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USE OF KNOTTIN AS A PSMA-TROPIC PEPTIDE CARRIER
Abstract
Prostate cancer is the most common type of cancer in males. Approximately 1.3 million cases of prostate cancer and over 400,000 deaths from the disease are diagnosed annually. The number of deaths is expected to double by 2040. Common methods of prostate cancer treatment have many disadvantages; one of them is the relapse risk. The shortcomings of traditional therapy have led to peptide-receptor radionuclide therapy. The aim of the study is to examine binding efficiency of Lu177 labeled knottins containing PSMA-tropic peptide in different domains in vitro and their biodistribution in vivo. Materials and Methods. We used prostate cancer cell (LNCaP, PC3) and ovarian fibroblast cell (CHO-K1) cultures. The peptides were synthesized using a peptide synthesizer (ResPepSL, Intavis). We studied peptide stability, their toxicity, binding to cell cultures, and biodistribution on the example of breast adenocarcinoma-bearing BALB/c mice. Chromatographic methods and radiometric techniques were used. Results. The synthesized peptides with GTIQPYPFSWGY sequence inserted into U5-cytotoxin-Sth1a node are more stable in blood plasma and saline than 177Lu-PSMA-617a, but have a similar degree of binding. Biodistribution studies in BALB/c mice show a higher binding index of the synthesized peptide if compared to 177Lu-PSMA-617. Conclusion. Modified peptides with a PSMA-tropic peptide inserted into the structure of U5-Sth1a toxin demonstrate high stability both in saline and in blood plasma, as well as good binding to cell cultures and tumors.
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Purpose
To define the efficacy of standard androgen deprivation therapy (ADT) in the treatment of metastatic prostate cancer (PCa).
Materials and methods
Fifty patients with mean age of 70.48 ± 9.95 years old (range 52–87) who had metastatic PCa and received ADT between 2014 and 2019 were retrospectively evaluated. Median values of pre-therapeutic PSA and Gleason scores were 50 ng/ml (range 8–1201) and 8 (range 6–9), respectively. All patients received luteinizing hormone-releasing hormone (LHRH) analogue and anti-androgen. The patients were evaluated in terms of age, pre-therapeutic PSA serum levels, Gleason scores, presence of metastasis, number and percentage of cores involved, nadir PSA, time to nadir PSA, duration of ADT, and PSA at last follow-up. Multivariate analysis was used to define the factors which have impact on ADT response. The mean follow-up period was 13.87 ± 7.78 months, (range 2–32).
Results
All patients showed reduction in serum PSA level after initiation of ADT, and the median value of nadir PSA was 1.12 ng/ml (range 0.02–50). The mean value of time to nadir PSA was 3.85 ± 1.57 months (range 2–7). The median value of PSA at last follow-up was 2 ng/ml (range 0.02–50.21). Multi-variant analysis showed that nadir PSA have a significant correlation with pre-therapeutic PSA, PSA at last follow-up, age, and Gleason scores ( p < .05).
Conclusion
Standard ADT is a feasible option in the treatment of metastatic PCa. Gleason scores, age, pre-therapeutic PSA, and PSA at last follow-up have significant impact on outcomes of ADT. Further studies of high number of patients with long-term follow-up including other chemo-hormonal therapy and androgen receptor blockers should be carried out to confirm and improve efficacy of ADT.
Background:
The combination of the unique properties of cancer cells makes it possible to find specific ligands that interact directly with the tumor, and to conduct targeted tumor therapy. Phage display is one of the most common methods for searching for specific ligands. Bacteriophages display peptides, and the peptides themselves can be used as targeting molecules for the delivery of diagnostic and therapeutic agents. Phage display can be performed both in vitro and in vivo. Moreover, it is possible to carry out the phage display on cells pre-enriched for a certain tumor marker, for example, CD44 and CD133.
Methods:
For this work we used several methods, such as phage display, sequencing, cell sorting, immunocytochemistry, phage titration.
