Theranostics In Prostate Cancer Research Articles

Update of PSMA Theranostics in Prostate Cancer: Current Applications and Future Trends.

There is now an increasing trend for targeting cancers to go beyond early diagnosis and actually improve Progression-Free Survival and Overall Survival. Identifying patients who might benefit from a particular targeted treatment is the main focus for Precision Medicine. Radiolabeled ligands can be used as predictive biomarkers which can confirm target expression by cancers using positron emission tomography (PET). The same ligand can subsequently be labeled with a therapeutic radionuclide for targeted radionuclide therapy. This combined approach is termed “Theranostics”. The prostate-specific membrane antigen (PSMA) has emerged as an attractive diagnostic and therapeutic target for small molecule ligands in prostate cancer. It can be labeled with either positron emitters for PET-based imaging or beta and alpha emitters for targeted radionuclide therapy. This review article summarizes the important concepts for Precision Medicine contributing to improved diagnosis and targeted therapy of patients with prostate cancer and we identify some key learning points and areas for further research.

Radiolabeled Peptide as Diagnostic, Therapeutic, and Theranostic agents for Prostate Cancer: Systematic Literature Review

Prostate cancer (PCa) is the most common sex-related malignancy and the second most common cause of mortality after lung cancer for men. Around 61.8% of Indonesian people undergo cancer treatment with surgery. This study aimed to figure out the use of radiolabeled peptides for diagnosis, therapy, and theranostics of prostate cancer. This study performed a literature review by searching the web databases such as PubMed, MDPI, Elsevier (Science Direct), and ACS Publications. The result showed that peptide compounds such RM2, VCN (Vicrostatin), DB15, and BBN7-14 were utilized as radionuclide-carriers for diagnostic imaging, meanwhile, peptides such as NeoBOMB1, PSMA-617, and [RGD-Glu-[DO3A]-6-Ahx-RM2] containing alpha or beta-emitted radionuclide were used as therapeutic and theranostic agents. They were tagged using 68Ga, 161Tb, 177Lu, 64Cu, 124I, 99mTc, 90Y, and 86Y radionuclides. Great efforts have been conducted in developing peptide-based radiopharmaceuticals for diagnosis and therapy of prostate cancer. Research groups focusing in nuclear medicine will continue to develop radiopharmaceuticals in the future, especially radiopeptide compounds for the diagnosis and therapy of prostate cancer.

Application Analysis of 124I-PPMN for Enhanced Retention in Tumors of Prostate Cancer Xenograft Mice.

BackgroundIn recent years, nuclear medicine imaging and therapy for prostate cancer have radically changed through the introduction of radiolabeled prostate-specific membrane antigen (PSMA)-binding peptides. However, these small molecular probes have some inherent limitations, including high nephrotoxicity and short circulation time, which limits their utility in biological systems.Methods and ResultsIn this study, organic melanin nanoparticles were used to directly label the long half-life radionuclide 124I (t1/2=100.8 h), and PSMA small molecular groups were efficiently bonded on the surface of nanoparticles to construct the PSMA-targeted long-retention nanoprobe 124I-PPMN, which has the potential to increase tumor uptake and prolong residence time. The results showed that the nanoprobe could substantially aggregate in the tumors of prostate cancer xenograft mice and was visible for more than 72 h. Positron Emission Computed Tomography (PET) imaging showed that the nanoprobe could be used for precise imaging of prostate cancer with high expression of PSMA. In addition, organic melanin nanoparticles labeled with an elemental radionuclide achieved a stable, metal-free structure. Cell experiments and mouse toxicity experiments indicated that the nanoprobe has high safety.ConclusionThe new nanoprobe constructed in this study has high specificity and biocompatibility. In the future, combined with the multifunctional potential of melanin nanoparticles, this nanoprobe is expected to be used in the integrated theranostics of prostate cancer.

Potential Targets Other Than PSMA for Prostate Cancer Theranostics: A Systematic Review.

