Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine–Glycine–Aspartate) Strategies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review discusses the latest advancements in dual-targeting strategies using RGD-based integrin-targeting approaches, primarily focusing on their application in cancer diagnosis and treatment. Integrins, specifically those binding to the RGD motif such as αvβ3, play critical roles in cancer progression, angiogenesis, and metastasis, making them prime targets for therapeutic and diagnostic applications. Despite the challenges faced in clinical translation, the paper outlines how dual-targeting strategies, which involve combining integrin-targeting with other receptors or tumor-specific markers, have the potential to improve therapeutic precision and efficacy. The review concludes with an analysis of recent developments in dual-targeting agents, including radiotracers and nanoparticles, and their promise in enhancing cancer treatment.

The manuscript covers a broad range of topics, but several sections would benefit from additional references to provide stronger support for claims. In introduction, General information of cancer therapy should be included for general readers, cite this paper for more information: “Cancer treatments: Past, present, and future, 2024”. More references are needed to support the claims about the increasing global cancer burden and projections for the future (lines 28-31). Recent data from major cancer organizations or epidemiological studies should be included. While dual-targeting is described as a promising approach, references to specific studies or clinical trials that validate the improved outcomes of such strategies over monotherapies should be provided in greater detail, especially in the section discussing recent radiotracers like 68Ga-NOTA-BBN-RGD (lines 348-355). The challenges related to tumor heterogeneity and integrin expression variability should be supported by additional citations (lines 284-289), particularly to recent studies that examine the impact of these issues on therapeutic outcomes. Previous Single cell sequencing analysis such as “Identification of the novel exhausted T cell CD8 + markers in breast cancer, 2024” should be mentioned and discussed for tumor heterogeneity and integrin expression variability. In addition, this review might provide insight into this as well: “Genetic expression in cancer research: Challenges and complexity, 2024”

Line 10: "Integrins, a crucial superfamily of cell adhesion receptors" – the word "crucial" could be replaced with "important" to avoid unnecessary emphasis.

Line 16: "Traditional RGD-based imaging and therapeutic agents have encountered several limitations..." could be rephrased for clarity. Consider: "Traditional RGD-based imaging and therapeutic agents have faced limitations, such as inconsistent target expression and rapid systemic clearance, which have reduced their effectiveness."

Introduction:

Line 28: The phrase "Cancer remains a pressing global health challenge" is too generic. Consider providing specific data to back up this statement and introduce the urgency of the issue.

Line 31: The phrase "the burden of cancer continues to rise" is vague. Include more precise figures or projections to clarify this point.

Line 36: "Highly specific peptide-, antibody-, and nanoparticle-based agents" – rephrase to "Agents based on peptides, antibodies, and nanoparticles offer highly specific targeting" to improve readability.

Fundamentals of Integrin Biology (Section 2.1):

Line 70: The sentence "Each subunit is a type 1 transmembrane protein characterized by..." is long and complex. Consider breaking it into two sentences to improve readability: "Each subunit is a type 1 transmembrane protein. These proteins have a large extracellular domain for ligand binding and a smaller intracellular region for signaling."

Line 79: "Integrins are grouped into four receptor classes..." – this statement would benefit from a brief description or example of each class.

Figures and Tables:

Figure legends need to be more descriptive to ensure clarity for readers who may refer to the figures independently. For example, the legend for Figure 1 (line 313) should briefly explain the concept of dual-targeting and how it improves upon traditional approaches.

Table 1 (line 335): Ensure consistency in the format of table headings, and clarify what each column represents. For instance, "Clinical Trial" should specify the phase or nature of the trial, if applicable.

Discussion:

Line 281: The sentence "Integrin-targeted therapies have shown substantial promise..." is vague. It would be helpful to specify which therapies have shown the most promise and in which cancer types.

Line 295: "This dynamic behavior of integrins across different stages of cancer adds complexity..." – this sentence could be expanded to explain why this complexity poses a challenge for drug development.

Conclusion:

Line 713: The phrase "RGD-derived molecules have faced several challenges" should be followed by a brief explanation of the most significant challenges encountered.

Line 721: "Future research should focus on refining dual-targeting approaches..." could be expanded to include specific research avenues that would be valuable to explore.

 

 

 

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Cancer theranostics is one of the most dynamically developing areas of medical science. A large number of articles, presenting the results of studies of new molecules for cancer diagnostic and therapy are published every year. The presented narrative review critically analyzed and summarized the data concerning RGD-based strategies, challenges and limitations in integrin targeting, dual-targeting approaches. The review is well written and will be of interest to readers. A substantial amount of modern data on integrin-targeted diagnostics and therapies was organized successfully by the authors. I have only a few suggestions to improve the article.

1.       The most important specific information from the experimental and clinical studies under discussion should be included in the section 'Targeting RGD-recognizing integrins for cancer diagnosis (e.g. the values of diagnostic efficiency; indicators characterizing the intensity of accumulation of the radiopharmaceutical in a tumor, etc.). Specific data from the studies under discussion should be included to other sections of the article, if possible.

2.       I propose to add a table, characterizing the radiotracers (similar to Table 1), in the section “Targeting RGD-recognizing integrins for cancer diagnosis”.

3.       Examples of images obtained with new radiopharmaceuticals (or clinical examples) will make the review even more interesting.

Author Response

Please see the attachment.

Author Response File: Author Response.docx