Results:
We performed phage display using different screening systems (in vitro and in vivo), different phage libraries (Ph.D-7, Ph.D-12, Ph.D-C7C) on CD44+/CD133+ and without enrichment U-87 MG cells. The binding efficiency of bacteriophages displayed tumor-targeting peptides on U-87 MG cells was compared in vitro. We also conducted a comparative analysis in vivo of the specificity of the accumulation of selected bacteriophages in the tumor and in the control organs (liver, brain, kidney and lungs).
Conclusions:
The screening in vivo of linear phage peptide libraries for glioblastoma was the most effective strategy for obtaining tumor-targeting peptides providing targeted delivery of diagnostic and therapeutic agents to glioblastoma.
Lu-PSMA-617 therapeutic agent was prepared successfully under optimized condition of pH=4.5, molar ratio of metal to ligand 1:10, temperature of 95°C and 40 min reaction time. ¹⁷⁷LuCl3 was obtained with specific activity of 70–80 GBq/mg by the thermal neutron irradiation (5×10¹³ n cm⁻² s⁻¹) of the enriched Lu2O3 (52% ¹⁷⁶Lu) samples. The radionuclidic purity of ¹⁷⁷LuCl3 (>99%) was checked by a HPGe detector. The radiochemical purities of ¹⁷⁷LuCl3 solution and ¹⁷⁷Lu-PSMA-617 compound (>98%) were checked by ITLC and HPLC techniques and stability studies were assayed in the presence of human serum. Biodistribution and imaging assessments in the breast adenocarcinoma-bearing mice showed a major accumulation of activity in the tumor and kidneys tissues, as the expression site of PSMA molecule and the main route of excretion, respectively.
Somatostatin receptors are overexpressed in neuroendocrine tumors, whose endogenous ligands are somatostatin. DOTA-TATE is an analogue of somatostatin, which shows high binding affinity to somatostatin receptors. We aim to evaluate the ⁶⁸Ga/¹⁷⁷Lu-labeling DOTA-TATE kit in neuroendocrine tumor model for molecular imaging and to try human–positron emission tomography/computed tomography imaging of ⁶⁸Ga-DOTA-TATE in neuroendocrine tumor patients. DOTA-TATE kits were formulated and radiolabeled with ⁶⁸Ga/¹⁷⁷Lu for ⁶⁸Ga/¹⁷⁷Lu-DOTA-TATE (M-DOTA-TATE). In vitro and in vivo stability of ¹⁷⁷Lu-DOTA-TATE were performed. Nude mice bearing human tumors were injected with ⁶⁸Ga-DOTA-TATE or ¹⁷⁷Lu-DOTA-TATE for micro–positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging separately, and clinical positron emission tomography/computed tomography images of ⁶⁸Ga-DOTA-TATE were obtained at 1 h post-intravenous injection from patients with neuroendocrine tumors. Micro–positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging of ⁶⁸Ga-DOTA-TATE and ¹⁷⁷Lu-DOTA-TATE both showed clear tumor uptake which could be blocked by excess DOTA-TATE. In addition, ⁶⁸Ga-DOTA-TATE–positron emission tomography/computed tomography imaging in neuroendocrine tumor patients could show primary and metastatic lesions. ⁶⁸Ga-DOTA-TATE and ¹⁷⁷Lu-DOTA-TATE could accumulate in tumors in animal models, paving the way for better clinical peptide receptor radionuclide therapy for neuroendocrine tumor patients in Asian population.
