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Sequence-activity relationship (SAR) analysis of a cyclic tumor targeting peptide using alanine scan and affinity measurements. (A) Scheme shows the sequential substitution of each amino acid residue (X) including the first and the last cysteine residues (C) with alanine (A in red) to generate peptide variants, 1-9. (B) Production of the recombinant target protein and synthesis of the original peptide and its variants (C) microscale thermophoresis (MST) and surface plasmon resonance (SPR) to study the molecular interactions. Figure was generated using prism 9.0.0 (GraphPad software, Inc., San Diego, CA, USA) and discovery studio visualizer v19.1.0.18287 (BIOVIA, San Diego, CA, USA) from Ayo et al. unpublished data
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Cancer is one of the leading causes of death worldwide. The development of cancer-specific diagnostic agents and anticancer toxins would improve patient survival. The current and standard types of medical care for cancer patients, including surgery, radiotherapy, and chemotherapy, are not able to treat all cancers. A new treatment strategy utilizin...
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... peptides identified using combinatorial screens or derived from native proteins are usually subjected to further modifications to improve their pharmacokinetics. Hence, after the target is known, it is essential to perform structureactivity relationship (SAR) analyses to characterize the active binding domains ( Figure 5). Upon target identification and validation, SAR-based assays, such as site-directed mutagenesis and affinity studies, are essential for successful development of viable tumor targeting peptides. ...
Citations
... Common TTPs include Lyp-1, RGD (iRGD, cRGD, sRGD, etc.), iNGR, and PL3, among others. [100] In recent studies, RGD (Arg-Gly-Asp), which targeted integrin receptor v 3, was used in an ICG/DOX-loaded polymeric NP [101] and DOX-loaded molybdenum disulfide (MoS 2 ) nanosheet for chemo-photothermal synergistic therapy. [76] Lots of other peptide ligands are utilized in PDDSs, [94] like RVG-29, [102] KC2S, [103] CDX, [104] A7R, [105] etc. ...
Photoresponsive drug delivery systems (PDDSs) have emerged as a promising toolbox for drug delivery, offering precise control over the site, duration, and dosage of light‐triggered medication. It allows controlled drug release, photo‐triggered targeting, diagnosis, and treatment, improving the precision and efficacy of therapies for various diseases. Despite progress in designing different PDDSs, clinical translation has been limited due to various obstacles. Herein, this review article focuses on three critical challenges of PDDSs: 1) accumulation at diseased lesions, 2) precision of light irradiation, and 3) penetration of light in tissues. Also, this article summarizes and discusses current advancements and strategies to address these challenges. Overall, it emphasizes the need to clarify the current challenges from bench to bedside and develop strategies to enhance therapeutic outcomes, increase compatibility and patient compliance, and unlock the possibilities in different clinical therapies.
... Ultimately, to enable clinical translation, fluorescence image-guided surgery should outperform conventional white-light approaches, with minimal risk to the patient. Extensive preclinical experiments should establish manufacturing quality, optical properties, metabolism, pharmacokinetics, acute and chronic toxicities, possible side effects, and short-term and long-term characteristics of new fluorescence probes 43,101 . Furthermore, their production has to meet the standards of good manufacturing practices, and adequate characterization standards need to be established to assess their structure, function and stability. ...
... The expertise field concerning radiolabeling peptidic analog development is highly active, with an important increase in the number of reports [131,132]. A new method being explored is the development of peptides that target highly specific proteins in tumors, such as glypican 3 for hepatocellular carcinoma. ...
Targeted radionuclide therapy has become increasingly prominent as a nuclear medicine subspecialty. For many decades, treatment with radionuclides has been mainly restricted to the use of iodine-131 in thyroid disorders. Currently, radiopharmaceuticals, consisting of a radionuclide coupled to a vector that binds to a desired biological target with high specificity, are being developed. The objective is to be as selective as possible at the tumor level, while limiting the dose received at the healthy tissue level. In recent years, a better understanding of molecular mechanisms of cancer, as well as the appearance of innovative targeting agents (antibodies, peptides, and small molecules) and the availability of new radioisotopes, have enabled considerable advances in the field of vectorized internal radiotherapy with a better therapeutic efficacy, radiation safety and personalized treatments. For instance, targeting the tumor microenvironment, instead of the cancer cells, now appears particularly attractive. Several radiopharmaceuticals for therapeutic targeting have shown clinical value in several types of tumors and have been or will soon be approved and authorized for clinical use. Following their clinical and commercial success, research in that domain is particularly growing, with the clinical pipeline appearing as a promising target. This review aims to provide an overview of current research on targeting radionuclide therapy.
