably stronger signals in irradiated tumors injected with 111In-labeled 3–6 compared with each of the nonirradiated tumors and the control antibody. The signals were observed in TNC-expressing stroma. Markedly increased uptake of 111In-labeled 3–6 in irradiated tumors supports our concept that an agent, such as an antibody, that recognizes a molecule involved in tissue injury repair, such as TNC, could enhance drug delivery to tumor tissues that have undergone therapy. The combination of antibody 3–6 coupled to a tumoricidal drug and conventional therapy has the potential to achieve better outcomes for patients with refractory cancer.

scholarly journals Proof of Concept Study for Increasing Tenascin-C-targeted Drug Delivery to Tumors Previously Subjected to Therapy: X-Irradiation Increases Tumor Uptake

2020 ◽  
Author(s):  
Aya Sugyo ◽  
Atsushi B. Tsuji ◽  
Hitomi Sudo ◽  
Kanako Takano ◽  
Moriaki Kusakabe ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Drug Delivery ◽  
Tissue Injury ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Tumor Uptake ◽  
Tenascin C ◽  
Biodistribution Studies ◽  
Tumor Tissues ◽  
X Irradiation

Background: In treatment-refractory cancers, tumor tissues damaged by therapy initiate the repair response; therefore, tumor tissues must be exposed to an additional burden before successful repair. We hypothesized that an agent recognizing a molecule that responds to anticancer treatment&ndash;induced tissue injury could deliver an additional antitumor agent including a radionuclide to damaged cancer tissues during repair. We selected the extracellular matrix glycoprotein tenascin-C (TNC) as such a molecule, and three antibodies recognizing human and murine TNC were employed to evaluate X-irradiation&ndash;induced changes in TNC uptake by subcutaneous tumors. Methods: TNC expression was assessed by immunohistochemical staining of BxPC-3 tumors treated with or without X-irradiation (30 Gy) for 7 days. Antibodies against TNC (3-6, 12-2-7, TDEAR) and a control antibody were radiolabeled with 111In and injected into nude mice having BxPC-3 tumors 7 days after X-irradiation, and temporal uptake was monitored for an additional 4 days by biodistribution and single-photon emission computed tomography with computed tomography (SPECT/CT) studies. Intratumoral distribution was analyzed by autoradiography. Results: The immunohistochemical signal for TNC expression was faint in nontreated tumors but increased and expanded with time until day 7 after X-irradiation. Biodistribution studies revealed increased tumor uptake of all three 111In-labeled antibodies and the control antibody. However, a statistically significant increase in uptake was evident only for 111In-labeled 3-6 (35%ID/g for 30 Gy vs. 15%ID/g for 0 Gy at day 1, P &amp;lt; 0.01; ID, injected dose), whereas limited changes in 111In-labeled TDEAR2, 12-2-27, and control antibody were observed (several %ID/g for 0 and 30 Gy). Serial SPECT/CT imaging with 111In-labeled 3-6 or control antibody provided consistent results. Autoradiography revealed noticeably stronger signals in irradiated tumors injected with 111In-labeled 3-6 compared with each of nonirradiated tumors and the control antibody. The signals were observed in TNC-expressing stroma. Conclusion: Markedly increased uptake of 111In-labeled 3-6 in irradiated tumors supports our concept that an agent, such as an antibody, that recognizes a molecule, such as TNC, involved in tissue-injury repair could enhance drug delivery to therapy-experienced tumor tissues. The combination of antibody 3-6 coupled to a tumoricidal drug and conventional therapy has the potential to achieve better outcomes for patients with refractory cancer.

scholarly journals Comparison of short nozzle and long nozzle spray in sinonasal drug delivery: a cadaveric study

2019 ◽  
Vol 98 (7) ◽  
pp. E97-E103
Author(s):  
Mustafa Kapadia ◽  
Precious Eunice R. Grullo ◽  
Muaaz Tarabichi
Keyword(s):  
Computed Tomography ◽  
Drug Delivery ◽  
Nasal Cavity ◽  
Frontal Sinus ◽  
Single Photon ◽  
Photon Emission ◽  
Sinus Surgery ◽  
Emission Computed Tomography ◽  
Fisher Exact Test ◽  
Exact Test