We radiolabeled a ligand, PSMA-617, of prostate-specific membrane antigen (PSMA) with copper-64 ((64)Cu), to evaluate the metabolism, biodistribution, and potential of [(64)Cu]PSMA-617 for PET imaging of prostate cancer. [(64)Cu]PSMA-617 was synthesized by heating PSMA-617 with [(64)Cu]CuCl2 in buffer solution at 90°C for 5 min. In vitro uptake was determined in two cell lines of prostate cancer. In vivo regional distributions were determined in normal and tumor-bearing mice. High radiolabeling efficiency of (64)Cu for PSMA-617 yielded [(64)Cu]PSMA-617 with >99% radiochemical purity. In vitro cellular uptake experiments demonstrated the specificity of [(64)Cu]PSMA-617 for PSMA-positive LNCaP cells. Biodistribution observations of normal mice revealed high uptake of radioactivity in the kidney and liver. PET with [(64)Cu]PSMA-617 visualized tumor areas implanted by PSMA-positive LNCaP cells in the mice. Two hours after the injection of [(64)Cu]PSMA-617 into mice, a radiolabeled metabolite was observed in the blood, liver, urine, and LNCaP tumor tissues. [(64)Cu]PSMA-617 was easily synthesized, and exhibited a favorable biodistribution in PSMA-positive tumors. Although this radioligand shows slow clearance for kidney and high liver uptake, change of its chelator moiety and easy radiolabeling may enable development of new (64)Cu or (67)Cu-labeled PSMA ligands for imaging and radiotherapy.
Background:
Cystine-knot miniproteins, also known as knottins, have shown great potential as molecular scaffolds for the development of targeted therapeutics and diagnostic agents. For this purpose, previous protein engineering efforts have focused on knottins based on the Ecballium elaterium trypsin inhibitor (EETI) from squash seeds, the Agouti-related protein (AgRP) neuropeptide from mammals, or the Kalata B1 uterotonic peptide from plants. Here, we demonstrate that Agatoxin (AgTx), an ion channel inhibitor found in spider venom, can be used as a molecular scaffold to engineer knottins that bind with high-affinity to a tumor-associated integrin receptor.
Methodology/principal findings:
We used a rational loop-grafting approach to engineer AgTx variants that bound to αvβ3 integrin with affinities in the low nM range. We showed that a disulfide-constrained loop from AgRP, a structurally-related knottin, can be substituted into AgTx to confer its high affinity binding properties. In parallel, we identified amino acid mutations required for efficient in vitro folding of engineered integrin-binding AgTx variants. Molecular imaging was used to evaluate in vivo tumor targeting and biodistribution of an engineered AgTx knottin compared to integrin-binding knottins based on AgRP and EETI. Knottin peptides were chemically synthesized and conjugated to a near-infrared fluorescent dye. Integrin-binding AgTx, AgRP, and EETI knottins all generated high tumor imaging contrast in U87MG glioblastoma xenograft models. Interestingly, EETI-based knottins generated significantly lower non-specific kidney imaging signals compared to AgTx and AgRP-based knottins.
Conclusions/significance:
In this study, we demonstrate that AgTx, a knottin from spider venom, can be engineered to bind with high affinity to a tumor-associated receptor target. This work validates AgTx as a viable molecular scaffold for protein engineering, and further demonstrates the promise of using tumor-targeting knottins as probes for in vivo molecular imaging.
Prostate cancer incidence is rising due to the ageing population and increased public and doctor awareness. The role of screening is still not clear due to the large number of asymptomatic men who would need to be screened and treated to prevent one death. Discussion of all treatment options should be undertaken, with the patient having the opportunity to meet a clinical oncologist and urological surgeon. Treatment options include active surveillance, external beam radiotherapy, brachytherapy and surgery. Low-dose rate brachytherapy involves the permanent insertion of radioactive seeds (half-life 60 days) under ultrasound guidance. It is a good option for many men as impotence and incontinence rates are lower than for surgery and it has reduced hospital costs and time off work and high rates of relapse-free survival (90-95% in low-risk disease). External beam radiotherapy offers a good treatment for men with more locally advanced disease and men who do not want to undergo an anaesthetic. New developments allow higher doses of radiotherapy to be given with reduced relapse rates and reduced toxicity to neighbouring structures such as bowel and bladder. High-dose rate brachytherapy involves the temporary insertion of applicators into the prostate so that a high energy source can temporarily be fed into different positions in the prostate, ensuring a high dose to the prostate gland but minimising dose to the bladder and bowel. It can be used as monotherapy or in combination with external beam radiotherapy.
