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REVIEW ARTICLE
Targeted Nanoparticles for Brain Cancer Therapy and Imaging Ajita Bhatt1, Ekta Gurnany1, Anuj Modi1, Arvind Gulbake2 and Aviral Jain3,* 1
Pharmaceutics Research Laboratory, Department of Pharmaceutics, Adina Institute of Pharmaceutical Sciences, Sagar (M.P.) 470002, India; 2Center for Interdisciplinary Research, D.Y. Patil University, Kolhapur (M.S.) 416006, India; 3 Pharmaceutics Research Laboratory, Department of Pharmaceutics, Ravishankar College of Pharmacy, Bhopal (M.P.) 462010, India
ARTICLE HISTORY Received: January 25, 2016 Revised: January 12, 2017 Accepted: January 13, 2017 DOI: 10.2174/1389557517666170927112150
Abstract: Objective: Cancer is one of the most important causes of morbidity and mortality all across the world. On an average, every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed around the world. Amongst all, tumors of brain account for nearly 85% to 90% of all primary central nervous system (CNS) tumors. Conclusion: Regardless of tremendous scientific efforts to develop newer diagnostic techniques and latest therapy, the management of brain cancer is still a challenge in neuro-oncology. Inadequate concentration of chemotherapeutics at the site of tumor restricts the complete destruction of malignant cells due to the presence of blood brain barrier. Besides, there is a necessity for improvement in tumor imaging for better characterization and visualization of tumor cells for surgical procedure. Nanoparticles offer the advantages upon many of these concerns i.e., diagnosis, capability to target therapeutic agents to the tumor sites and the ability of getting across the blood-brain barrier. Thus utilization of nanoparticles may lead to breakthrough in brain cancer management.
Keywords: Blood-brain barrier, brain cancer, diagnosis, drug delivery, imaging, nanoparticles, theranostic. 1. INTRODUCTION Nanotechnology aims at the study of matter on an atomic and molecular scale, exploration is usually at a range of 11000 nm. Therefore nanotechnology is a multidisciplinary field including the designing, characterizing, manipulation, construction and application of assemblies, devices and systems at nanometer scale present exclusive and superior physicochemical properties. Nanomedicine, an offset of nanotechnology, illustrates extremely explicit medical intervention at the molecular level for the treatment or repairing of damaged tissues. It has been applied since 1960's, by designing first lipid vesicles well-known as liposomes. Even though, the earlier properties of nanomaterials considered were for its physical, mechanical, electrical, magnetic, chemical and biological applications, lately, interest has been geared towards its pharmaceutical application, particularly in the field of drug delivery. Some of the challenges confronted by nearly all drug delivery formulation comprise reduced bioavailability, in-vivo stability, solubility, sustained and site specific delivery, side effects, and plasma wavering of drugs.
Nanostructures have the capability to provide protection to the encapsulated protein and peptide from hydrolytic and enzymatic degradation in the upper part of gastrointestinal tract through the peroral route of administration. They can deliver highly water insoluble drugs; bypass first pass metabolism; enhance oral bioavailability through specific uptake mechanisms i.e., absorptive endocytosis and are proficient to remain in the blood for a longer time, releasing the drug in a sustained and controlled manner leading to less plasma wavering and ultimately reduces adverse effects. The uptake of nanostructures was found to be 15-250 times greater as compared to microparticles in 1-10µm range [1-5]. Through exploiting the characteristics of polymers, release of drug from nanostructures can be controlled to attain desired therapeutic concentration for desired interval and by conjugating those with targeting moieties the targeted delivery can be obtained (Fig. 1). By incorporation of amino acids, lipids, peptides or small chains as spacer molecules, linkage can be achieved. The targeted drug delivery is essential for the delivery of chemotherapeutics, where a drug should target only the tumor site, while protecting the healthy cells.
*Address correspondence to this author at the Pharmaceutics Research Laboratory, Department of Pharmaceutics, Ravishankar College of Pharmacy, Bhopal (M.P.) 462010, India; Tel: 0755-4232746; Fax: 91-9425172137; E-mail:
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The use of nanostructures such as nanoparticles is an effective approach for brain delivery of drugs to manage brain tumors, neurodegenerative disorders, cerebrovascular
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Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 0
Bhatt et al.
