Cellular Trojan horses for delivery of nanomedicines to brain tumors: Where do we stand and what is next?

Abstract

Brain tumors have the ability to exist even at a small size, thus making them extremely difficult to diagnose and cure. For this reason they are often considered as one of the most highly destructive and lethal groups of brain diseases, being responsible for the fourth-highest number of years of life lost in the world?s population [1]. The incidence of this type of cancer is increasing; also, mortality rate has been reported to be 4.6 per 100,000 person-years worldwide [2]. These tumors seem to be more and more frequent, not only because of a true increase in their incidence, but also due to the increase in life expectancy of the general population and technological advances that allow an opportune and early diagnosis. Brain cancers, also referred as central nervous system (CNS) cancers, are a group of several types of tumors from different origins, mostly from neuronal and glial precursor cells. The most common histological types of primary CNS tumors are gliomas?a group of malignant brain tumors, including high-grade glioma or glioblastoma (GBM) and low-grade gliomas (astrocytoma, oligodendroglioma). Within these types of gliomas, GBM is still associated with an extremely poor patient prognosis with no curative treatment options available and the 5-year survival of GBM-diagnosed patients remains lower than 6% [3]. Despite a greater understanding of the disease over the last few years, first-line treatment options in the management of GBM remain as tumor resection, radiotherapy and the administration of chemotherapeutic alkylating agents such as temozolomide [4]. Malignant gliomas are a source of mortality and morbidity for which diagnosis and treatment require extensive resource allocation for more sophisticated diagnostic and therapeutic technologies [5]. In this sense, nanomedicine brings novel nano-based drug developments to expand the therapeutic options for the management of brain tumors, specifically for GBM [6,7]. Over the past two decades, many research groups have reported the development of different types of theragnostic nanoparticles for GBM treatment, and other forms of CNS cancers, including magnetic nanoparticles [8], gold nanoparticles [9], liposomes [10], carbon-based nanostructures [11] and polymeric nanoparticles [12]. Although several in vitro and in vivo studies have been performed to demonstrate the efficacy and therapeutic potential of these nanotechnology and nanocarrier-based treatments, only a few of them have completed clinical trials on their own or in combination with other treatments.Ideally, the design of multifunctional nanoparticulate brain tumor-targeted delivery systems involves bioconjugation with ligands, antibodies, aptamers or peptides, which increase accumulation specifically at the tumor site within the CNS and favors minimal toxicity in healthy tissue. However, there are numerous barriers to overcome if this treatment strategy based on active targeting is to be successful. For instance, the common method to achieve intracerebral location is intravascular administration, and once nanoparticles are in the bloodstream, they face several barriers or obstacles until they reach the brain parenchyma. The first of which is the opsonization of plasma proteins and formation of a protein corona around the nanoparticles, which, in turn, favors phagocytosis by the mononuclear phagocytic system (MPS) from liver, spleen and lungs leading to a rapid clearance from the circulation with limited circulation time, and thus to reduced crossing of the blood-brain barrier (BBB). The brain is protected by the highly specialized BBB, which tightly regulates the transport of metabolically important molecules between the blood and the brain and thus, the BBB constitutes another barrier that nanoparticles need to overcome. This barrier is formed by specialized microvessel endothelial cells and pericytes. In addition, astrocytes and interneurons also contribute to the BBB structure. On the other hand, brain tumors, especially malignant gliomas, possess a blood?brain tumor barrier (BBTB) which is formed during tumor progression [13]. A feature of GBM tumor heterogeneity is the coexistence of both types of barriers with differential permeability to drugs in the different tumor regions. Nano-based therapeutics need to be able to overcome these barriers and penetrate the brain to reach the tumor cells. This has led to the search for additional ways to deliver nanomaterials to the CNS by using cell-based delivery systems with the purpose of conquering the traditional active targeting methods by avoiding or overcoming the aforementioned obstacles.