Widespread use of testing for prostate-specific antigen (PSA) has led to a migration in the stage and grade of prostate cancer (PCa), with most men presenting with localized disease. However, 20%-35% of patients still present with high-risk disease (PSA > 20 ng/mL, biopsy Gleason score 8-10, or clinical stage T3). Despite advances in various treatment modalities, patients with high-risk disease have a significant chance of recurrence and death after surgery, often because of the presence of early occult metastasis at time of diagnosis. The optimal management of high-risk pca remains controversial. The present article aims to discuss the traditional approaches and the more recent evolution toward multimodal therapies.
Men with high-risk localized prostate cancer (PCa) remain a challenge for clinicians. Until recently, surgery was not the preferred approach, in part because risk of subclinical metastatic disease, elevated rates of positive surgical margins, absence of randomized studies, and suboptimal cancer control did not justify the morbidity of surgery. No randomized data comparing surgery with radiation therapy are yet available. Data for and comparisons between treatment options should therefore be analyzed with extreme caution.When selecting the best treatment for patients with clinically localized high-risk PCa, considerations should include the life expectancy of the patient, the natural history of PCa, the curability of the disease, and the morbidity of treatment. High-grade PCa managed with noncurative intent greatly reduces life expectancy, but overall, it must also be remembered that radical prostatectomy (RP) and radiotherapy (RT) appear to have similar effects on quality of life. In this population, RP necessitates an extended pelvic lymph node dissection (PLND), but in selected cases, nerve-sparing is a therapeutic possibility and may offer a significant advantage over rt in terms of local control and-although absolutely not yet proved-maybe even in survival. One clear advantage is the ease of administering adjuvant or salvage external-beam rt (EBRT) after rp; conversely, salvage rp after failed EBRT is an exceedingly difficult surgery, with major complications. Surgery therefore has its place, but must be considered in the context of multimodality treatment and the risk of micrometastatic disease. Awaited trial results will help to further refine management in this group of patients.
In this work we describe the first results of radiolabeling with lutetium-177 (177Lu) and in vivo biodistribution and pharmacokinetics studies in normal Balb-c mice of a new bombesin analog (BEFG2)--DOTA-Phe-X-BBN(6-14), where X is a spacer of two aminoacids. Bombesin (BBN) is an amphibian analog of human gastrin releasing peptide (GRP). Development of radiolabeled BBN derivatives as agents for diagnostic imaging and systemic radiotherapy has increased considerable because of the observation that GRP receptors (GRPr) are over-expressed in a variety of human tumor cells, such as prostate tumor cells. 177Lu-labeled peptides are attractive due to the excellent radiophysical properties and commercial availability of the radiometal. BEFG2 was successfully labeled with high yield and kept stable for more than 96 hours at 2-8 degrees C and 1 hour in human plasma. Data analysis obtained from the in vivo studies showed that the amount of BEFG2 present in plasma decreased rapidly and became almost undetectable at 60 min p.i., indicating rapid peptide excretion, which is performed mainly by renal pathway. In addition, biodistribution and single photon emission tomography showed low abdominal accumulation of 177Lu-DOTA- Phe-X-BBN(6-14), indicating that this analog is a potential candidate for tumors target therapy. .
The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.
Background
Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term follow-up is sparse.
Methods
We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model.
Results
By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer).
Conclusions
Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer. (Funded by the Swedish Cancer Society and others.)
The high incidence rates of prostate cancer (PCa) raise demand for improved therapeutic strategies. Prostate tumors specifically express the prostate‐specific membrane antigen (PSMA), a membrane‐bound protease. As PSMA is highly overexpressed on malignant prostate tumor cells and as its expression rate correlates with the aggressiveness of the disease, this tumor‐associated biomarker provides the possibility to develop new strategies for diagnostics and therapy of PCa. Major advances have been made in PSMA targeting, ranging from immunotherapeutic approaches to therapeutic small molecules. This review elaborates the diversity of PSMA targeting agents while focusing on the radioactively labeled tracers for diagnosis and endoradiotherapy. A variety of radionuclides have been shown to either enable precise diagnosis or efficiently treat the tumor with minimal effects to nontargeted organs. Most small molecules with affinity for PSMA are based on either a phosphonate or a urea‐based binding motif. Based on these pharmacophores, major effort has been made to identify modifications to achieve ideal pharmacokinetics while retaining the specific targeting of the PSMA binding pocket. Several tracers have now shown excellent clinical usability in particular for molecular imaging and therapy as proven by the efficiency of theranostic approaches in current studies. The archetypal expression profile of PSMA may be exploited for the treatment with alpha emitters to break radioresistance and thus to bring the power of systemic therapy to higher levels.
