Current Drug Discovery Technologies - Volume 9, Issue 4, 2012

With an average life expectancy of 14 months, Glioblastoma multiforme (GBM), is the most aggressive primary brain tumor. Our growing understanding of the immune system and its role in oncogenesis has helped develop cancer vaccines as a promising treatment modality against this disease. What follows is a comprehensive discussion on the history of immunotherapy and the various vaccine based therapies being developed and utilized for the treatment of malignant gliomas.

Gliomas are the most common primary brain tumors and result in dismal outcomes when present at high grades. Surgery is the first-line treatment, and maximum safe resection is recommended. However, the infiltrative nature of malignant gliomas makes complete resection difficult as tumor margins are unclear. The use of fluorescence to delineate tumor margins intraoperatively has emerged as a safe and effective tool for increasing the extent of resection. This review discusses several exogenous agents that have been investigated in humans. Aminolevulinic acid is the most studied fluorophore and has been used in many clinical trials, including a multi-center phase III randomized controlled trial. It has been shown to increase extent of resection, progression-free survival, and overall survival. Another fluorophore, fluorescein, has also demonstrated utility in increasing resection quality and overall survival. Developing technologies such as fluorescence spectroscopy to enhance endogenous fluorescence has fairly recently been shown to delineate tumor margins intraoperatively. This method does not require the administration of exogenous agents, but instead distinguishes tumor from normal brain by using changes in the fluorescence emission profile of the tissue. This review also discusses various agents such as nanoparticles that are currently in preclinical testing. Fluorescence-guided resections show great promise for furthering our surgical abilities, and in the foreseeable future will become the standard of care for patients diagnosed with gliomas.

Malignant glioma remains a disease with poor prognosis despite recent advances in the multidisciplinary care of this disease. Herein we review the evolution of and recent advances in radiation therapy for malignant glioma that have allowed for more targeted therapy, potentially improving efficacy while decreasing normal tissue toxicity. Current and emerging techniques are presented, including stereotactic radiotherapy and radiosurgery, brachytherapy, radioimmunotherapy, and charged particle therapy, as well as the combination of these modalities with novel targeted biochemotherapies.

Brain function depends upon complex metabolic interactions amongst only a few different cell types, with astrocytes providing critical support for neurons. Astrocyte functions include buffering the extracellular space, providing substrates to neurons, interchanging glutamate and glutamine for synaptic transmission with neurons, and facilitating access to blood vessels. Whereas neurons possess highly oxidative metabolism and easily succumb to ischemia, astrocytes rely more on glycolysis and metabolism associated with synthesis of critical intermediates, hence are less susceptible to lack of oxygen. Astrocytoma and higher grade glioma cells demonstrate both basic metabolic mechanisms of astrocytes as well as tumors in general, e.g. they show a high glycolytic rate, lactate extrusion, ability to proliferate even under hypoxia, and opportunistic use of mechanisms to enhance metabolism and blood vessel generation, and suppression of cell death pathways. There may be differences in metabolism between neurons, normal astrocytes and astrocytoma cells, providing therapeutic opportunities against astrocytomas, including a wide range of enzyme and transporter differences, regulation of hypoxia-inducible factor (HIF), glutamate uptake transporters and glutamine utilization, differential sensitivities of monocarboxylate transporters, presence of glycogen, high interlinking with gap junctions, use of NADPH for lipid synthesis, utilizing differential regulation of synthetic enzymes (e.g. isocitrate dehydrogenase, pyruvate carboxylase, pyruvate dehydrogenase, lactate dehydrogenase, malate-aspartate NADH shuttle) and different glucose uptake mechanisms. These unique metabolic susceptibilities may augment conventional therapeutic attacks based on cell division differences and surface receptors alone, and are starting to be implemented in clinical trials.

Glioblastoma multiforme (GBM) represents one of the most common aggressive types of primary brain tumors. Despite advances in surgical resection, novel neuroimaging procedures, and the most recent adjuvant radiotherapy and chemotherapy, the median survival after diagnosis is about 12-14 months. Targeting migrating GBM cells is a key research strategy in the fight against this devastating cancer. Though the vast majority of the primary tumor focus can be surgically resected, these migrating cells are responsible for its universal recurrence. Numerous strategies and technologies are being explored to target migrating glioma cells, with small molecular inhibitors as one of the most commonly studied. Small molecule inhibitors, such as protein kinase inhibitors, phosphorylation site inhibitors, protease inhibitors, and antisense oligonucleotides show promise in slowing the progression of this disease. A better understanding of these small molecule inhibitors and how they target various extra- and intracellular signaling pathways may eventually lead to a cure for GBM.

The blood brain barrier (BBB) poses a significant challenge for drug delivery of macromolecules into the brain. Convection-enhanced delivery (CED) circumvents the BBB through direct intracerebral infusion using a hydrostatic pressure gradient to transfer therapeutic compounds. The efficacy of CED is dependent on the distribution of the therapeutic agent to the targeted region. Here we present a review of convection enhanced delivery of macromolecules, emphasizing the role of tracers in enabling effective delivery anddiscuss current challenges in the field.

Colon-targeted delivery of bioactives has recently gained importance in addressing specific needs in the therapy of colon based diseases. Many approaches have been attempted for the development of colon-specific delivery systems, with not much success in the past. With the advancement in the field of chronobiology, modern drug delivery approaches have elevated to a new concept of chronopharmacology i.e. the ability to deliver the therapeutic agent to a patient in a staggered profile. The increasing research interest surrounding this delivery system has widened the areas of pharmaceutics in particular with many more sub-disciplines expected to coexist in the near future. Chronopharmaceutics based technology has eliminated the drawbacks associated with the conventional colon specific delivery systems. This review on chronopharmaceutics based delivery lays emphasis on the existing technologies and future development.

Multi drug resistance and non specific targeting is a major problem with conventional therapy. To overcome this problem, nanoparticles (NPs) have emerged as an important tool to deliver conventional drugs, recombinant proteins, vaccines and more recently, nucleotides. NPs modify the drug release pattern, absorption, distribution, metabolism, excretion (ADME) and therapeutic response. This review focuses on the potential of nanotechnology in cancer and discusses the different nanoparticulate drug-delivery systems including quantum dot, iron oxide nanoparticles, gold nanoparticles, carbon nanotubes, silica nanoparticles, dendrimer, graphene and polymeric nanoparticles with their applications in therapeutics, diagnostics, and imaging pattern. Further, the recent development and progress of theranostic nanoparticles in the treatment of cancer and toxicity associated with nanoparticles is also covered here.