Chitosan—A versatile semi-synthetic polymer in biomedical applications

Current medical imaging technologies allow visualization of tissue anatomy in the human body at resolutions ranging from 100 micrometers to 1 millimeter. These technologies are generally not sensitive enough to detect early-stage tissue abnormalities associated with diseases such as cancer and atherosclerosis, which require micrometer-scale resolution. Here, optical coherence tomography was adapted to allow high-speed visualization of tissue in a living animal with a catheter-endoscope 1 millimeter in diameter. This method, referred to as "optical biopsy," was used to obtain cross-sectional images of the rabbit gastrointestinal and respiratory tracts at 10-micrometer resolution.

In Vivo Endoscopic Optical Biopsy with Optical Coherence Tomography

The conundrum of modality selection in clinical diagnostic imaging is that modalities with the highest sensitivity have relatively poor resolution, while those with high resolution have relatively poor sensitivity In recent years, the idea of using multiple modalities in conjunction has gained in popularity and researchers have come to realize that the complementary abilities of different imaging modalities could be harnessed to great effect by using them in tandem The idea of combining imaging technologies moved to the mainstream with the advent of the first successful commercial fused instruments The first fused PET/CT instrument, developed in 1998 by Townsend and colleagues in collaboration with Siemens Medical, was available commercially in 2001 The “Biograph” was named as one of the “Inventions of the Year” in 2000 by Time magazine, and its success was such that by 2003 fused PET/CT instruments were available from all of the major clinical instrument manufacturers, GE, Philips, CTI, and Siemens1 Over the ensuing years, PET/CT sales increased with such vigor that by the year 2006 there were virtually no sales of standalone PET instruments; all PET sales were as part of multimodality systems2–4 The next wave of innovation has been in PET/MRI-fused instruments, which have generated much hope for improved patient safety and imaging capability over PET/CT Although research on PET/MRI instruments was initiated around the same time as PET/CT, the economic and engineering challenges of merging the two modalities slowed development, and the first commercial PET/MRI prototype for a human scale hybrid scanner was not unveiled until 20075,6 With hybrid technology clearly on the rise, the excitement over these new instruments has triggered a tumult of activity in probe design and development as investigators seek to boost the clinical benefits of hybrid instrument technology

As the preponderance of recent reviews and increase in attention at scientific meetings will attest, there has been a surge in research on multimodal contrast agent development over the past few years5,7–17 For molecular imaging, particularly, the rise in multimodal instrumentation has sparked hopes for new ways to track multiple molecular targets simultaneously, or to use different imaging methods in combination to more clearly delineate localization and expression of biochemical markers In the best of situations, the combined imaging methods and probes work synergistically to allow high-resolution, high-sensitivity investigation of biological activity For example, with dual function probes for PET/MRI, the high sensitivity of PET can be used as a whole body screen to identify regions of interest, thereby reducing the volume of tissue that needs to be scanned; this reduces scan time required for high-resolution imaging by MRI5,18 However, probe design and development has sometimes preceded the identification of clear applications that merit use of the multimodal principle There are many literature examples of probes that are “all dressed up with nowhere to go”; they possess unique physical properties that have yet to find a clear province in medicine or biology Nonetheless, it is not unusual for technology to sometimes presage the need, and it is these advances that can spur imaginative solutions to problems that had been intractable with the previously existing technology The goal of multimodal functionality has already reaped benefits by driving innovation in many areas of chemical synthesis, most notably in nanotechnology

While combining multimodal detectability in the same probe is not necessitated by all applications, there can be advantages to this arrangement A single probe helps to ensure the same pharmacokinetics and colocalization of signal for each modality if that is a concern It also can avoid putting the additional stress on the body’s blood clearance mechanisms that can accompany administration of multiple doses of agents The caveat is that because the sensitivities of different imaging modalities can vary by 3 orders of magnitude, it may not be practical to simply add all functionalities to one molecule, although we will see that is a common design, because the requirements for contrast agent concentrations can be vastly different between modalities In this review, we provide an overview of the many strategies that have been applied to achieve multimodal functionality in a single probe unit These span the range from small molecule to nanoparticulate systems and vary in complexity from facile encapsulation or conjugation of commercially available probes to de novo synthesis This review is limited to reports from the last approximately 5 years that deal with agents that carry two or more species of contrast enhancers Tables summarizing the physical properties from cited articles are included with each major category of probe to facilitate “browsing” by the reader