Cancer is one of the leading causes of death in the United States along with heart disease. The hallmark of cancer treatment has been conventional chemotherapy. Chemotherapeutic drugs are designed to target not only rapidly dividing cells, such as cancer cells, but also certain normal cells, such as intestinal epithelium. Over the past several years, a new generation of cancer treatment has come to the forefront, i.e, targeted cancer therapies. Like conventional chemotherapy, targeted cancer therapies use pharmacological agents that inhibit growth, increase cell death and restrict the spread of cancer. As the name suggests, targeted therapies interfere with specific proteins involved in tumorigenesis. Rather than using broad base cancer treatments, focusing on specific molecular changes which are unique to a particular cancer, targeted cancer therapies may be more therapeutically beneficial for many cancer types, including lung, colorectal, breast, lymphoma and leukemia. Moreover, recent advances have made it possible to analyze and tailor treatments to an individual patient's tumor. There are three main types of targeted cancer therapies; 1) monoclonal antibodies, 2) small molecule inhibitors and 3) immunotoxins. This review will discuss these three classes of targeted therapies in detail, as well as the biology behind targeted cancer therapies.
Cystine-knot miniproteins, also known as knottins, constitute a large family of structurally related peptides with diverse amino acid sequences and biological functions. Knottins have emerged as attractive candidates for drug development as they potentially fill a niche between small molecules and protein biologics, offering drug-like properties and the ability to bind to clinical targets with high affinity and selectivity. Due to their extremely high stability and unique structural features, knottins also demonstrate promise in addressing challenging drug development goals, including the potential for oral delivery and the ability to access intracellular drug targets. Several naturally-occurring knottins have recently received approval for treating chronic pain and irritable bowel syndrome, while others are under development for tumor imaging applications. To expand beyond nature's repertoire, rational and combinatorial protein engineering methods are generating tumor-targeting knottins for use as cancer diagnostics and therapeutics.
Cystine knot miniproteins define a class of peptides in the size range of approximately 28-35 amino acid residues that often combine high chemical and biological stability with high potency and selectivity. They share a common structural motif that is defined by three intramolecular disulfide bonds that gives rise to a very stable scaffold. Members of this family cover a broad spectrum of natural bioactivities ranging from antimicrobial and antiviral activities to selective blockage or activation of ion channels, cell surface receptors and extracelluar proteases. In recent years, the spectrum of natural bioactivities of this class of miniproteins was further expanded by application of protein design and directed evolution technologies. Miniproteins have been developed that inhibit platelet aggregation, block asthma-related proteases, act as growth factor mimics or address human tumor targets. Recent reports on miniproteins binding to cancer specific targets indicate that these biomolecules due to their particularly high in vivo stability, high target affinity, good tissue distribution, and fast body clearance are very promising agents that can be endowed with important beneficial features for imaging and therapeutic applications. With the first cystine-knot miniprotein already marketed as an analgesic, more candidates can be expected to find their way into the clinic for diagnostic and therapeutic applications over next years.