The aim of this study is to compare the delivery site of topical drugs using the short nozzle and the long nozzle. Fourteen fresh frozen cadaver heads were obtained. All cadaver specimens underwent bilateral endoscopic wide maxillary antrostomy, frontal sinusotomy, and complete sphenoethmoidectomy. The right nasal cavity of each cadaver was sprayed with radiolabeled saline using the short nozzle (short nozzle group), while the left nasal cavity was sprayed using the long nozzle (long nozzle group). The distribution of radioactive saline within the sinus cavities was determined using single-photon emission computed tomography/computed tomography. The distribution of the radiolabeled saline in reference with the maxillary line, vestibule, maxillary, ethmoid, sphenoid, and frontal sinus was compared between the 2 groups using Fisher exact test. The number of specimens that demonstrated radioactivity above the maxillary line is higher in the long nozzle group (14 cadavers, 100%) compared to short nozzle group (9 cadavers, 64.3%; p = .02). There are fewer specimens that demonstrated deposition of radioactive saline in the vestibule in the long nozzle group (6 cadavers, 42.86%) compared to short nozzle group (13 cadavers, 92.86%; P = .006). Compared to short nozzle group, there are more specimens demonstrating radioactivity in the maxillary, ethmoid, sphenoid, and frontal sinus in the long nozzle group, but the differences were not statistically significant ( p = 0.241, 0.347, 0.126, 0.5). Compared to short nozzle, long nozzle more frequently delivers intranasal drugs beyond the maxillary line and less frequently in the vestibule. These findings support the hypothesis that the use of long and narrow nozzle, instead of the conventional short nozzle, can improve sinonasal drug delivery in post-endoscopic sinus surgery nose.

Quantitative Tumor Apoptosis Imaging Using Technetium-99m–HYNIC Annexin V Single Photon Emission Computed Tomography

2003 ◽  
Vol 21 (18) ◽  
pp. 3483-3487 ◽  
Author(s):  
Christophe Van de Wiele ◽  
Christophe Lahorte ◽  
Hubert Vermeersch ◽  
D. Loose ◽  
Kris Mervillie ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Head And Neck ◽  
Tumor Volume ◽  
Photon Emission ◽  
Annexin V ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Emission Computed Tomography ◽  
Apoptotic Cells ◽  
Tumor Uptake ◽  
Technetium 99M

Purpose: Radiolabeled annexin V may allow for repetitive and selective in vivo identification of apoptotic cell death without the need for invasive biopsy. This study reports on the relationship between quantitative technetium-99m– (99mTc-) 6-hydrazinonicotinic (HYNIC) radiolabeled annexin V tumor uptake, and the number of tumor apoptotic cells derived from histologic analysis. Patients and Methods: Twenty patients (18 men, two women) suspected of primary (n = 19) or recurrent (n = 1) head and neck carcinoma were included. All patients underwent a spiral computed tomography (CT) scan, 99mTc-HYNIC annexin V tomography, and subsequent surgical resection of the suspected primary or recurrent tumor. Quantitative 99mTc-HYNIC annexin V uptake in tumor lesions divided by the tumor volume, derived from CT, was related to the number of apoptotic cells per tumor high-power field derived from terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assays performed on sectioned tumor slices. Results: Diagnosis was primary head and neck tumor in 18 patients, lymph node involvement of a cancer of unknown primary origin in one patient, and the absence of recurrence in one patient. Mean percentage absolute tumor uptake of the injected dose per cubic centimeter tumor volume derived from tomographic images was 0.0003% (standard deviation [SD], 0.0004%) at 1 hour postinjection (PI) and 0.0001% (SD, 0.0000%) at 5 to 6 hours PI (P = .012). Quantitative 99mTc-HYNIC annexin V tumor uptake correlated well with the number of apoptotic cells if only tumor samples with no or minimal amounts of necrosis were considered. Conclusion: In the absence of necrosis, absolute 99mTc-HYNIC annexin V tumor uptake values correlate well with the number of apoptotic cells derived from TUNEL assays.

scholarly journals Polyethylenimine-Based Theranostic Nanoplatform for Glioma-Targeting Single-Photon Emission Computed Tomography Imaging and Anticancer Drug Delivery