... Functionalization of metallic silver nanoparticles (AgNPs) and iron oxide nanoworms (NWs) with PL3 peptide improved systemic nanoparticles' affinity for prostate cancer and glioblastoma xenograft lesions in mice. Studies have revealed an accumulation of PL3coated nanoparticles in NRP-1 and TNC-C positive regions of tumor tissue (Lingasamy et al. 2020;Ayo and Laakkonen 2021). ...
Introduction: Tumor-homing peptides have gained great attention as tools for the development of non-invasive and targeting drug delivery systems (DDS) to minimize drug systemic toxicity and enhance bioavailability. This study aims to improve antitumor targeting in prostate cancer via uploading a drug to a DDS comprised of a cell penetrating peptide decorated with a tumor-homing peptide, PL3. Material and Methods: The DDS was constructed via solid-phase peptide synthesis and then characterized via mass spectrum and high performance liquid chromatography. A cell viability assessment to evaluate its cytotoxicity on both tumor (prostate cancer cells) and normal cells was conducted, while a confocal laser scanning microscope and flow-cytometer were employed to investigate internalization. To inspect the effectiveness of the drug-loaded DDS, a biochemical enzyme inhibition assay on the target enzyme dihydrofolate reductase (DHFR) was performed. Results and Discussion: The findings supported the succeeded synthesis and loading of the drug into this carrier system and demonstrated its high efficacy in cytotoxic effect and inhibiting DHFR with considerable cellular uptake in prostate cancer cells. Conclusion: The drug was delivered to the target prostate cancer cells by the PL3-functionalized DDS, limiting its localization to tumor cells rather than normal cells. Therefore, the study results highlighted the significance of the DDS in tumor therapy interventions. Graphical Abstact
... The expertise field concerning radiolabeling peptidic analog development is higly active, with an important increase in the number of reports [126,127]. A new method being explored is the development of peptides that target highly specific proteins in tumors, such as glypican 3 for hepatocellular carcinoma. ...
Targeted radionuclide therapy is become increasingly prominent as a nuclear medicine subspe-cialty. For many decades, treatment with radionuclides has been mainly restricted to the use of iodine-131 in thyroid disorders. Currently, radiopharmaceuticals, consisting of a radionuclide coupled to a vector that binds to a desired biological target with high specificity, are being de-veloped. The objective is to be as selective as possible at the tumor level, while limiting the dose received at the healthy tissue level. In recent years, a better understanding of molecular mecha-nisms of cancer, as well as the appearance of innovative targeting agents (antibodies, peptides, small molecules) and the availability of new radioisotopes, have enabled considerable advances in the field of vectorized internal radiotherapy with a better therapeutic efficacy, radiation safety and personalized treatments. For instance, targeting the tumor microenvironment, instead of the cancer cells, now appears as particularly attractive. Several radiopharmaceuticals for therapeutic targeting have shown clinical value in severals types of tumors and have been or will soon be approved and authorized for clinical use.
... Hence, several proteins and peptides involved in tumor progression and cancer metastasis can be identified and targeted for cancer therapy. Peptides are small-sized molecules, around 40 amino acids or less, which can be derived either naturally or developed synthetically [5][6][7][8][9][10]. Mainly, the naturally derived peptides must be modified using several chemical processes to use them in cancer therapeutics. ...
... These peptides can target the tumors at their specific site or deliver a particular anticancer drug to the tumor site, becoming one of the most promising ways to treat cancer. Several types of peptides can be created, and the focus can be made towards targeting the homing ability of the mesenchymal stem cells (MSCs), targeting the function of the ligand/receptor, targeting a particular organelle like the mitochondria, or directly entering into the nucleus of the tumor cells to induce apoptosis and cell death [6]. Hence, these techniques can be utilized to develop peptide conjugates that can enhance the tumor cells' apoptosis and help in cancer therapy. ...