Prostate cancer is the most frequently diagnosed cancer and the second most common cause of cancer death in men in the United States. Such men can experience a continuum of disease presentations from indolent to highly aggressive. For physicians who care for these men, a significant challenge has been and continues to be identifying and treating those men with localized cancer who are at a higher risk of dying from their disease. We discuss the risk stratification of patients in order to better identify those patients at higher risk of progression. A comprehensive review of the literature was then performed reviewing the roles of surgery, radiotherapy, hormone therapy, and chemotherapy, as well as combinations of these modalities, in treating these challenging patients. An integrated approach combining local and systemic therapies can be beneficial in the management of high-risk localized prostate cancer. The choice of therapy or combination of therapies is dependant upon many considerations, including patient preference and quality of life aspects. It is becoming clearer that the addition of hormonal therapies or chemotherapies to established therapies, such as radiotherapy or surgery, will have significant benefits. As evidence accumulates regarding the efficacy of these new regimens, our hope is that the challenge of optimizing the management of high-risk prostate cancer will be delivered. However, many important questions remain unresolved regarding the optimal type, combination, timing of therapy, and duration of therapy. Such questions will only be answered with large, well-designed prospective clinical trials.
Recently, the cDNA encoding a novel candidate for prostate cancer-specific antigen, named prostate-specific membrane antigen (PSM), was cloned from the LNCaP prostate cancer cell line (R. S. Israeli, C. T. Powell, W. R. Fair, and W. D. W. Heston, Cancer Res., 53: 227-230,1993). More recently, they also identified an alternatively spliced variant of PSM in normal prostate tissues (S. L. Su, I-P. Huang, W. R. Fair, C. T. Powell, and W. D. W. Heston, Cancer Res., 55: 1441-1443, 1995). The cDNA of this variant, named PSM', lacks 266 nucleotides present in PSM cDNA, so the transcripts derived from this particular nucleotide sequence can be regarded as PSM-specific transcripts. In this study, we investigated the expression of PSM-specific transcripts in 15 specimens of prostate cancer obtained by needle biopsy using in situ hybridization with a newly developed RNA probe. PSM-specific transcripts were detected in most of the carcinoma cells in all of the specimens examined, and the level of expression was higher in carcinoma cells from hormone-refractory patients than in the cells of those who showed a good response to hormonal therapy. In addition, increased expression of PSM-specific transcripts was also associated with an increased Gleason score. In the normal prostate, on the other hand, PSM-specific transcripts were limited to the basal cells of the prostate glands. These results clearly show that expression of PSM-specific transcripts is closely associated with malignant transformation of the prostate; thus, in situ hybridization for detection of the transcripts is useful for the diagnosis of prostate cancer.
The Diagnosis and Treatment of Prostate Cancer
- M S Litwin
- H.-J Tan
Kapitsa Technology Research Institute
- Beloborodov Evgeniy Alekseevich
- Post-Graduate
- Junior Student
- S P Researcher
Beloborodov Evgeniy Alekseevich, Post-graduate Student, Junior Researcher, S.P. Kapitsa Technology Research Institute, Ulyanovsk State University. 432017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail: beloborodov.evgeniy.a@gmail.com, ORCID ID: https://orcid.org/0000-0002-5666-5154.
Chair of General and Clinical Pharmacology with a Course in Microbiology
- Senior Rastorgueva Evgeniya Vladimirovna
- Lecturer
Rastorgueva Evgeniya Vladimirovna, Senior Lecturer, Chair of General and Clinical Pharmacology with a
Course in Microbiology, Ulyanovsk State University. 432017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail:
rastorgueva.e.v@yandex.ru, ORCID ID: https://orcid.org/0000-0003-1518-4677.
V. Ispol'zovanie knottina kak nositelya peptida, tropnogo PSMA
- E A Beloborodov
- E V Yurova
- E V Rastorgueva
- E S Pogodina
- D E Sugak
- A N Fomin
- Yu Saenko
Beloborodov E.A., Yurova E.V., Rastorgueva E.V., Pogodina E.S., Sugak D.E., Fomin A.N., Saenko Yu.V.
Ispol'zovanie knottina kak nositelya peptida, tropnogo PSMA [Use of knottin as a PSMA-tropic peptide carrier].
Ul'yanovskiy mediko-biologicheskiy zhurnal
Ul'yanovskiy mediko-biologicheskiy zhurnal. 2022; 2: 117-127. DOI: 10.34014/2227-1848-2022-2-117-127 (in Russian).