Polymeric and lipid-based drug delivery systems for treatment of glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is the most aggressive, malignant brain tumor found in adults, and has a short median survival time (MST). GBM is a heterogeneous group of brain tumors, is highly prone to develop resistance and likely to recur. In the context of GBM, the delivery of anti-cancer drugs is challenging because the blood brain barrier (BBB) restricts the passage of small molecules. Currently, nanomedicines based on liposomes, micelles, polymeric nanoparticles, and microparticles have attracted much attention, because they can cross the BBB and deliver anti-cancer drugs specifically to brain tumors. In this context, hydrogel-based systems incorporating nanoparticles, implantable carmustine wafers, microspheres, and lipid-based nanoparticles now appear to offer more effective, safer treatment strategies than conventional chemotherapeutic regimens. This review describes different polymeric hydrogel, chitosan, dendrimers, wafers, microspheres, and lipid-based nanoparticles like liposomes and solid-lipid nanoparticles that offers prominent strategies for the treatment and diagnosis of GBM.

Introduction

Glioblastoma multiforme (GBM) is a heterogeneous primary malignant brain tumor [1], [2]. GBM emerges from astrocytes and its cells rapidly reproduce due to the presence of a large network of blood vessels [3]. Uncontrolled cellular proliferation, resistance to radio and chemotherapy, growth of glial stem cells, invasion and infiltration of tumor cells, and apoptosis are characteristic of GBM [4]. GBM is also called the “octopus tumor” because it can extend tendrils to normal neighboring parenchymal cells [4], [5].

The World Health Organization (WHO) has classified astrocytoma into four grades (I, II, III and IV), and in grade IV, GBM has an incidence of 45–50%, although it may develop from low grade astrocytoma [6], [7]. The global incidence of GBM is 10 per 100,000 people [8]. According a report issued by the Central Brain Tumor Registry of the United States (CBTRUS, 2013), 12,760 new cases of GBM were predicted in 2018 [9]. In this report, relations between GBM incidence and age, gender were studied. Accordingly, due to expected increases in the size and mean age of the US population, the number of cases is expected to increase. Others have reported the incidence of GBM is highest in 75 to 84 year olds (at 15%) [8], [9], [10], and that it is greater for men than women [8], [11].

In the majority of cases, GBM is idiopathic, but some factors such as age, gender, family history, exposure to infections or strong electromagnetic fields, race, ethnicity, and a history of head injury or exposure to N-nitroso compounds are considered causes of GBM [12], [13], [14]. The clinical manifestations of GBM include edema, hemorrhage, and an altered mental status [15].

GBM is a highly aggressive neoplasm with an MST of 3 months if left untreated [16], though this can be improved by surgery plus radiotherapy or surgery plus chemotherapy or surgery plus radiotherapy and chemotherapy [17], [18], [19]. In 2004, the European Organization for Research and Treatment of Cancer stated GBM patients treated with radiotherapy plus temozolomide (TMZ) had an MST of 13–14 months, and radiotherapy alone had an MST of 11–13 months [8], [19].

GBM is aggressive, tends to recur, and is difficult to treat completely [20]. For newly diagnosed or recurrent GBM, the gold standard treatment is surgical resection followed by radiotherapy or chemotherapy with concomitant adjuvant TMZ chemotherapy [5] [Fig. 1]. Systemic treatments based on cytotoxic chemotherapy (e.g., TMZ [21], everolimus [22], or lomustine [23]) or hormonal therapy (e.g., using progesterone inhibitors, aromatase inhibitors, or hormone release growth hormone inhibitors [24]) are also commonly used to treat GBM [25].

In addition, molecular targeted therapies such as bevacizumab (targets vascular endothelial growth factor), cetuximab or nimotuzumab (target epidermal growth factor receptor), and CSF-1R inhibitor PLX3397 [26] or BLZ945 [27] (target colony stimulating factor-1 receptor) are emerging treatments for GBM [28]. Moreover, immunotherapies such as adoptive T-cell [29], tumor vaccine [30], and immune checkpoint [31] therapies have become a focus of current research. Programmed death-1 (PD-1), T-cell immunoglobulin mucin-3 (TIM-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3), which inhibit T-cell activation, are negative regulators of the immune system in GBM [32], and these ligands are also viewed as possible targets for GBM therapy [33]. In particular, programmed death ligand 1 (PD-L1) is overexpressed in GBM and monoclonal antibodies that inhibit PD-L1 or PD-1 receptor or its interactions with ligands offer other means of addressing its treatment [34]. Although, no Food and Drug Administration (FDA)-approved immunotherapy is available for GBM, the phase III trial of Ipilimumab and Nivolumab in GBM patients at different stages of treatment was initiated in 2014 (NCT02017717) [33].