2020 ◽  
Author(s):  
Lingzhou Zhao ◽  
Jingyi Zhu ◽  
Jiali Gong ◽  
Ningning Song ◽  
Shan Wu ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Drug Delivery ◽  
Single Photon ◽  
Photon Emission ◽  
Spect Imaging ◽  
Emission Computed Tomography ◽  
Single Photon Emission ◽  
Anticancer Drug Delivery ◽  
Single Photon Emission Computed ◽  
Photon Emission Computed Tomography

Abstract Background: Glioma is the deadliest brain cancer in adults because the blood-brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system. The development of BBB-penetrating drug delivery systems for glioma therapy still remains a great challenge. In this study, we aimed to design and develop a theranostic nanocomplex with enhanced BBB penetrability and tumor-targeting efficiency for glioma single-photon emission computed tomography (SPECT) imaging and anticancer drug delivery.Results: This multifunctional nanocomplex was manufactured using branched polyethylenimine (PEI) as a template to sequentially conjugate with methoxypolyethylene glycol (mPEG), glioma-targeting peptide chlorotoxin (CTX), and diethylenetriaminepentaacetic acid (DTPA) for 99mTc radiolabeling on the surface of PEI. After the acetylation of the remaining PEI surface amines using acetic anhydride (Ac2O), the CTX-modified PEI (mPEI-CTX) was utilized as a carrier to load chemotherapeutic drug doxorubicin (DOX) in its interior cavity. The formed mPEI-CTX/DOX complex had excellent water dispersibility and released DOX in a sustainable and pH-dependent manner; furthermore, it showed targeting specificity and therapeutic effect of DOX toward glioma cells in vitro and in vivo (a subcutaneous tumor mouse model). Owing to the unique biological properties of CTX, the mPEI-CTX/DOX complex was able to cross the BBB and accumulate at the tumor site in an orthotopic rat glioma model. In addition, after efficient radiolabeling of PEI with 99mTc via DTPA, the 99mTc-labeled complex could help to visualize the drug accumulation in tumors of glioma-bearing mice and the drug delivery into the brains of rats through SPECT imaging.Conclusions: These results indicate the potential of the developed PEI-based nanocomplex in facilitating glioma-targeting SPECT imaging and chemotherapy.

scholarly journals Polyethylenimine-based theranostic nanoplatform for glioma-targeting single-photon emission computed tomography imaging and anticancer drug delivery

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Lingzhou Zhao ◽  
Jingyi Zhu ◽  
Jiali Gong ◽  
Ningning Song ◽  
Shan Wu ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Drug Delivery ◽  
Single Photon ◽  
Photon Emission ◽  
Spect Imaging ◽  
Emission Computed Tomography ◽  
Single Photon Emission ◽  
Anticancer Drug Delivery ◽  
Single Photon Emission Computed ◽  
Photon Emission Computed Tomography

Abstract Background Glioma is the deadliest brain cancer in adults because the blood–brain-barrier (BBB) prevents the vast majority of therapeutic drugs from entering into the central nervous system. The development of BBB-penetrating drug delivery systems for glioma therapy still remains a great challenge. In this study, we aimed to design and develop a theranostic nanocomplex with enhanced BBB penetrability and tumor-targeting efficiency for glioma single-photon emission computed tomography (SPECT) imaging and anticancer drug delivery. Results This multifunctional nanocomplex was manufactured using branched polyethylenimine (PEI) as a template to sequentially conjugate with methoxypolyethylene glycol (mPEG), glioma-targeting peptide chlorotoxin (CTX), and diethylenetriaminepentaacetic acid (DTPA) for 99mTc radiolabeling on the surface of PEI. After the acetylation of the remaining PEI surface amines using acetic anhydride (Ac2O), the CTX-modified PEI (mPEI-CTX) was utilized as a carrier to load chemotherapeutic drug doxorubicin (DOX) in its interior cavity. The formed mPEI-CTX/DOX complex had excellent water dispersibility and released DOX in a sustainable and pH-dependent manner; furthermore, it showed targeting specificity and therapeutic effect of DOX toward glioma cells in vitro and in vivo (a subcutaneous tumor mouse model). Owing to the unique biological properties of CTX, the mPEI-CTX/DOX complex was able to cross the BBB and accumulate at the tumor site in an orthotopic rat glioma model. In addition, after efficient radiolabeling of PEI with 99mTc via DTPA, the 99mTc-labeled complex could help to visualize the drug accumulation in tumors of glioma-bearing mice and the drug delivery into the brains of rats through SPECT imaging. Conclusions These results indicate the potential of the developed PEI-based nanocomplex in facilitating glioma-targeting SPECT imaging and chemotherapy.

