Giuseppe Raudino

Could nanoparticle systems have a role in the treatment of cerebral gliomas

UNLABELLED Malignant brain tumors are difficult to manage clinically and are associated with high rates of morbidity and mortality. Late diagnosis and the limitations of conventional therapies that may result from inefficient delivery of the therapeutic or contrast agent to brain tumors due to the blood-brain barrier and nonspecificity of the agents, are major reasons for this unsolved clinical problem. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the difficulties of modern strategies. Moreover, multifunctionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. This review reports the latest research in nanoparticle-based glioma treatment. FROM THE CLINICAL EDITOR In recent years, nanoparticles have emerged as potential delivery vectors targeting brain tumors, including multifunctional NP-s allowing tumor-specific detection, treatment, and follow-up monitoring. This review summarizes the latest research in nanoparticle-based glioma treatment.

Antisense Oligonucleotides as an Innovative Therapeutic Strategy in the Treatment of High-Grade Gliomas

Despite the intensive recent research in cancer therapy, the prognosis in patients affected by high-grade gliomas is still very unfavorable. The efficacy of classical anti-cancer strategies is seriously limited by lack of specific therapies against malignant cells. The extracellular matrix plays a pivotal role in processes such as differentiation, apoptosis, and migration in both the normal and the pathologic nervous system. Glial tumors seem to be able to create a favorable environment for the invasion of glioma cells in cerebral parenchyma when they combine with the extracellular matrix via cell surface receptors. Glioma cells synthesize matrix proteins, such as tenascin, laminin, fibronectin that facilitate the tumor cells motility. New treatments have shown to hit the acting molecules in the tumor growth and to increase the efficacy and minimize the toxicity. Antisense oligonucleotides are synthetic stretches of DNA which hybridize with specific mRNA strands. The specificity of hybridization makes antisense method an interesting strategy to selectively modulate the expression of genes involved in tumorigenesis. In this review we will focus on the mechanisms of action of antisense oligonucleotides and report clinical and experimental studies on the treatment of high-grade gliomas. We will also report the patents of preclinical and/or clinical studies that adopt the antisense oligonucleotide therapy list in cerebral gliomas.

Nanotechnology Platforms in Diagnosis and Treatment of Primary Brain Tumors

Despite aggressive multimodal strategies, the prognosis in patients affected by primary brain tumors is still very unfavorable. Glial tumors seem to be able to create a favorable environment for the invasion of neoplastic cells into the cerebral parenchyma when they interact with the extracellular matrix via cell surface receptors. The major problem in drug delivery into the brain is due to the presence of the blood brain barrier which limits drug penetration. Nanotechnology involves the design, synthesis and characterization of materials that have a functional organization at least in one dimension on the nanometer scale. Nanoengineered devices in medical applications are designed to interface and interact with cells and tissues at the molecular level. Nanoparticle systems can represent ideal devices for delivery of specific compounds to brain tumors, across the blood brain barrier. In this brief review, we report the results of studies related to the emerging novel applications of nanoparticle systems in diagnosis and treatment of primary brain tumors, and also the patents of studies that adopt nanoparticle systems as drug delivery carriers in brain tumor diagnosis and therapy.

Nanoparticle-based cerebral drug-delivery systems and antiangiogenic approach in gliomas treatment.

The efficacy of current anti-cancer multimodal therapeutic strategies in gliomas is limited by the lack of specific therapies against malignant cells and the prognosis in patients affected by cerebral gliomas remains very unfavorable. Glial tumors seem to be able to create a favorable environment for the invasion of neoplastic cells when they combine with the extracellular matrix through the up-regulation of crucial pathways such as angiogenesis and invasion. The major problem in brain drug delivery is the presence of the blood brain barrier which limits the delivery of many chemotherapeutic agents and other kinds of therapeutic molecules. This event often contributes to the failure of the treatment. Nanoparticle systems can represent ideal devices for delivery of specific compounds to brain tumors across the blood brain barrier. The specificity of hybridization makes antisense method an interesting strategy to selectively modulate the expression of genes involved in tumorigenesis. In this review we will focus on the mechanisms of angiogenesis into gliomas, their importance into tumor progression and the possibilities to block these mechanisms with new nanoparticle-based therapeutic strategies. We will also report the results of preclinical and/or clinical studies that adopt nanoparticle-based antiangiogenic therapeutic approach in cerebral gliomas, considering also some patents deal with antiangiogenic strategy.

Nanomedicine and Brain Tumors Treatment

Malignant brain tumors represent a class of aggressive neoplasms generally associated with high rates of morbidity and mortality. Late diagnosis and the limitation of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agent to brain tumors are major reasons for this unsolved clinical problem. Recent advances in our understanding of molecular genetic and tumor biology have lead to a new class of modern antitumoral agents. Consequently, new tools have emerged to target molecules in specific signaling pathways with the objective to increase efficacy and reduce toxicity. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticles have emerged as a potential vector for brain delivery able to overcome the difficulties of modern strategies. Nanoparticle systems provide prolonged drug delivery directly to the tumor following direct intracerebral injection or by functionalizing the material surface with peptides and ligands allowing the drug-loaded material to be specifically target the tumor cells. In this chapter, we will first describe the principal events in glioma biology. We will then report about the applications of nanotechnologies tumor treatment. Finally, we will report various experiences of preclinical and/or clinical studies in cerebral gliomas treatment.