Background: Prostate-specific membrane antigen (PSMA) is not sufficiently overexpressed in a small proportion of prostate cancer (PCa) patients, who require other strategies for imaging and/or treatment. We reviewed potential targets other than PSMA for PCa theranostics in nuclear medicine that have already been tested in humans. Methods: We performed a systematic web search in the PubMed and Cochrane databases, with no time restrictions by pooling terms (“prostate cancer”, “prostatic neoplasms”) and (“radioligand”, “radiotracer”). Included articles were clinical studies. The results were synthetized by the target type. Results: We included 38 studies on six different targets: gastrin-releasing peptide receptors (GRPRs) (n = 23), androgen receptor (n = 11), somatostatin receptors (n = 6), urokinase plasminogen activator surface receptor (n = 4), fibroblast activation protein (n = 2 studies) and integrin receptors (n = 1). GRPRs, the most studied target, has a lower expression in high-grade PCa, CRPC and bone metastases. Its use might be of higher interest in treating earlier stages of PCa or low-grade PCa. Radiolabeled fibroblast activation protein inhibitors were the most recent and promising molecules, but specific studies reporting their interest in PCa are needed. Conclusion: Theranostics in nuclear medicine will continue to develop in the future, especially for PCa patients. Targets other than PSMA exist and deserve to be promoted.

The History of Prostate-Specific Membrane Antigen as a Theranostic Target in Prostate Cancer: The Cornerstone Role of the Prostate Cancer Foundation.

Prostate-specific membrane antigen (PSMA) is a credentialed imaging and therapy (theranostic) target for the detection and treatment of prostate cancer. PSMA-targeted PET imaging and molecular radiotherapy are promising evolving technologies that will improve the outcomes of prostate cancer patients. In anticipation of this new era in prostate cancer theranostics, this article will review the history of PSMA from discovery through early- and late-stage clinical trials. Since 1993, the Prostate Cancer Foundation has funded critical and foundational PSMA research that established this theranostic revolution. The history and role of Prostate Cancer Foundation funding in this field will be discussed.

D2B antibody and its scFvD2B fragment in nanomedicine: promising tools in the theranostics of prostate cancer

Prostate cancer (PC) is ranked the sixth deadliest cancers among men. If PC is diagnosed at metastasised stages, traditional surgery and radiation therapy have limitations. In the last few decades, antibody therapy has emerged to deliver radioactive drugs to any metastatic PC tumours; thus, improving theranostics results and prolonged patient’s survival via effective targeting of prostate specific membrane antigens (PSMA). Full length anti-PSMA antibody, D2B, and its single chain variable fragment, scFvD2B, have been extensively studied as naked or combined with nanoparticles (NPs) in targeted antibody therapy. Such a combination is considered a current hotspot in research as a means to enhance the delivery, binding specificity, and stability of therapeutic or diagnostic agents. In this review, we summarise and compare data from studies published between 1993 & 2021 to highlight the major outputs from in vivo and in vitro applications of D2B and scFvD2B antibodies in PC theranostics. Special focus is set on gold nanoparticles (AuNPs) as a delivery vehicle given their unique physicochemical and biological properties. Our conclusion supports the use of AuNPs-scFvD2B conjugates in future biomedical approaches.

Targeting LIN28: a new hope in prostate cancer theranostics.

The mortality and morbidity rates for prostate cancerhave recently increased to alarming levels, risinghigher than lung cancer. Due to alack of drug targets and molecular probes, existing theranostic techniques are limited. Human LIN28A and its paralog LIN28B overexpression are associated with a number of tumors resulting in a remarkable increase in cancer aggression and poor prognoses. The current review aims to highlight recent work identifying the key roles of LIN28A and LIN28B in prostate cancer, and to instigate further preclinical and clinical research in this importantarea.

Biomarkers in Prostate-Specific Membrane Antigen Theranostics

Theranostics of prostate cancer (PC) represents a growing area of development of imaging agents and targeted radionuclide therapeutics against a major target, prostate specific membrane antigen (PSMA). In view of the encouraging efficacy from the use of 177Lu and other radionuclides in metastatic castration-resistant prostate cancer (mCRPC), it is becoming increasingly important to identify surrogate markers that can help predict which patients are more likely to respond and experience improved survival. This review discusses potential predictors of efficacy of PSMA-targeted radionuclide therapies (TRT) segregated in three major categories: imaging, clinical and molecular.

