Review Research Protocol. Advances in the administration of nanoparticles for the treatment of glioblastoma.

• Introduction

Glioblastoma multiforme (GBM) is the most common and detrimental primary brain tumor. It represents 57% of gliomas and 48% of all primary malignant tumors of the central nervous system. Its incidence in the United States is 3.21 cases per 100,000 inhabitants, it increases with age, it is 1.58 times more common in men, 1.93 times more common in Caucasians, and only 5.6% of patients survived 5 years after diagnosis [1]. In Mexico, available statistical data indicate that gliomas represent 33% of all brain tumors and the average age of GBM diagnosis is 46.4 years. However, this percentage belongs specifically to the National Institute of Neurology and Neurosurgery, which may not be representative of the incidence in the Mexican population throughout the country [2]. In general, the survival prognosis is less than two years. Standard treatment is multimodal. It includes maximal resection surgery, followed by radiation therapy and chemotherapy treatments using temozolomide (TZM), which when administered to GBM cells causes double-stranded breaks in DNA, cell cycle arrest, and eventual cell death. However, TMZ attacks DNA indiscriminately, also causing damage to the patient's hematopoietic stem cells. Due to the ineffectiveness in completely eliminating the tumor and the high recurrence rate, there is a need to search for better treatment options, one of them being the targeted administration of drugs [3], [4].
Biological factors such as the blood-brain barrier (BBB) and the immune microenvironment of the tumor make it difficult to develop new therapies [3]. The BBB maintains the homeostatic balance of the brain, acting as a protective layer that prevents the direct contact of pathogens present in the bloodstream with the cerebral fluid. Unfortunately, BBB limits therapeutic efficacy and this is why it represents one of the most formidable obstacles in the development of new drugs for the treatment of neurodegenerative diseases and brain tumors [5]. In 1955, Jatzkewitz reported the preparation of the first polymer-drug conjugate, polyvinylpyrrolidone-mescaline, which is considered the first therapeutic nanoparticle. In the 1960s, the use of liposomes was discovered as the first nanotechnology based on a drug delivery system [6]. In the late 1960s, Professor Peter Paul Speiser and his research group developed the first nanoparticles for drug and vaccine delivery [7].
In recent years, the use of nanoparticles in drug delivery systems has received much attention, especially for the treatment of cancer, as they represent a possible alternative to crossing the BBB [8]. Design features have been incorporated to deal with biological barriers. For example, they frequently include targeting active moieties for better uptake in specific cells, or stimulus-response release components based on methods such as thermosensitivity or ultrasound [9]. In 2015, a study was presented by Y.-C. Kuo et al. in which lipid nanoparticles with p-aminophenyl-α-D-mannopyranoside and folic acid were applied to encapsulate an etoposide commonly used to treat cancer. The objective was to promote the antiproliferation of GBM. The nanoparticles were able to penetrate the BBB and delayed the spread of tumor cells, showing inhibitory efficacy for cancer therapy [10].
Despite the advances proposed in the formulation of nanoparticles to improve drug delivery in brain tumors, most of these efforts have met with little success. Unfortunately, the accumulation of nanoparticles in brain tumors is very low [11]. Such was the case of Silva et al. who in 2020 conducted a study to measure the effect of gold nanoparticles (AuNPs) alone and coated with anti-VEGF antibody on in vitro cell proliferation in GL261 glioblastoma cells, as well as tumor induced in mice in vivo. No favorable results were obtained: there were no changes in tumor volume, no AuNPs were found in the tumor area or in the peritumoral area, and it was confirmed that there was no acceptance by the tumor cells regarding AuNPs. It was concluded that the lack of antitumor effect is due to the fact that AuNPs were not internalized by the GL261 cell membrane or by BBB in sufficient quantities [12]. Its ability to cross the BBB would reduce the therapeutic limitations faced by targeted drug delivery systems. The use of nanoparticles has been studied for their possibility of being accumulated in tumor areas to effectively inhibit the proliferation and metastasis of tumor cells, either on their own or in combination with other therapies such as photothermal, photodynamic or chemotherapy therapy. among others [13]. Elucidating what type of nanoparticles penetrate the BBB can guide the design of drug delivery systems that exhibit an inhibitory effect, identifying factors such as optimal size and shape.