/pdf/multimodality-imaging-probes-design-and-challenges-2s9gb4o9ti.pdf

Multimodality Imaging Probes: Design and Challenges

1.1. Cancer and Early Detection
Cancer is the second most common cause of death in the United States, trailing only heart disease in incidence. Despite significant worldwide investment in research, cancer remains responsible for 1 in 4 deaths in developed countries.1 Globally, over 14 million cancer diagnoses were reported in 2012, a figure expected to increase to over 22 million cases per annum in the next two decades.2 Estimated to kill over 1/2 million U.S. citizens, and with over 1.6 million new cases predicted to be diagnosed this year,3 cancer continues to present a major, yet unmet challenge to healthcare both globally and in the United States.

Cancer emerges from our own tissues, complicating both detection and treatment methods due to the similarities between the diseased tissue and healthy tissue.4,5 Despite this fact, the mortality rate from cancer is often greatly reduced by early detection of the disease. For example, non-small-cell lung cancer is responsible for the most cancer related deaths worldwide, with patients in the advanced stages of the disease having only 5–15% and <2% 5-year survival rates for stage III and IV patients, respectively.6 In contrast, patients who start therapy in the early stages of the disease (stage I) have markedly improved survival rates, with an 80% overall 5-year survival rate.6 Consequently, early diagnosis is essential to improving cancer patient prognosis.

At present, clinical detection of cancer primarily relies on imaging techniques or the morphological analysis of cells that are suspected to be diseased (cytology) or tissues (histopathology). Imaging techniques applied to cancer detection, including X-ray, mammography, computed tomography (CT), magnetic resonance imaging (MRI), endoscopy, and ultrasound, have low sensitivity and are limited in their ability to differentiate between benign and malignant lesions.7,8 While cytology, such as testing for cervical cancer via a Pap smear or occult blood detection, may be used to distinguish between healthy and diseased cells or tissues, it is not effective at detecting cancer at early stages. Similarly, histopathology, which generally relies on taking a biopsy of a suspected tumor, is typically used to probe the malignancy of tissues that are identified through alternative imaging techniques, such as CT or MRI, and may not be used alone to detect cancer in its early stages. As such, the development of assays and methods for early detection of cancer, before the disease becomes symptomatic, presents a major challenge.

Recent research within the field of nanotechnology has focused on addressing the limitations of the currently available methods for cancer diagnosis. Certain nanoparticle probes possess several unique properties that are advantageous for use in the detection of cancer at the early stages. In this review, we will discuss the advances in the development of nanoparticle-based methods for the detection of cancer by fluorescence spectroscopy. We will divide this topic into three categories: techniques that are designed for (1) the detection of extracellular cancer biomarkers, (2) the detection of cancer cells, and (3) the detection of cancerous tissues in vivo. We will discuss these strategies within the context of the nanoparticle probe used as well as the recognition moieties applied in each approach. Ultimately, the translation of these methods from the laboratory to the clinic may enable earlier detection of cancer and could extend patient survival through the ability to administer therapeutic treatment in the early stages of the disease.

While this review provides a comprehensive overview of the nanoparticle probes that are used to detect cancer in vitro and in vivo through fluorescence, there are several other relevant reviews that may be of interest to our readers, who may refer to the references for more generalized reviews of nanomaterials used for diagnostics and therapy,9–12 or more detailed insight into the specific types of nanoparticle probes (i.e., quantum dots,13 gold nanoparticles,14,15 upconversion nanoparticles,16 polymer dots,17,18 silica nanoparticles,19 polymeric nanoparticles, 20 etc.) for cancer diagnosis.

Prashant Agrawal

Papers

Chitosan-based systems for molecular imaging

A high relaxivity Gd(III)DOTA-DSPE-based liposomal contrast agent for magnetic resonance imaging.

Surface modification of PLGA nanospheres with Gd-DTPA and Gd-DOTA for high-relaxivity MRI contrast agents

A multimodal mass spectrometry imaging approach for the study of musculoskeletal tissues