Several proteins and peptides have therapeutic potential and can be used for cancer therapy. By binding to cell surface receptors and other indicators uniquely linked with or overexpressed on tumors compared to healthy tissue, protein biologics enhance the active targeting of cancer cells, as opposed to the passive targeting of cells by conventional small-molecule chemotherapeutics. This study focuses on peptide medications that exist to slow or stop tumor growth and the spread of cancer, demonstrating the therapeutic potential of peptides in cancer treatment. As an alternative to standard chemotherapy, peptides that selectively kill cancer cells while sparing healthy tissue are developing. A mountain of clinical evidence supports the efficacy of peptide-based cancer vaccines. Since a single treatment technique may not be sufficient to produce favourable results in the fight against cancer, combination therapy is emerging as an effective option to generate synergistic benefits. One example of this new area is the use of anticancer peptides in combination with nonpeptidic cytotoxic drugs or the combination of immunotherapy with conventional therapies like radiation and chemotherapy. This review focuses on the different natural and synthetic peptides obtained and researched. Discoveries, manufacture, and modifications of peptide drugs, as well as their contemporary applications, are summarized in this review. We also discuss the benefits and difficulties of potential advances in therapeutic peptides.
... As highlighted in the introduction, tLyp-1 is a potent targeting ligand for the NRP-1 receptor [38,39,66]. The effect of this targeting ligand on in vivo biodistribution was studied in the subcutaneous CFPAC-1 (human pancreatic cancer cell line) xenograft tumor model. ...
K-RAS is a highly relevant oncogene that is mutated in approximately 90% of pancreatic cancers and 20-25% of lung adenocarcinomas. The aim of this work was to develop a new anti-KRAS siRNA therapeutic strategy through the engineering of functionalized lipid nanoparticles (LNPs). To do this, first, a potent pan anti-KRAS siRNA sequence was chosen from the literature and different chemical modifications of siRNA were tested for their transfection efficacy (KRAS knockdown) and anti-proliferative effects on various cancer cell lines. Second, a selected siRNA candidate was loaded into tLyp-1 targeted and non-targeted lipid nanoparticles (LNPs). The biodistribution and antitumoral efficacy of selected siRNA-loaded LNP-prototypes were evaluated in vivo using a pancreatic cancer murine model (subcutaneous xenograft CFPAC-1 tumors). Our results show that tLyp-1-tagged targeted LNPs have an enhanced accumulation in the tumor compared to non-targeted LNPs. Moreover, a significant reduction in the pancreatic tumor growth was observed when the anti-KRAS siRNA treatment was combined with a classical chemotherapeutic agent, gemcitabine. In conclusion, our work demonstrates the benefits of using a targeting approach to improve tumor accumulation of siRNA-LNPs and its positive impact on tumor reduction.
... Ultimately, to enable clinical translation, fluorescence image-guided surgery should outperform conventional white-light approaches, with minimal risk to the patient. Extensive preclinical experiments should establish manufacturing quality, optical properties, metabolism, pharmacokinetics, acute and chronic toxicities, possible side effects, and short-term and long-term characteristics of new fluorescence probes 43,101 . Furthermore, their production has to meet the standards of good manufacturing practices, and adequate characterization standards need to be established to assess their structure, function and stability. ...
Intraoperative fluorescent imaging can provide real-time identification of tumours, lymph nodes, nerves and other healthy and malignant tissues during oncological surgery, contributing to better surgical outcomes. Various fluorescent probes have been clinically approved for surgical applications, improving tumour resection precision and preventing iatrogenic injury. In this Review, we discuss the development and application of fluorescent probes for image-guided surgery, including systemically and locally applied probes that are either non-targeted or targeted to specific tumours and tissues. We discuss the optimization and clinical potential of these probes, and highlight their current and future applications in oncological surgery. In addition, we examine the hardware of fluorescence imaging equipment, and discuss how artificial intelligence can enable real-time quantification to guide surgical decision-making. Finally, we highlight the remaining challenges in the field of image-guided surgery, including the need for standardization to achieve regulatory approval of new probes, and the required team effort for new probe development. Fluorescence imaging-guided surgery enables tumour resection with high precision, while preventing injury of healthy tissues. This Review discusses the clinical application and preclinical development of intraoperative fluorescence imaging probes and imaging equipment, including artificial intelligence algorithms. Fluorescence image-guided surgery offers real-time intraoperative visualization of tumours and/or nearby healthy tissues, enabling high-precision tumour resection and prevention of iatrogenic injury.Several fluorescence imaging probes have been clinically approved for oncological surgery, including non-targeted and tumour-targeted probes, and various new probes are being explored at the preclinical stage.Hardware improvements and artificial intelligence software of intraoperative fluorescence imaging systems have improved imaging quality and enable image quantification, optimized ergonomics and straightforward human–machine interaction.The clinical translation of new fluorescent imaging probes will require equipment standardization, interdisciplinary cooperation and technological development. Fluorescence image-guided surgery offers real-time intraoperative visualization of tumours and/or nearby healthy tissues, enabling high-precision tumour resection and prevention of iatrogenic injury. Several fluorescence imaging probes have been clinically approved for oncological surgery, including non-targeted and tumour-targeted probes, and various new probes are being explored at the preclinical stage. Hardware improvements and artificial intelligence software of intraoperative fluorescence imaging systems have improved imaging quality and enable image quantification, optimized ergonomics and straightforward human–machine interaction. The clinical translation of new fluorescent imaging probes will require equipment standardization, interdisciplinary cooperation and technological development.