• Research Question

Does the use of nanoparticles in the targeted delivery of drugs to treat glioblastoma multiforme have an inhibitory effect on tumor cell growth in animal models?

• Inclusion criteria

• Records that investigate the use of nanoparticles in the targeted administration of drugs for the treatment of glioblastoma that mention whether or not there were changes in tumor growth or cell growth.
• Records that investigate the ability of nanoparticles to cross the blood-brain barrier and their effects on tumor cells, whether in inhibiting tumor growth, reducing the proliferative activity of cancer cells or changes in tumor volume.
• Studies carried out in murine models.
• The articles included must have been published from 2015 to 2021.
• Records that are in the English language.
• Clinical trials on the application of nanoparticles in the administration of drugs.

• Exclusion criteria

• Records that investigate the use of nanoparticles for the localization of glioblastoma by imaging, not including their use in therapy.
• Records that cannot be accessed in full text.
• Records that are in languages other than English.
• Systematic reviews that include the use of nanoparticles in glioblastoma therapy.
• Records of conferences, theses and other unpublished data were excluded.

• General objective

• To determine whether the use of nanoparticles in the targeted administration of drugs as a treatment for glioblastoma multiforme has an inhibitory effect on the growth of tumor cells.

• Specific objectives

• Highlight the characteristics that give nanoparticles used in the targeted delivery of drugs the ability to cross the blood-brain barrier.
• Record which nanoparticles used in targeted drug delivery have effects on the proliferative activity of glioblastoma tumor cells.
• Describe whether there is a relationship between the inhibitory effect and the ability to cross the blood-brain barrier of nanoparticles.

• Justification for study

Since glioblastoma multiforme is one of the most common and aggressive brain tumors, with a very low survival rate and whose standard treatment is not very effective, the development of new technologies that increase the effectiveness of treatment is essential. In recent years, the search for new approaches and strategies has aroused the interest of the scientific community, which is why the literature is vast, scattered and continues to grow exponentially. Consequently, the search for relevant information on the use of nanoparticles in glioblastoma therapy, as well as its methods, efficacy and adverse effects needs to be synthesized in order to understand which strategies are better. Currently, it is known that the use of nanoparticles as targeted drug delivery systems are a promising alternative for the treatment of glioblastoma, as they respond to some of the obstacles that limit the efficacy of current treatments. To allow us to know the current status of this treatment, there is a need to collect updated information on the subject to help us understand how the blood-brain barrier (BBB) and the tumor microenvironment are related to the inhibitory effect that some nanoparticles present against Carcinogenic cells. This would serve as a starting point for the development of designs that focus on the BBB and the microenvironment, as well as the optimal shape and sizes of the nanoparticles to cross them and provide a specific and effective treatment in tumor shrinkage.

• Proposed methodology

1. Carrying out the search for scientific records that address the subject in the databases: Web of Science, ScienceDirect and PubMed. Records will also be taken from sources such as ClinicalTrials.
The keywords and booleans to be used are the following:
(glioblastoma) AND (nanoparticles) AND ("drug delivery") ("mice") AND ("tumor growth" OR "cell growth" OR "tumor size") AND ("inhibition" OR "inhibit $")
2. Compilation of the existing literature on the administration of nanoparticles as drug-targeted delivery systems, the results of which show effects on the growth of glioblastoma tumor cells.
3. Preparation of the flow chart applying inclusion and exclusion criteria for the selection and discarding of articles.
4. Analysis of the selected registries in which the nanoparticles are reported as capable of crossing the blood-brain barrier.
5. Analysis of the selected registries in which the nanoparticles used in the targeted administration of drugs have an inhibitory effect on tumor cells.
6. Synthesis of the selected articles.
7. Preparation of a comparative table on the nanoparticles used in the targeted administration of drugs that are capable of crossing the blood-brain barrier.
8. Preparation of a comparative table on the nanoparticles used in the targeted administration of drugs that have an inhibitory effect on tumor cells.
9. Preparation of the review document