Current Pharmaceutical Biotechnology - Volume 14, Issue 8, 2013

MRI plays a unique role in cancer treatment from three perspectives: Firstly, MRI has superior soft tissue resolution, which makes it indispensible in delineating, staging and monitoring treatment efficacy for certain tumors; Secondly, several techniques which use real-time MRI to map such physiological parameters as temperature, water content or pH have been developed to guide course of anticancer therapies; Thirdly, different targeted probes or hybrid nanoparticles are being developed to facilitate the diagnosis and treatment of tumor under guidance of MRI. In this review article, we will briefly review the first two aspects of MRI guided cancer therapy, followed by a more comprehensive review on the third part focusing on targeted MR imaging probes for personalized medicine.

Optical molecular imaging holds great promise for image guiding cancer therapy. The non-invasive guidance of therapeutic strategies would enable the removal of cancerous tissue while avoiding side effects and systemic toxicity, preventing damage of healthy tissues and decreasing the risk of postoperative problems. This review article highlights the advantages and disadvantages of the optical imaging techniques that are currently available, including their recent applications in image-guided cancer therapy. Three approaches for optical image-guided cancer therapy were discussed in this review, namely, bioluminescence imaging (BLI), fluorescence imaging (FI) and Cerenkov luminescence imaging (CLI). BLI is always used in small animal imaging for the in vivo tracking of therapeutic gene expression and cell-based therapy. To the contrary, FI display high promising for clinical translation. The applications of FI include image-guided surgery, radiotherapy, gene therapy, drug delivery and sentinel lymph node fluorescence mapping. CLI is a novel radioactive optical hybrid imaging strategy and its use for animal and clinical translation was also discussed. Perspectives on the translation of optical image-guided cancer therapy into clinical practice were provided.

Over the last several decades, development of various imaging techniques such as computed tomography, magnetic resonance imaging, and positron emission tomography greatly facilitated the early detection of cancer. Another important aspect that is closely related to the survival of cancer patients is complete tumor removal during surgical resection. The major obstacle in achieving this goal is to distinguish between tumor tissue and normal tissue during surgery. Currently, tumor margins are typically assessed by visual assessment and palpation of the tumor intraoperatively. However, the possibility of microinvasion to the surrounding tissues makes it difficult to determine an adequate tumor-free excision margin, often forcing the surgeons to perform wide excisions including the healthy tissue that may contain vital structures. It would be ideal to remove the tumor completely, with minimal safety margins, if surgeons could see precise tumor margins during the operation. Molecular imaging with optical techniques can visualize the tumors via fluorophore conjugated probes targeting tumor markers such as proteins and enzymes that are upregulated during malignant transformation. Intraoperative use of this technique may facilitate complete excision of the tumor and tumor micromasses located beyond the visual capacity of the naked eye, ultimately improving the clinical outcome and survival rates of cancer patients.

Ultrasound mediated drug delivery using microbubbles is a safe and noninvasive approach for spatially localized drug administration. This approach can create temporary and reversible openings on cellular membranes and vessel walls (a process called "sonoporation"), allowing for enhanced transport of therapeutic agents across these natural barriers. It is generally believed that the sonoporation process is highly associated with the energetic cavitation activities (volumetric expansion, contraction, fragmentation, and collapse) of the microbubble. However, a thorough understanding of the process was unavailable until recently. Important progress on the mechanistic understanding of sonoporation and the corresponding physiological responses in vitro and in vivo has been made. Specifically, recent research shed light on the cavitation process of microbubbles and fluid motion during insonation of ultrasound, on the spatio-temporal interactions between microbubbles and cells or vessel walls, as well as on the temporal course of the subsequent biological effects. These findings have significant clinical implications on the development of optimal treatment strategies for effective drug delivery. In this article, current progress in the mechanistic understanding of ultrasound and microbubble mediated drug delivery and its implications for clinical translation is discussed.

Swine flu and avian flu outbreaks have occurred in recent years in addition to seasonal flu. As mortality rate records are not available at the early stage of an outbreak, two parameters may be useful to assess the viral virulence : 1. the time required for the first domestic case in a newly involved region, and 2. the doubling time of new infected cases. Viral virulence is one of the most important factors in guiding short term and immediate responses. Although routine surveillance and repeated vaccination are useful efforts, some novel strategies that may be relevant to prevent and control the spread of influenza among human beings and domestic animals are discussed.

With the convergence of modern technology in genomics, proteomics, carbohydrate, protein and lipid biochemistry as well as decades of experience in vaccine development and delivery of immunization programs, the Global Vaccine Action Plan has declared 2011 to 2020 as ‘The Decade of Vaccines’. This review focuses on bacterial vaccines and summarises the current state of vaccinology in bacteriology and looks forward to the potential of how the newer technologies can impact our knowledge of bacterial diseases and their control through vaccine development. The major breakthroughs in the last couple of decades include low cost high throughput genomics, proteomics, cellular immunology and the delicate network of immune-cytokines, bioinformatics, immune-informatics, and disease modelling. Together, these newer developments can provide a real impact on our understanding of infectious diseases and their control by vaccination.

Midkine is a heparin-binding growth factor that promotes cell growth, survival, and migration. Externally added midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction in the mouse. Preclinical testing of this protein is in progress. Externally added pleiotrophin, a member of the midkine protein family, promotes functional recovery after neural transplantation in rats. Thus, pleiotrophin is also a candidate therapeutic protein. Large amounts of these proteins were obtained by using the heterologous protein expression system of Pichia pastoris, and the recombinant P. pastoris clones were cultured in a controlled fermentor. Intracellular expression yielded about 300 mg/L recombinant human (rh)-midkine, which was extracted, renatured, and purified. From 1 L of the culture, 64 mg of rh-midkine was purified. Secretory expression induced by the midkine secretion signal resulted in about 100 mg of rhmidkine in 1 L of the culture supernatant, but over 70% of the rh-midkine had yeast-specific glycosylation. Three threonyl residues that are targets for glycosylation were substituted with alanyl residues, and nonglycosylated, active rh-midkine was obtained. In secretory expression using α-mating factor prepro-sequence, about 640 mg/L rh-midkine was obtained, but it was partially truncated. Therefore, a protease-deficient host was used, and about 360 mg/L intact rh-midkine was then obtained. The rh-midkine was recovered and purified, with 70% final yield. All purified rh-midkine, regardless of expression method, was able to promote mammalian cell proliferation. In secretory expression of rh-pleiotrophin using α- mating factor prepro-sequence, 260 mg/L rh-pleiotrophin could be secreted. The rh-pleiotrophin was recovered and efficiently purified with 72% final yield.