... Caspases cleave the proteins and carryout the cell death. 10 major classes of caspases are caspases (2,8,9,10), execution caspases (3,6,7), inflammatory caspases (1,4,5). 8 Other caspases include caspase 11 to regulate apoptosis and cytokine maturation. ...
Cancer has gained major importance among noncommunicable disorders as the group of proliferative diseases and emerged as fatal around the globe. The conventional methods such as radiological, chemotherapeutic and pharmacotherapeutic advances have shown some severe effects in the patients. The costs and technical requirements are the two limitations. Bioactive peptides provided evidence as an alternative treatment for cancer because of their specificity, modifications, smaller size and their penetration into cell membrane. Bioactive peptides with their natural availability and efficacy with minimal side effects have opened new windows for cancer therapy. This review gives information about the sources of bioactive peptides from plants and animals and their mechanisms against different cancer cell lines as a potential remedy for cancer.
... Ultimately, to enable clinical translation, fluorescence image-guided surgery should outperform conventional white-light approaches, with minimal risk to the patient. Extensive preclinical experiments should establish manufacturing quality, optical properties, metabolism, pharmacokinetics, acute and chronic toxicities, possible side effects, and short-term and long-term characteristics of new fluorescence probes 43,101 . Furthermore, their production has to meet the standards of good manufacturing practices, and adequate characterization standards need to be established to assess their structure, function and stability. ...
Background:
No investigations have thoroughly explored the feasibility of combining magnetic resonance (MR) images and deep-learning methods for predicting the progression of knee osteoarthritis (KOA). We thus aimed to develop a potential deep-learning model for predicting OA progression based on MR images for the clinical setting.
Methods:
A longitudinal case-control study was performed using data from the Foundation for the National Institutes of Health (FNIH), composed of progressive cases [182 osteoarthritis (OA) knees with both radiographic and pain progression for 24-48 months] and matched controls (182 OA knees not meeting the case definition). DeepKOA was developed through 3-dimensional (3D) DenseNet169 to predict KOA progression over 24-48 months based on sagittal intermediate-weighted turbo-spin echo sequences with fat-suppression (SAG-IW-TSE-FS), sagittal 3D dual-echo steady-state water excitation (SAG-3D-DESS-WE) and its axial and coronal multiplanar reformation, and their combined MR images with patient-level labels at baseline, 12, and 24 months to eventually determine the probability of progression. The classification performance of the DeepKOA was evaluated using 5-fold cross-validation. An X-ray-based model and traditional models that used clinical variables via multilayer perceptron were built. Combined models were also constructed, which integrated clinical variables with DeepKOA. The area under the curve (AUC) was used as the evaluation metric.
Results:
The performance of SAG-IW-TSE-FS in predicting OA progression was similar or higher to that of other single and combined sequences. The DeepKOA based on SAG-IW-TSE-FS achieved an AUC of 0.664 (95% CI: 0.585-0.743) at baseline, 0.739 (95% CI: 0.703-0.775) at 12 months, and 0.775 (95% CI: 0.686-0.865) at 24 months. The X-ray-based model achieved an AUC ranging from 0.573 to 0.613 at 3 time points. However, adding clinical variables to DeepKOA did not improve performance (P>0.05). Initial visualizations from gradient-weighted class activation mapping (Grad-CAM) indicated that the frequency with which the patellofemoral joint was highlighted increased as time progressed, which contrasted the trend observed in the tibiofemoral joint. The meniscus, the infrapatellar fat pad, and muscles posterior to the knee were highlighted to varying degrees.
Conclusions:
This study initially demonstrated the feasibility of DeepKOA in the prediction of KOA progression and identified the potential responsible structures which may enlighten the future development of more clinically practical methods.
