Dataset Information

Engineering A11 Minibody-Conjugated, Polypeptide-Based Gold Nanoshells for Prostate Stem Cell Antigen (PSCA)-Targeted Photothermal Therapy.

ABSTRACT: Currently, there is no curative treatment for advanced metastatic prostate cancer, and options, such as chemotherapy, are often nonspecific, harming healthy cells and resulting in severe side effects. Attaching targeting ligands to agents used in anticancer therapies has been shown to improve efficacy and reduce nonspecific toxicity. Furthermore, the use of triggered therapies can enable spatial and temporal control over the treatment. Here, we combined an engineered prostate cancer-specific targeting ligand, the A11 minibody, with a novel photothermal therapy agent, polypeptide-based gold nanoshells, which generate heat in response to near-infrared light. We show that the A11 minibody strongly binds to the prostate stem cell antigen that is overexpressed on the surface of metastatic prostate cancer cells. Compared to nonconjugated gold nanoshells, our A11 minibody-conjugated gold nanoshell exhibited significant laser-induced, localized killing of prostate cancer cells in vitro. In addition, we improved upon a comprehensive heat transfer mathematical model that was previously developed by our laboratory. By relaxing some of the assumptions of our earlier model, we were able to generate more accurate predictions for this particular study. Our experimental and theoretical results demonstrate the potential of our novel minibody-conjugated gold nanoshells for metastatic prostate cancer therapy.

SUBMITTER: Mayle KM

PROVIDER: S-EPMC6071911 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Engineering A11 Minibody-Conjugated, Polypeptide-Based Gold Nanoshells for Prostate Stem Cell Antigen (PSCA)-Targeted Photothermal Therapy.

Mayle Kristine M KM Dern Kathryn R KR Wong Vincent K VK Chen Kevin Y KY Sung Shijun S Ding Ke K Rodriguez April R AR Knowles Scott S Taylor Zachary Z Zhou Z Hong ZH Grundfest Warren S WS Wu Anna M AM Deming Timothy J TJ Kamei Daniel T DT

SLAS technology 20160926 1

Currently, there is no curative treatment for advanced metastatic prostate cancer, and options, such as chemotherapy, are often nonspecific, harming healthy cells and resulting in severe side effects. Attaching targeting ligands to agents used in anticancer therapies has been shown to improve efficacy and reduce nonspecific toxicity. Furthermore, the use of triggered therapies can enable spatial and temporal control over the treatment. Here, we combined an engineered prostate cancer-specific tar ...[more]

PMID: 27659802

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Project description:Prostate stem cell antigen (PSCA) is expressed on the cell surface in 83%-100% of local prostate cancers and 87%-100% of prostate cancer bone metastases. In this study, we sought to develop immunoPET agents using (124)I- and (89)Zr-labeled anti-PSCA A11 minibodies (scFv-CH3 dimer, 80 kDa) and evaluate their use for quantitative immunoPET imaging of prostate cancer.A11 anti-PSCA minibody was alternatively labeled with (124)I- or (89)Zr-desferrioxamine and injected into mice bearing either matched 22Rv1 and 22Rv1×PSCA or LAPC-9 xenografts. Small-animal PET data were obtained and quantitated with and without recovery coefficient-based partial-volume correction, and the results were compared with ex vivo biodistribution.Rapid and specific localization to PSCA-positive tumors and high-contrast imaging were observed with both (124)I- and (89)Zr-labeled A11 anti-PSCA minibody. However, the differences in tumor uptake and background uptake of the radiotracers resulted in different levels of imaging contrast. The nonresidualizing (124)I-labeled minibody had lower tumor uptake (3.62 ± 1.18 percentage injected dose per gram [%ID/g] 22Rv1×PSCA, 3.63 ± 0.59 %ID/g LAPC-9) than the residualizing (89)Zr-labeled minibody (7.87 ± 0.52 %ID/g 22Rv1×PSCA, 9.33 ± 0.87 %ID/g LAPC-9, P < 0.0001 for each), but the (124)I-labeled minibody achieved higher imaging contrast because of lower nonspecific uptake and better tumor-to-soft-tissue ratios (22Rv1×PSCA:22Rv1 positive-to-negative tumor, 13.31 ± 5.59 (124)I-A11 and 4.87 ± 0.52 (89)Zr-A11, P = 0.02). Partial-volume correction was found to greatly improve the correspondence between small-animal PET and ex vivo quantification of tumor uptake for immunoPET imaging with both radionuclides.Both (124)I- and (89)Zr-labeled A11 anti-PSCA minibody showed high-contrast imaging of PSCA expression in vivo. However, the (124)I-labeled A11 minibody was found to be the superior imaging agent because of lower nonspecific uptake and higher tumor-to-soft-tissue contrast. Partial-volume correction was found to be essential for robust quantification of immunoPET imaging with both (124)I- and (89)Zr-labeled A11 minibody.

Project description:PURPOSE:Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic ?-radioimmunotherapy (?-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the ?-particle emitter 211At-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. METHODS:PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of ?-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9?MBq) and on i.t. microtumors (~100-200??m; 0, 0.8 or 1.5?MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. RESULTS:Tumor targeting of 211At-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6?weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5?MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4?MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5?MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 ± 0.003?mm3 versus 3.79 ± 1.24?mm3 (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). CONCLUSION:Evaluating fractionated ?-RIT with 211At-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90?days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of 211At-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of ?-RIT or by altering the size of the targeting vector.

