Melbourne Medical School Collected Works - Research Publications
Permanent URI for this collection
Search Results
1 - 4 of 4
-
ItemIn vivo fluorescence imaging: success in preclinical imaging paves the way for clinical applications(BMC, 2022-10-15)Advances in diagnostic imaging have provided unprecedented opportunities to detect diseases at early stages and with high reliability. Diagnostic imaging is also crucial to monitoring the progress or remission of disease and thus is often the central basis of therapeutic decision-making. Currently, several diagnostic imaging modalities (computed tomography, magnetic resonance imaging, and positron emission tomography, among others) are routinely used in clinics and present their own advantages and limitations. In vivo near-infrared (NIR) fluorescence imaging has recently emerged as an attractive imaging modality combining low cost, high sensitivity, and relative safety. As a preclinical tool, it can be used to investigate disease mechanisms and for testing novel diagnostics and therapeutics prior to their clinical use. However, the limited depth of tissue penetration is a major challenge to efficient clinical use. Therefore, the current clinical use of fluorescence imaging is limited to a few applications such as image-guided surgery on tumors and retinal angiography, using FDA-approved dyes. Progress in fluorophore development and NIR imaging technologies holds promise to extend their clinical application to oncology, cardiovascular diseases, plastic surgery, and brain imaging, among others. Nanotechnology is expected to revolutionize diagnostic in vivo fluorescence imaging through targeted delivery of NIR fluorescent probes using antibody conjugation. In this review, we discuss the latest advances in in vivo fluorescence imaging technologies, NIR fluorescent probes, and current and future clinical applications.
-
ItemA novel phosphocholine-mimetic inhibits a pro-inflammatory conformational change in C-reactive protein(WILEY, 2023-01-11)C-reactive protein (CRP) is an early-stage acute phase protein and highly upregulated in response to inflammatory reactions. We recently identified a novel mechanism that leads to a conformational change from the native, functionally relatively inert, pentameric CRP (pCRP) structure to a pentameric CRP intermediate (pCRP*) and ultimately to the monomeric CRP (mCRP) form, both exhibiting highly pro-inflammatory effects. This transition in the inflammatory profile of CRP is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine lipid head groups. We designed a tool compound as a low molecular weight CRP inhibitor using the structure of phosphocholine as a template. X-ray crystallography revealed specific binding to the phosphocholine binding pockets of pCRP. We provide in vitro and in vivo proof-of-concept data demonstrating that the low molecular weight tool compound inhibits CRP-driven exacerbation of local inflammatory responses, while potentially preserving pathogen-defense functions of CRP. The inhibition of the conformational change generating pro-inflammatory CRP isoforms via phosphocholine-mimicking compounds represents a promising, potentially broadly applicable anti-inflammatory therapy.
-
ItemNanobiotechnology approaches for cardiovascular diseases: site-specific targeting of drugs and nanoparticles for atherothrombosis(BMC, 2022-02-08)Atherosclerosis and atherothrombosis, the major contributors to cardiovascular diseases (CVDs), represent the leading cause of death worldwide. Current pharmacological therapies have been associated with side effects or are insufficient at halting atherosclerotic progression effectively. Pioneering work harnessing the passive diffusion or endocytosis properties of nanoparticles and advanced biotechnologies in creating recombinant proteins for site-specific delivery have been utilized to overcome these limitations. Since CVDs are complex diseases, the most challenging aspect of developing site-specific therapies is the identification of an individual and unique antigenic epitope that is only expressed in lesions or diseased areas. This review focuses on the pathological mechanism of atherothrombosis and discusses the unique targets that are important during disease progression. We review recent advances in site-specific therapy using novel targeted drug-delivery and nanoparticle-carrier systems. Furthermore, we explore the limitations and future perspectives of site-specific therapy for CVDs.
-
ItemActivated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases(IVYSPRING INT PUBL, 2019)Rationale: Platelets are increasingly recognized as mediators of tumor growth and metastasis. Hypothesizing that activated platelets in the tumor microenvironment provide a targeting epitope for tumor-directed chemotherapy, we developed an antibody-drug conjugate (ADC), comprised of a single-chain antibody (scFv) against the platelet integrin GPIIb/IIIa (scFvGPIIb/IIIa) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE). Methods: We developed an ADC comprised of three components: 1) A scFv which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets. 2) A highly potent microtubule inhibitor, monomethyl auristatin E. 3) A drug activation/release mechanism using a linker cleavable by cathepsin B, which we demonstrate to be abundant in the tumor microenvironment. The scFvGPIIb/IIIa-MMAE was first conjugated with Cyanine7 for in vivo imaging. The therapeutic efficacy of the scFvGPIIb/IIIa-MMAE was then tested in a mouse metastasis model of triple negative breast cancer. Results: In vitro studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity. In vivo fluorescence imaging demonstrated that the newly generated ADC localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established. Importantly, we demonstrated that the scFvGPIIb/IIIa-MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects. Conclusion: Here, we demonstrate the utility of a novel ADC that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor. This unique targeting mechanism, specific to the tumor microenvironment, holds promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack specific molecular epitopes for drug targeting.