A Highly Specific Multiple Enhancement Theranostic Nanoprobe for PET/MRI/PAI Image‐Guided Radioisotope Combined Photothermal Therapy in Prostate Cancer

An integrated molecular probe for combined tumor-targeted multimodal imaging and therapy in the era of precision medicine requires a multiplexed platform that simultaneously has high targeting specificity, versatile conjugation capability, and biocompatibility. Here, a novel biocompatible melanin nanoprobe (PMNs-II-813) coupled with a highly specific prostate-specific membrane antigen small molecule inhibitor is developed for the targeted multimodal diagnosis and treatment of prostate cancer. The melanin nanoparticles demonstrate photoacoustic imaging and photothermal therapy (PTT) functionalities via strong near-infrared absorption. The imaging contrast agents 89 Zr and Mn2+ are stably conjugated to the nanoparticles for positron emission tomography (PET) and magnetic resonance imaging (MRI). Fusion PET/MRI with PMNs-II-813 enables the monitoring of treatment effects in real time and lasts for more than 1 week, demonstrating the capability for multimodal theranostics in prostate cancer. Labeling with a therapeutic radionuclide, 131 I, simultaneously endows the nanoprobe with the capability for radioisotope therapy (RIT) and PTT under triple-modal imaging guidance. Combined PTT and RIT has an inhibitory effect on prostate cancer growth (tumor inhibition rate of ≈93% 20 days after treatment), which is significantly better than that with the single treatment. Overall, it is believed that PMNs-II-813 has potential for clinical translation to treat prostate cancer.

A survivin-driven, tumor-activatable minicircle system for prostate cancer theranostics

Gene vectors regulated by tumor-specific promoters to express transgenes specifically in cancer cells are an emerging approach for cancer diagnosis and treatment. Minicircles are shortened plasmids stripped of prokaryotic sequences that have potency and safety characteristics beneficial for clinical translation. Previously, we developed minicircles driven by the tumor-specific survivin promoter, which exhibits elevated transcriptional activity in aggressive cancers, to express a secreted reporter for blood-based cancer detection. Here we present the first activatable, cancer theranostic minicircle system featuring a pair of diagnostic and therapeutic minicircles expressing Gaussia luciferase for urine-based cancer detection or cytosine deaminase:uracil phosphoribosyltransferase for gene-directed enzyme prodrug therapy. Diagnostic minicircles revealed urinary reporter output related to cellular survivin levels. Notably, mice with aggressive prostate tumors exhibited significantly higher urine reporter activity than mice with non-aggressive tumors and healthy mice after intratumoral minicircle administration. Therapeutic minicircles displayed specific cytotoxicity in survivin-rich cancer cells and significantly attenuated growth of aggressive orthotopic prostate tumors in mice. Use of these minicircles together creates a theranostic system that can first identify individuals carrying aggressive prostate cancer via a urinary test, followed by stringent control of tumor progression in stratified individuals who carry high-risk prostate lesions.

PSMA-targeted melanin-like nanoparticles as a multifunctional nanoplatform for prostate cancer theranostics.

Prostate-specific membrane antigen (PSMA) is highly expressed on the surface of most prostate tumor cells and is considered a promising target for prostate cancer imaging and treatment. It is possible to establish a PSMA-targeted theranostic probe to achieve early diagnosis and treatment of this cancer type. In this contribution, we prepared a multifunctional melanin-like polydopamine (PDA) nanocarrier decorated with a small-molecule PSMA inhibitor, N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-l-lysine (DCL). PDA-DCL was then functionalized with perfluoropentane (PFP) and loaded with the photosensitizer chlorin e6 (Ce6) to give Ce6@PDA-DCL-PFP, which was successfully used for ultrasound-guided combined photodynamic/photothermal therapy (PDT/PTT) of prostate cancer. Compared with the corresponding non-targeted probe (Ce6@PDA-PEG-PFP), our targeted probe induced higher cellular uptake in vitro (6.5-fold) and more tumor accumulation in vivo (4.6-fold), suggesting strong active targeting capacity. Meanwhile, this new nanoplatform significantly enhanced the ultrasound contrast signal at the tumor site in vivo, thus facilitating precise and real-time detection of the tumor. In addition, this Ce6-loaded PDA nanoplatform produced a synergistic effect of PDT and PTT under 660 nm and 808 nm irradiation, inducing a more efficient killing effect compared with the individual therapy in vitro and in vivo. Furthermore, the tumor in the targeted group was more effectively suppressed than that in the non-targeted group under the same irradiation condition. This multifunctional probe may hold great potential for precise and early theranostics of prostate cancer.