As regards anti-cancer drugs, FDA approved TMZ as a first line drug for the treatment of GBM in 1999. TMZ is an alkylating anti-cancer drug that has been shown to increase patient survival [35], [36]. TMZ is converted intracellularly into MTIC (5-(3-methyltriazen-1-yl) imidazole-4-carboxamide) and methylates DNA at the N⁷ and O⁶ positions of guanine residues, which disrupts the cell repair mechanism and eventually causes cell death by breaking down double-stranded DNA [19], [37] [Fig. 2]. Standard TMZ based treatments include the combined use of TMZ, surgery, and radiation, but treatment efficacies are limited.

Development of different injectable hydrogel system have been developed for the treatment of diseases that are difficult to control like GBM. Such injectable hydrogel systems have potent capacity to encapsulate anti-cancer drugs and deliver successfully and efficiently at the site of action. The implantation of injectable hybrid hydrogel composed of protein-polymer conjugate to generate an effective platform for encapsulation and delivery of a DNA vaccine [38]. Similarly, pH- and temperature-responsive biodegradable copolymers were concomitant with human serum albumin to developed hybrid injectable hydrogels, that upgrade the stability and half-life of the biological drug [39]. Furthermore, the in situ forming injectable hydrogel [40] and stimuli‐sensitive injectable polymeric hydrogels [41] can also be the promising formulation for the delivery of therapeutic agents. These types of injectable formulation may control the anticancer drug release and subsequently eradicate the GBM.

Anatomical locations, high tumor heterogeneity leading to uncontrolled cellular proliferation, resistance to radiotherapy and chemotherapy, glial stem cell growth, invasion and infiltration of tumor cells, and apoptosis are the main reasons why GBM treatments are limited. On the other hand, resection has the shortcomings of causing collateral damage to neurological tissue, adversely affecting cognitive function of patients, and the different physical barrier in central nervous system (CNS) can delay in delivering of the anti-cancer agent to the tumor site [5]. Accordingly, different delivery strategies using drug carriers such as gold nanoparticles [42], [43], microspheres, or dendrimers that deliver anti-cancer drugs to tumor site without affecting neighboring healthy cells are being actively investigated [44], [45].

Cancer regrowth at original or different sites is problematic [46]. The main problem for this is that tumors can recur at original sites or migrate/metastasize to other parts of the body [47]. Primary treatment destroys most GBM cells, but some remain viable and continue to grow. GBM tumor cells have “finger-like tentacles”, which enable the disease to spread throughout the brain [48], [49], [50]. Furthermore, under the favorable microenvironment in the presence of neighboring cells, the vascular lymphatic network, hypoxic condition, and growth factor infiltered glial stem cells (GSCs) may grow into new tumor cells [49], [51] [Fig. 3].

Hypoxia is a stimulus found in the brain tumors. Hypoxia-responsive (HR) nanoparticles may show better anti-tumor effects in tumor treatment [52], [53], [54]. However, the treatment of GBM using HR-nanoparticles has not well-developed.

GBM recurrence is due to the ability of cancer cells to resist chemotherapy and radiotherapy [55], [56]. In one study, conventional therapies were found to cause GSCs to become temporarily latent [57]. The MST of patients that experience GBM recurrence is 8–9 months [55], which is extended by non-invasive stereotactic radiosurgery to 6.5–30 months. On the other hand, the MST of patients that undergo second surgery or are treated with TMZ for recurrence are 3.5–9 and 4.5 months, respectively [8], [58]. These reports shows TMZ is a moderately effective treatment for recurrent GBM [58], [59], [60], as re-surgery and re-irradiation may adversely affect quality of life.