scholarly journals Recent Insights in Barium-131 as a Diagnostic Match for Radium-223: Cyclotron Production, Separation, Radiolabeling, and Imaging

2020 ◽  
Vol 13 (10) ◽  
pp. 272
Author(s):  
Falco Reissig ◽  
David Bauer ◽  
Martin Ullrich ◽  
Martin Kreller ◽  
Jens Pietzsch ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Single Photon ◽  
Photon Emission ◽  
Small Animal ◽  
Emission Computed Tomography ◽  
Radium Isotopes ◽  
Radium 223 ◽  
Biodistribution Studies ◽  
First Time

Barium-131 is a single photon emission computed tomography (SPECT)-compatible radionuclide for nuclear medicine and a promising diagnostic match for radium-223/-224. Herein, we report on the sufficient production route 133Cs(p,3n)131Ba by using 27.5 MeV proton beams. An average of 190 MBq barium-131 per irradiation was obtained. The SR Resin-based purification process led to barium-131 in high radiochemical purity. An isotopic impurity of 0.01% barium-133 was detectable. For the first time, radiolabeling of the ligand macropa with barium-131 was performed. Radiolabeling methods under mild conditions and reaction controls based on TLC systems were successfully applied. Small animal SPECT/ computed tomography (CT) measurements and biodistribution studies were performed using [131Ba]Ba(NO3)2 as reference and 131Ba-labeled macropa in healthy mice for the first time. Biodistribution studies revealed the expected rapid bone uptake of [131Ba]Ba2+, whereas 131Ba-labeled macropa showed a fast clearance from the blood, thereby showing a significantly (p < 0.001) lower accumulation in the bone. We conclude that barium-131 is a promising SPECT radionuclide and delivers appropriate imaging qualities in small animals. Furthermore, the relative stability of the 131Ba-labeled macropa complex in vivo forms the basis for the development of sufficient new chelators, especially for radium isotopes. Thereby, barium-131 will attain its goal as a diagnostic match to the alpha emitters radium-223 and radium-224.

scholarly journals Synthesis, radiolabelling, and biodistribution studies of triazole derivatives for targeting melanoma

2016 ◽  
Vol 94 (9) ◽  
pp. 773-780 ◽  
Author(s):  
Stephanie M. Rathmann ◽  
Nancy Janzen ◽  
John F. Valliant
Keyword(s):  
Computed Tomography ◽  
Single Photon ◽  
Click Reaction ◽  
Photon Emission ◽  
Molecular Probes ◽  
High Signal ◽  
Emission Computed Tomography ◽  
In Vivo Evaluation ◽  
Biodistribution Studies

Molecular probes that target specific markers expressed in solid tumours are in demand for cancer imaging and radionuclide therapy applications. The synthesis, characterization, and in vivo evaluation of radioiodinated triazoles designed as probes to target melanoma are described here. Compounds were prepared using a thermal click reaction between ethynylstannane and methyl 2-azidoacetate, resulting in preferential formation of the corresponding 1,4-tin triazole. The primary amine of various targeting vectors was then coupled to the resulting tin triazole methyl ester. These precursors were labelled with no carrier added 123I or 125I and purified by high performance liquid chromatography to give isolated radiochemical yields between 6% and 51% and radiochemical purities of >95% in all cases. Among the evaluated compounds, N-(2-diethylamino-ethyl)-2-(4-iodo-[1,2,3]triazol-1-yl)acetamide (7a) and N-(1-benzylpiperidin-4-yl)-2-(4-iodo-1H-1,2,3-triazol-1-yl)acetamide (7d) showed the most promising in vivo data, and their 123I-labelled forms were used in single photon emission computed tomography computed tomography (SPECT–CT) imaging studies. The imaging data showed excellent tumour visualization with a very high signal to noise ratio.

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