Fig. (1). Drug distribution in targeted and non-targeted delivery.
and inflammatory diseases. Polyalkylcyanoacrylate nanoparticles loaded with anticancer drugs were described in the late 1970s, since then nanoparticles are considered as promising drug carriers that deliver drugs more precisely to tumor cells and maintain their therapeutic concentration over a long period [6, 7]. 2. BRAIN CANCER Cancer is one of the most important causes of morbidity and mortality worldwide. Amongst all types of tumors, tumors of brain account for nearly 85% to 90% of all primary CNS tumors [8]. Brain tumors are heterogeneous group of primary and metastatic neoplasms in the brain and spinal cord, with low survival rate and the incidence of primary malignant brain tumors is approximately 24,000 cases annually [9, 10]. The three main brain tumors include astrocytomas, oligodendrogliomas and oliogoastrocytomas. Astrocytomas are tumors arising from astrocytes, a type of glial cell located in the brain; classified by World Health Organization (WHO) according to their malignant grade as Anaplastic astrocytomas (grade III) and glioblastomas (grade IV) [11-13]. Among them glioblastomamultiforme (GBM) (a grade IV astrocytoma) are most common and aggressive form in nature as they diffusely infiltrate all over the brain and expand far away from the actual tumor mass. Unfortunately, this characteristic pretends that not every last tumor cell can be removed surgically [14, 15]. Another important category of tumor in the central nervous system is the brain metastases which originate mainly from systemic cancers in the organs and occur at a high frequency [16, 17]. The treatment of brain cancer is one of the hardest challenges in oncology. In late 1970s the surgical resertion of brain tumors leads a survival time of 3 months, since then several endeavors have been carried out to increase the effects of the treatments as absolute eradication of tumor is not generally accomplished. In fact, how much tumor is removed depends on the position and the kind of glioma within the brain [18, 19].
It is already an established fact that the aggressive surgical removal of a brain tumor followed by radiation and adjuvant chemotherapy administered at different time points leads to a noteworthy survival advantage [20-22]. The cytotoxic and cytostatic agents are two main classes of chemotherapy used to treat brain tumors. Unconventional therapies such as gene therapy, immunotherapy and photodynamic therapy (PDT) are still under clinical trials and are potential adjuvant treatments for brain tumors. These newer therapies provide widened spectrum of therapeutic approaches for brain tumors [23]. 3. MAJOR OBSTRUCTIONS IN BRAIN CANCER TREATMENT Regardless of tremendous scientific efforts to develop newer diagnostic techniques and latest therapy, the management of brain cancer is still a challenge in neuro-oncology. The major obstructions in the way of successful treatment include the structural intricacy of the brain, acquired drug resistance to chemotherapy, inadequate concentration of chemotherapeutics at the tumor site, complexity in recognizing tumor margins and distributed tumor burdens and heterogeneous and invasive character of numerous brain tumors. Brain regulates large number of body functions and debatably is the most multifaceted system in the body. It is a fragile organ, and evolution built very efficient ways to guard it. Regrettably, the same mechanisms that guard it against intrusive chemicals can also aggravate therapeutic interventions. Because of the intricacy of brain functions, the management of brain tumors needs robust as well as extremely selective eradication of all cancerous cells. [23, 24]. As cited above, the incapability of intravenously administered anticancer drugs to reach the brain parenchyma is one of the key factors in failure of chemotherapy. The efficiency of systemic delivery of therapeutic agents to brain tumors is hindered by different physiological barriers. Blood–brain barrier (BBB), an endothelial cell monolayer linked with
Targeted Nanoparticles for Brain Cancer Therapy and Imaging
pericytes and astrocytes, separates the blood from the cerebral parenchyma and checks the penetration of drugs into the CNS (Fig. 2).
Fig. (2). Various components of BBB.
Paul Ehrlich was the first to give concept of BBB in 1885 which was later confirmed by Edwin Goldmann [25, 26]. Blood brain barriers is seems like a semi-permeable and selective barrier that protects the brain from substances (e.g., potassium, glycine, and glutamate) which are neurotoxic in physiological concentrations and at the same time, which supplies the brain with required biologically essential molecules (glucose or hormones) [27]. BBB is a physical barrier characterized by presence of tight intracellular junctions (zonaoccludens) and absence of fenestrations which limits permeability for therapeutic molecules. Different factors which affect the drug transport across BBB are shown in Fig. (3). The exchange of anticancer agents between the plasma and the CNS is also limited by the deficiency in pinocytic vesicles and the high metabolic capacity of cerebral endothelial cells. Besides, a high level of ATP-binding cassette (ABC) transporters like P-glycoprotein in the cerebral endothelium is involved in drug efflux mechanisms. Thus, the BBB forbid the crossing of almost all large-molecule and only small (
