Li-Peng Yap

A Nanoscale Tool for Photoacoustic-Based Measurements of Clotting Time and Therapeutic Drug Monitoring of Heparin

Heparin anticoagulation therapy is an indispensable feature of clinical care yet has a narrow therapeutic window and is the second most common intensive care unit (ICU) medication error. The active partial thromboplastin time (aPTT) monitors heparin but suffers from long turnaround times, a variable reference range, limited utility with low molecular weight heparin, and poor correlation to dose. Here, we describe a photoacoustic imaging technique to monitor heparin concentration using methylene blue as a simple and Federal Drug Administration-approved contrast agent. We found a strong correlation between heparin concentration and photoacoustic signal measured in phosphate buffered saline (PBS) and blood. Clinically relevant heparin concentrations were detected in blood in 32 s with a detection limit of 0.28 U/mL. We validated this imaging approach by correlation to the aPTT (Pearsons r = 0.86; p < 0.05) as well as with protamine sulfate treatment. This technique also has good utility with low molecular weight heparin (enoxaparin) including a blood detection limit of 72 μg/mL. We then used these findings to create a nanoparticle-based hybrid material that can immobilize methylene blue for potential applications as a wearable/implantable heparin sensor to maintain drug levels in the therapeutic window. To the best of our knowledge, this is the first use of photoacoustics to image anticoagulation therapy with significant potential implications to the cardiovascular and surgical community.

Tumor Targeting of a cell penetrating peptide by fusing with a pH-sensitive histidine-glutamate co-oligopeptide

Cell penetrating peptides (CPPs) have been well established as potential carriers for intracellular delivery of protein/peptide therapeutics. However, their lack of selectivity impedes their application in vivo. In order to increase their specificity, a highly pH-sensitive histidine-glutamate (HE) co-oligopeptide was fused with a CPP, i.e. model amphipathic peptide (MAP), and was expressed as a fusion protein with glutathione S-transferase (GST) acting as a cargo protein. Compared with two other fusion proteins containing either HE or MAP, only the fused peptide (HE-MAP) could effectively deliver the cargo GST protein to cells at pH 6.5 or below, while maintaining low delivery to cells at pH 7.0 and above. Using a xenograft mouse model of human breast cancer, fluorescent imaging showed that only HE-MAP could effectively target GST to the tumor site, while reducing non-specific association of MAP in other organs. The data presented in this report demonstrate the diagnostic and/or therapeutic potential of the fused peptide, HE-MAP, for targeting the acidic tumor microenvironment. The concise design for this pH-sensitive peptide offers a simple way to overcome CPPs lack of selectivity, which could lead to increased application of CPPs and macromolecular therapeutics.