New Therapeutic Strategies in Gliomas Treatment

Gliomas account for about 45% of all primary central nervous system (CNS) tumors and 77% of all malignant primary CNS tumors. Gliomas develop from diverse histological lineages, including oligodendrogliomas, astrocytoma and mixed oligoastrocytoma and all have the potential to become highly malignant neoplasms. Recent studies in molecular biology have better depicted the mechanisms involved in the genesis of cerebral gliomas. It is now generally understood that tumor genesis occurs either by over-expression of oncogenes or inactivation of tumor suppressor genes. Cerebral gliomas represent an interesting target for local gene therapy because of its restricted anatomical location and absence of metastases outside the CNS. This allows delivery of vectors directly to the desired site only a small risk of systemic toxicity (Immonen et al., 2004). The two main gene groups involved in brain tumor development are proto-oncogenes and tumor suppressor genes, respectively upregulated and downregulated during the tumor initiation and progression. In these processes are activated growth factors signaling pathways, marked angiogenesis, downregulation of apoptotic genes and upregulation of antiapoptotic genes. The principal proto-oncogenes involved in gliomagenesis encode for growth factors, growth factors receptors, or downstream effectors of growth factors function, including c-sis (PDGFB chain), erb-B (EGFR), ras (second messenger for GFRs) and myc (transcription factor). Other important genes and protein functions involved in brain tumor development are bcl2, protein kinase C-┙ (PKC-┙), c-raf-1, protein kinase A-Type I (PKA I), telomerase, MDM2, IGF I and insulin-like growth factor I receptor (IGF-IR), HER-2 (encoded from c-erbB-2 gene), bFGF, fibroblast growth factor receptor (FGFR), TGF-┙, TGF-┚2, vascular endothelial growth factor (VEGF), integrins and genes and proteins involved in the cell cycle control, cell proliferation and programmed cell death, angiogenesis and invasiveness pathways. Its evident that the modulation of gene expression at more levels, such as DNA, mRNA, proteins and transduction signal pathways, may be the most effective modality to downregulate or silence specific genic functions. In addition to tumor-suppressor genes and proto-oncogenes, there are, also, the suicide genes. These last ones encodes for a nonmammalian enzyme, that is used to convert a non-toxic prodrug into its active cytotoxic metabolite within the cancerous cells.

Patented nanomedicines for the treatment of brain tumors

Patients affected by malignant brain tumors present an extremely poor prognosis, notwithstanding improvements in surgery techniques and therapeutic protocols. Brain tumor treatment has been principally hampered by limited drug delivery across the blood-brain barrier (BBB). An efficacious chemotherapeutic treatment requires a pharmacological agent that can penetrate the BBB and target neoplastic cells. Nanotechnology involves the design, synthesis and characterization of materials that have a functional organization in at least one dimension on the nanometer scale. Nanoparticle systems can represent optimal devices for delivery of various drugs into the brain across the BBB. Nanoparticle drug-delivery systems can also be used to provide targeted delivery of drugs, improve bioavailability and sustain release of drugs for systemic delivery. In this patent review, the recent studies of certain nanoparticle systems in treatment of brain tumors are summarized. Common nanoparticles systems include polymeric nanoparticles, lipid nanoparticles and inorganic nanoparticles. Various patents of nanoparticle systems able to across the BBB to target brain tumors are also reported and discussed.

Gliomas Biology: Angiogenesis and Invasion

Glial tumors, within neuroepitelial-derived lesions, are the most common intra-assial neo‐ plastic histotypes. Gliomas account for about 45% of all primary central nervous system (CNS) tumors and 77% of all malignant primary CNS tumors. Gliomas can originate from neural stem cells, progenitor cells, or from de-differentiated mature neural cells transformed into cancer stem cells. Although brain tumors constitute only a small proportion of overall human malignancies, they carry high rates of morbidity and mortality. Mortality is still close to 100% and the average survival of patients with glioblastoma multiforme (GBM) is less than 1 year when classical treatment is used. Recent progresses in multimodal treatment has led to only a slight increase in average survival up to 15-18 months [1]. The effectiveness of the actual chemotherapeutic approach and multimodal targeted therapies remains modest in gliomas.

Antisense Oligonucleotides in the Treatment of Malignant Gliomas

Brain tumor therapy, despite the recent progress in neuro-oncology, in neurosurgical and neuroradiological techniques, represents a hard challenge for molecular biomedicine. Gene expression in neoplastic cells is a complex multistep process. During this event, single or multiple gene mutation can developed, resulting in clonal neoplastic cells selection. Studies on epigenetic regulation of gene expression during normal cell, tissue, and organism differentiation and evolution have, in the last decade, induced to the possibility to modulate therapeutically genome expression in cancer cells to revert or modify these toward normal cell phenotype. This kind of approach points the attention to the development of molecular therapeutic strategies based on the interaction with specific nucleotide sequences, at level of DNA or RNA, by specular nucleotide-based short molecules capable of hybridizing specific genomic DNA sequences or mRNA transcripted and translated in proteins.