68Ga, 44Sc and 177Lu-labeled AAZTA5-PSMA-617: synthesis, radiolabeling, stability and cell binding compared to DOTA-PSMA-617 analogues

BackgroundThe AAZTA chelator and in particular its bifunctional derivative AAZTA5 was recently investigated to demonstrate unique capabilities to complex diagnostic and therapeutic trivalent radiometals under mild conditions. This study presents a comparison of 68Ga, 44Sc and 177Lu-labeled AAZTA5-PSMA-617 with DOTA-PSMA-617 analogues. We evaluated the radiolabeling characteristics, in vitro stability of the radiolabeled compounds and evaluated their binding affinity and internalization behavior on LNCaP tumor cells in direct comparison to the radiolabeled DOTA-conjugated PSMA-617 analogs.ResultsAAZTA5 was synthesized in a five-step synthesis and coupled to the PSMA-617 backbone on solid phase. Radiochemical evaluation of AAZTA5-PSMA-617 with 68Ga, 44Sc and 177Lu achieved quantitative radiolabeling of > 99% after less than 5 min at room temperature. Stabilities against human serum, PBS buffer and EDTA and DTPA solutions were analyzed. While there was a small degradation of the 68Ga complex over 2 h in human serum, PBS and EDTA/DTPA, the 44Sc and 177Lu complexes were stable at 2 h and remained stable over 8 h and 1 day. For all three compounds, i.e. [natGa]Ga-AAZTA5-PSMA-617, [natSc]Sc-AAZTA5-PSMA-617 and [natLu]Lu-AAZTA5-PSMA-617, in vitro studies on PSMA-positive LNCaP cells were performed in direct comparison to radiolabeled DOTA-PSMA-617 yielding the corresponding inhibition constants (Ki). Ki values were in the range of 8–31 nM values which correspond with those of [natGa]Ga-DOTA-PSMA-617, [natSc]Sc-DOTA-PSMA-617 and [natLu]Lu-DOTA-PSMA-617, i.e. 5–7 nM, respectively. Internalization studies demonstrated cellular membrane to internalization ratios for the radiolabeled 68Ga, 44Sc and 177Lu-AAZTA5-PSMA-617 tracers (13–20%IA/106 cells) in the same range as the ones of the three radiolabeled DOTA-PSMA-617 tracers (17–20%IA/106 cells) in the same assay.ConclusionsThe AAZTA5-PSMA-617 structure proved fast and quantitative radiolabeling with all three radiometal complexes at room temperature, excellent stability with 44Sc, very high stability with 177Lu and medium stability with 68Ga in human serum, PBS and EDTA/DTPA solutions. All three AAZTA5-PSMA-617 tracers showed binding affinities and internalization ratios in LNCaP cells comparable with that of radiolabeled DOTA-PSMA-617 analogues. Therefore, the exchange of the chelator DOTA with AAZTA5 within the PSMA-617 binding motif has no negative influence on in vitro LNCaP cell binding characteristics. In combination with the faster and milder radiolabeling features, AAZTA5-PSMA-617 thus demonstrates promising potential for in vivo application for theranostics of prostate cancer.

Prostate-specific membrane antigen theranostics in advanced prostate cancer: an evolving option.

To review current data for the role of prostate specific membrane antigen (PSMA) radioligand therapy (RLT) for patients with advanced prostate cancer. This review provides an update for multidisciplinary teams on the current and potential future applications of theranostics in prostate cancer. Narrative review focussing on PSMA as a target for RLT, and data using RESULTS: RLT with PSMA is an exciting therapeutic alternative to the existing management options already in use for patients with metastatic castrate-resistant prostate cancer (mCRPC). To date, most evidence exists regarding small-molecule PSMA inhibitors bound to beta-emitting radioisotopes such as 177Lu (Lu-PSMA). Prospective phase II data supports the safety and efficacy of Lu-PSMA in men with heavily pre-treated progressive mCRPC, and several late-phase randomised trials of Lu-PSMA are underway, with many more in the pipeline. Early results are encouraging, indicating that the theranostic approach may play a vital role in management of advanced prostate cancer and perhaps even in much earlier disease states. PSMA RLT is a promising new treatment option for men with mCPRC, and may also have utility in less advanced prostate cancer.

Changing the Goal Posts: Prostate-specific Membrane Antigen Targeted Theranostics in Prostate Cancer.