Project description:PurposeRadioimmunotherapy uses tumor-specific antibodies to deliver therapeutic radionuclides, but hematological toxicity due to the long serum half-life of intact antibodies remains a challenge. We evaluated a smaller antibody fragment, the minibody, with faster kinetics and a potentially improved therapeutic index.ProceduresThe anti-prostate stem cell antigen (PSCA) minibody (A11 Mb) was radiolabeled with iodine-124 ([124I]I-A11 Mb) or conjugated with deferoxamine (DFO) and labeled with zirconium-89 ([89Zr]Zr-DFO-A11 Mb) for surrogate immunoPET to profile pharmacokinetics in a human prostate cancer xenograft model. Subsequently, minibodies labeled with two therapeutic beta emitters, directly iodinated [131I]I-A11 Mb (non-residualizing) and 177Lu chelated using DTPA ([177Lu]Lu-DTPA-A11 Mb) (residualizing), were compared for in vitro antigen-specific cytotoxicity. Full biodistribution studies (in 22Rv1-PSCA tumor bearing and hPSCA knock-in mice) were conducted for dosimetry calculations. Finally, the lead candidate [131I]I-A11 Mb was evaluated in a radioimmunotherapy experiment. Escalating single doses (3.7, 11, or 37 MBq) and saline control were administered to 22Rv1-PSCA tumor bearing mice and anti-tumor effects (tumor volume) and toxicity (body weight) were monitored.ResultsMinibodies radiolabeled with therapeutic beta emitters [131I]I-A11 Mb and [177Lu]Lu-DTPA-A11 Mb exhibited comparable tumor cell growth inhibition in vitro. In vivo surrogate immunoPET imaging using [89Zr]Zr-DFO-A11 Mb showed activity retention in liver and kidney up to 72 h, while [124I]I-A11 Mb cleared from liver, kidney, and blood by 48 h. Based on full biodistribution and dosimetry calculations, administering 37 MBq [131I]I-A11 Mb was predicted to deliver a favorable dose to the tumor (35 Gy), with a therapeutic index of 22 (tumor:bone marrow). For [177Lu]Lu-DTPA-A11 Mb, the kidneys would be dose-limiting, and the maximum tolerated activity (7.4 MBq) was not predicted to deliver an effective radiation dose to tumor. Radioimmunotherapy with a single dose of [131I]I-A11 Mb showed dose-dependent tumor inhibition with minimal off-target toxicity and improved median survival (19 and 24 days, P < 0.001) compared with untreated mice (12 days).ConclusionsThese findings show the potential of the anti-PSCA minibody for targeted radioimmunotherapy with minimal toxicity, and the application of immunoPET and dosimetry for personalized treatment.

Project description:Inadequate diagnostic methods for prostate cancer lead to over- and undertreatment, and the inability to intraoperatively visualize positive margins may limit the success of surgical resection. Prostate cancer visualization could be improved by combining the complementary modalities of immuno-positron emission tomography (immunoPET) for preoperative disease detection, and fluorescence imaging-guided surgery (FIGS) for real-time intraoperative tumor margin identification. Here, we report on the evaluation of dual-labeled humanized anti-prostate stem cell antigen (PSCA) cys-minibody (A11 cMb) for immunoPET/fluorescence imaging in subcutaneous and orthotopic prostate cancer models. Methods: A11 cMb was site-specifically conjugated with the near-infrared fluorophore Cy5.5 and radiolabeled with 124I or 89Zr. 124I-A11 cMb-Cy5.5 was used for successive immunoPET/fluorescence imaging of prostate cancer xenografts expressing high or moderate levels of PSCA (22Rv1-PSCA and PC3-PSCA). 89Zr-A11 cMb-Cy5.5 dual-modality imaging was evaluated in an orthotopic model. Ex vivo biodistribution at 24 h was used to confirm the uptake values, and tumors were visualized by post-mortem fluorescence imaging. Results: A11 cMb-Cy5.5 retained low nanomolar affinity for PSCA-positive cells. Conjugation conditions were established (dye-to-protein ratio of 0.7:1) that did not affect the biodistribution, pharmacokinetics, or clearance of A11 cMb. ImmunoPET using dual-labeled 124I-A11 cMb-Cy5.5 showed specific targeting to both 22Rv1-PSCA and PC3-PSCA s.c. xenografts in nude mice. Ex vivo biodistribution confirmed specific uptake to PSCA-expressing tumors with 22Rv1-PSCA:22Rv1 and PC3-PSCA:PC3 ratios of 13:1 and 5.6:1, respectively. Consistent with the immunoPET, fluorescence imaging showed a strong signal from both 22Rv1-PSCA and PC3-PSCA tumors compared with non-PSCA expressing tumors. In an orthotopic model, 89Zr-A11 cMb-Cy5.5 immunoPET was able to detect intraprostatically implanted 22Rv1-PSCA cells. Importantly, fluorescence imaging clearly distinguished the prostate tumor from surrounding seminal vesicles. Conclusion: Dual-labeled A11 cMb specifically visualized PSCA-positive tumor by successive immunoPET/fluorescence, which can potentially be translated for preoperative whole-body prostate cancer detection and intraoperative surgical guidance in patients.

Dataset Information

Engineering A11 Minibody-Conjugated, Polypeptide-Based Gold Nanoshells for Prostate Stem Cell Antigen (PSCA)-Targeted Photothermal Therapy.

Publications

Engineering A11 Minibody-Conjugated, Polypeptide-Based Gold Nanoshells for Prostate Stem Cell Antigen (PSCA)-Targeted Photothermal Therapy.

Similar Datasets

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