Evaluation of 18F-DEG-VS-NT for NTR1 targeted imaging in prostate cancer

This interesting book is one of a series that aims to provide a systematic framework for understanding imaging choices based on evidence reported in the literature. Written mostly by radiologists and clinicians, the book is intended to be a reference for decision making in clinical practice and contains information on the use of neuroimaging in every possible clinical case of brain, spine, and head and neck disorders. The imaging modalities that are discussed include CT, MR imaging, MR angiography, SPECT (mostly of the spine), and PET (mostly of head and neck masses). On the basis of the clinical literature as evaluated from cost-effectiveness-analysis and evidence-based-medicine perspectives, each chapter poses questions such as “in this condition, which imaging method is warranted, and why?” and then answers those questions. The authors pay most attention to the results of clinical trials that did or did not include neuroimaging options, attempting to prove or disprove the value of neuroimaging studies in the outcomes of patients with cerebrovascular diseases, spine disorders, or head and neck cancers. The authors also predict the future value of newer neuroimaging methods that may soon be used to evaluate some of the more incomprehensible and intractable pediatric neurodevelopmental and neurodegenerative diseases. Interestingly, every chapter has a section that describes further research needed to optimize the use of current neuroimaging methods or, in the case of MR imaging, to expand its use to newer sequences. Almost all the chapters include physiologic imaging as an example of such a modality, along with the use of SPECT and PET for seizure disorders; bone SPECT for spinal injection for low back pain; PET for brain cancer, neck masses, neck adenopathy, and diagnosis of cervical lymph node metastasis in head and neck cancer; and MR spectroscopy. Readers can easily refer to this book for the answers to probable clinical questions and supporting evidence for those answers. Readers can also use the “Key Points” sections to quickly determine whether a certain modality, such as PET or SPECT, is dealt with in those questions. The chapters are in a hierarchical format that allows readers to quickly find specific questions and answers of interest and then broaden their search if desired. The consistency in the depth and style of each chapter will assure readers that each is consistently informative and credible. For nuclear medicine physicians, the information on CT, MR imaging, and angiography for brain, spine, and head and neck disorders will help them grasp the big picture on the current best practice and changes expected in the near future. The only area that is lacking is information about nuclear medicine imaging—a surprising shortcoming considering the comprehensiveness of the book, and I frowned to see that many chapters described 18F-FDG PET using just the generic term PET. This lack may have occurred because the literature does not include enough publications with sound evidence supporting the use of nuclear medicine imaging in clinical decision making, which would be required in a book on evidence-based medicine such as this one. Another possibility is that the authors simply chose not to describe evidence in the field of nuclear medicine. For example, in the chapter on seizure disorders, 18F-FDG PET is cited with less frequency than in the literature, and in the chapters on acute ischemic stroke and atherosclerotic disease of the cervical carotid artery, I would have expected acetazolamide stress SPECT (either 123I-b-methyliodophenylpentadecanoic acid or 99mTchexamethylpropyleneamine oxime) to be described but it was entirely left out. Likewise, the chapter on brain cancer neglected to mention 11C-methionine PET. Omitting evidence-based information on various uses of SPECT and PET warrants the issuing of a new edition that is truly about neuroimaging instead of merely radiologic neuroimaging. This book would be best utilized by clinicians who are interested in fields other than their own, such as a neurovascular expert who is interested in epilepsy or neurodevelopmental disorders (attention deficit–hyperactivity disorder or autism spectrum disorder) or a nuclear medicine physician who is interested in neuroimaging of patients undergoing endovascular treatment for acute ischemic stroke or patients undergoing spinal injections for low back pain. If readers are interested in an in-depth, balanced interpretation of their own field, they may find other, more specialized references and books preferable to this one. However, this book is the right one for readers interested in how to collect and combine a database to understand the currently optimal, recognized clinical use of a neuroimaging modality and for readers interested in the scientific background for the state-of-the-art use of CT, MR imaging, and angiography. The beauty of this book is that parts I and II describe the principles of evidence-based imaging and neuroimaging in the radiologic field and compose an ideal introduction to the remainder of the book. Part II imparts knowledge about the decision-support process, as well as covering how best to use neuroimaging as a screening tool and how to handle any incidental findings. Also detailed is how to comply with the economic and regulatory changes in the United States—information that readers in Asia and Europe can apply by analogy to their own regulatory situation. I believe that the timing of this book is perfect from the perspective of health care reform in the United States, because neuroimaging is as yet neither an integrative diagnostic procedure (unlike auscultation or palpation) nor an independent procedure. Neuroimaging is costly in both money and time, and its use in clinical practice requires sufficient supporting evidence to persuade layperson policy makers and referring physicians. If we, the nuclear medicine physicians, want our nuclear neuroimaging to be used more often by clinicians and approved by the health-care system, we now know what data we should collect and publish so that secondary literature such as the Cochrane Library or this type of book will reflect our consensus. Reading this book cover to cover was an enlightening adventure for me, educational yet sometimes confusing or frustrating. Certain terms are abbreviated differently COPYRIGHT

Performance comparison of GENISYS4 and microPET preclinical PET scanners

Genisys4 is a new preclinical positron emission tomography (PET) scanner, which consists of four detector panels. Due to its unique design, the performance characteristics of the system is different from the conventional multiple detector ring preclinical PET scanners. In this paper, we compare the performance of the four-panel Genisys4 with two ring-geometry scanners: microPET R4 and Inveon. For this purpose, a NEMA NU 4-2008 image quality phantom and two mice injected with 18F-FDG were scanned. The results will aid investigators in using the appropriate PET scanner for their preclinical studies.

Abstract 370: Tetrazine trans-cyclooctene ligation: An efficient 18F labeling method for cysteine containing peptides and proteins

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL 18F PET has a number of attributes that make it clinically attractive, including almost 100% positron efficiency, very high specific radioactivity, and short half-life of ∼110 min. However, the short half-life of 18F and the poor nucleophilicity of fluoride make it difficult to incorporate 18F in complex molecules. Recently, the tetrazine-trans-cyclooctene ligation has been introduced as a novel 18F labeling method that proceeds with fast reaction rates without any catalysis. To further explore the scope of this reaction, herein we reported an efficient method for 18F-lableing of free cysteine-containing bioligands based on the tetrazine-trans-cyclooctene ligation. The newly developed method was tested for site specific labeling of both c(RGDyC) and VEGF-SH protein. Starting with 4 mCi of 18F-trans-cyclooctene and only 10 μg of tetrazine-RGD (80-100 µM) or 15 μg of tetrazine-VEGF (6.0 µM), the 18F labeled RGD peptide or VEGF protein could be obtained in 95% yield and 75% yield within five minutes. The obtained tracers were then evaluated in small animals. In conclusion, a highly efficient method has been developed for site-specific 18F labeling of cysteine containing peptides and proteins. The special characteristics of the tetrazine-trans-cyclooctene ligation provide unprecedented opportunities to synthesize 18F-labeled probes with high specific activity for PET applications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 370. doi:1538-7445.AM2012-370