Prostate-specific membrane antigen (PSMA) theranostics is changing the face of prostate cancer diagnosis and therapy. PSMA, a transmembrane protein over-expressed in many prostate cancers, is a promising target for theranostics. Theranostics is the concept of small molecule proteins that are labelled to different radionuclides and can be used for either diagnosis or therapy, dependent on whether they are labelled with an imaging or therapy radionuclide. By directly targeting the cancer cells with imaging and then for therapy, this approach embodies the philosophy of precision medicine - right drug, right time, right dose. The question is how to best utilise these new imaging and therapy agents in clinical practice. This review will evaluate the importance of PSMA in prostate cancer, its role in diagnostic imaging, and its potential as a therapy of advanced prostate cancer. Electronic databases including MEDLINE, Scopus, professional websites were searched. PSMA-directed theranostics has an expanding role in prostate cancer because of its utility as a sensitive diagnostic tool that can be coupled with efficacious and low-toxicity therapeutic options. Ongoing research is required to determine how to use this effective tool for best patient care. PSMA theranostics is rapidly being incorporated into the routine care of men with prostate cancer. Understanding its strengths, its limitations, and where it may be valuable in clinical care is important in undertaking best patient practice.

Theranostics in Prostate Cancer.

Metastatic castration resistant prostate cancer (mCRPC) is a highly mortal disease, requiring safe and effective therapeutic agents to improve the patient outcome. Prostate-specific membrane antigen (PSMA) is over expressed in many prostate cancer cells, and act as target for molecular imaging (MI) and radionuclide therapy (RNT). The introduction of Gallium-68 (68Ga) PSMA- PET/CT in 2012 has changed the management of prostate cancer. In addition to its importance in identifying PSMA expression for selection of patients suitable for PSMA RNT, PSMA- PET/CT showed superior diagnostic accuracy to combined CT and bone scan. Lutetium-177 (177Lu) PSMA-617 is the most investigated PSMA radio ligand for RNT in prostatecancer, it is a radiolabelled small molecule, binds with high affinity to PSMA, enabling beta-particles emissions with short tissue penetration depth (mean range of 0.7 mm and maximum range of 2.1 mm in soft tissue). Since 2014 multiple studies showed a highly impressive therapeutic efficacy and safety of 177Lu-PSMA RNT. The evidence achieved by these studies paved the way to ongoing randomized clinical trials, and currently this therapy is being applied and clinically accepted in many centers worldwide. The aim of this article is to share the practical aspect of PSMA Theranostics for prostate cancer, including patient selection, therapy protocol and follow-up.

Preclinical Evaluation of a High-Affinity Sarcophagine-Containing PSMA Ligand for 64Cu/67Cu-Based Theranostics in Prostate Cancer.

The application of small molecules targeting prostate-specific membrane antigen (PSMA) has emerged as a highly promising clinical strategy for visualization and treatment of prostate cancer. Ligands that integrate the ability to both quantify the distribution of radioactivity and treat disease through the use of a matched pair of radionuclides have particular value in clinical and regulatory settings. In this study, we describe the development and preclinical evaluation of RPS-085, a ligand that binds PSMA and serum albumin and exploits the 64/67Cu radionuclide pair for prostate cancer theranostics. RPS-085 was synthesized by conjugation of a PSMA-targeting moiety, an Nε-(2-(4-iodophenyl)acetyl)lysine albumin binding group, and a bifunctionalized MeCOSar chelator. The IC50 of the metal-free RPS-085 was determined in a competitive binding assay. The affinity for human serum albumin of the radiolabeled compound was determined by high-performance affinity chromatography. Radiolabeling was performed in NH4OAc buffer at 25 °C. The stability of the radiolabeled compounds was assessed in vitro and in vivo. The biodistribution of [64/67Cu]Cu-RPS-085 was determined following intravenous administration to male BALB/c mice bearing LNCaP tumor xenografts. The radiochemical yields of [64/67Cu]Cu-RPS-085 were nearly quantitative after 20 min. The metal-free complex is a potent inhibitor of PSMA (IC50 = 29 ± 2 nM), and the radiolabeled compound has moderate affinity for human serum albumin (Kd = 9.9 ± 1.7 μM). Accumulation of the tracer in mice was primarily evident in tumor and kidneys. Activity in all other tissues, including blood, was negligible, and the radiolabeled compounds demonstrated high stability in vitro and in vivo. Tumor activity reached a maximum at 4 h post injection (p.i.) and cleared gradually over a period of 96 h. By contrast, activity in the kidney cleared rapidly from 4 to 24 h p.i. As a consequence, by 24 h p.i., the tumor-to-kidney ratio exceeds 2, and the predicted dose to tumors is significantly greater than the dose to kidneys. [64Cu]Cu-RPS-085 combines rapid tissue distribution and clearance with prolonged retention in LNCaP tumor xenografts. The pharmacokinetics should enable radioligand therapy using [67Cu]Cu-RPS-085. By virtue of its rapid kidney clearance, the therapeutic index of [67Cu]Cu-RPS-085 likely compares favorably to its parent structure, [177Lu]Lu-RPS-063, a highly avid PSMA-targeting compound. On this basis, [64/67Cu]Cu-RPS-085 show great promise as PSMA-targeting theranostic ligands for prostate cancer imaging and therapy.

Functional Optimization of Radionuclide Pairs in Theranostics of Prostate Cancer

The functional optimization of the composition of radiopharmaceutical pairs based on the prostatespecific membrane antigen (PSMA) for the radionuclide theranostics of castration-resistant prostate cancer was carried out. The analysis of radiation-physical and dosimetric characteristics of 9 radionuclides for diagnostic components of theranostic pairs and 6 radionuclides for therapeutic components is carried out. It was shown that positron-emitting radionuclides 18F and 68Ga should be considered optimal for the diagnosis and monitoring of the effectiveness of theranostics, and 177Lu beta-emitting radionuclide and 225Ac alphabeta-emitting radionuclide should be considered as the radionuclide therapy. The values of the total and organ radiation risks of secondary radiation-induced cancers in patients who have completed several courses of theranostics are calculated. It is shown that for 2 teranostic pairs based on 177Lu‑PSMA the radiation risk is higher than significant, while for 2 teranostic pairs based on 225Ac the risk falls within the range of a significant level. The calculated radiological criteria for discharge of patients after a course of theranostics from nuclear medicine departments show the fundamental possibility of performing an outpatient treatment regimen using any of the 4 considered theranostic pairs.

Emerging Theranostic Silver and Gold Nanomaterials to Combat Prostate Cancer: A Systematic Review

Prostate cancer has emerged as the common malignancy in men and is considered as a global issue. Among different strategies to combat prostate cancer, nanobiotechnology appears as a novel approach for prostate cancer theranostics. The current systematic review discussing the recent development in the prostate anticancer activity of biologically synthesized silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) through laboratory investigations. The databases including Cochrane, Web of Science, PubMed, Scopus, Science Direct, ProQuest, and Embase were used to identify the records. It was found that most of the studies used herbal extracts for preparation of AgNPs and/or AuNPs. Majority of biosynthesized nanoparticles (NPs) were formed with spherical morphology. Besides, all studies reported the size of NPs less than 100 nm. Moreover, PC-3 prostate cancer cell was the predominant cell line that was evaluated for prostate anticancer activity of NPs. In the present study, we provided valuable information suggesting the significant prostate anticancer potential of biogenic AgNPs and/or AuNPs. However, further, in vivo investigations are required to provide stronger evidence of the efficacy of bio-mediated synthesized AgNPs and/or AuNPs to combat prostate cancer.

Dawn of Theranostics in Myanmar (Dream, Reality, and Constraint).

Prostate cancer is third common malignancy in men of old age (average 65years) in Myanmar. Currently, serum PSA and bone scan are the markers of choice. Because of the evidence-based, promising success of 68Ga-PSMA PET-CT and 177Lu-PSMA theranostics in prostate cancer worldwide, 99mTc-PSMA SPECT-CT imaging and 177Lu-PSMA therapy has launched as a stepping-stone of theranostics in Myanmar with the available facilities. Twelve cases of prostate cancer patients were imaged with 600MBq of 99mTc-PSMA I+S SPECT-CT. Four metastatic castration resistant prostate cancer (MCRPC) patients with abnormal result were treated with 177Lu-PSMA. The protocol consists of 6-8GBq of 177Lu-PSMA, three successive doses at interval of 4-6weeks. Post-therapy SPECT-CT imaging was done. All treated patients were improved by free of bone pain, and fall/rise in serum PSA level. Two patients with extensive skeletal metastases succumbed to complications. The results are well documented and present at the multidisciplinary conferences for clinical awareness. Theranostics in prostate cancer with available facilities is an additional boon to our health care professionals to upgrade cancer management in Myanmar. This paper provides the technology with cost effectiveness and benefit to prostate cancer patients of Myanmar.

Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics.

Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 (225Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 (177Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177Lu is quantitatively accurate and can be used to perform treatment planning. [177Lu]hu11B6 therefore has significant potential as a theranostic agent.Materials and Methods: Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [177Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR).Results: Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [177Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [177Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177Lu and decreasing tumor volumes. For [177Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017).Conclusions: This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225Ac labeled hu11B6, however emerging at a later timepoint.