Macromolecular Drug Carriers for Targeted Glioblastoma Therapy: Preclinical Studies, Challenges, and Future Perspectives

Abstract

Glioblastoma, the most common, aggressive brain tumor, ranks among the least curable cancers—owing to its strong tendency for intracranial dissemination, high proliferation potential, and inherent tumor resistance to radiation and chemotherapy. Current glioblastoma treatment strategies are further hampered by a critical challenge: adverse, non-specific treatment effects in normal tissue combined with the inability of drugs to penetrate the blood brain barrier and reach the tumor microenvironment. Thus, the creation of effective therapies for glioblastoma requires development of targeted drug-delivery systems that increase accumulation of the drug in the tumor tissue while minimizing systemic toxicity in healthy tissues. As demonstrated in various preclinical glioblastoma models, macromolecular drug carriers have the potential to improve delivery of small molecule drugs, therapeutic peptides, proteins, and genes to brain tumors. Currently used macromolecular drug delivery systems, such as liposomes and polymers, passively target solid tumors, including glioblastoma, by capitalizing on abnormalities of the tumor vasculature, its lack of lymphatic drainage, and the enhanced permeation and retention (EPR) effect. In addition to passive targeting, active targeting approaches include the incorporation of various ligands on the surface of macromolecules that bind to cell surface receptors expressed on specific cancer cells. Active targeting approaches also utilize stimulus responsive macromolecules which further improve tumor accumulation by triggering changes in the physical properties of the macromolecular carrier. The stimulus can be an intrinsic property of the tumor tissue, such as low pH, or extrinsic, such as local application of ultrasound or heat. This review article explores current preclinical studies and future perspectives of targeted drug delivery to glioblastoma by macromolecular carrier systems, including polymeric micelles, nanoparticles, and biopolymers. We highlight key aspects of the design of diverse macromolecular drug delivery systems through a review of their preclinical applications in various glioblastoma animal models. We also review the principles and advantages of passive and active targeting based on various macromolecular carriers. Additionally, we discuss the potential disadvantages that may prevent clinical application of these carriers in targeting glioblastoma, as well as approaches to overcoming these obstacles.

Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

“…Although in recent years the neuro-oncology research community has directed more attention to the use of patient-derived xenograft models for therapeutic testing, the syngeneic, immunocompetent rodent models and the GEM models continue to serve a critically important role in brain tumor research, mainly for preclinical testing of therapies [66]. Many advanced techniques are used to assist and improve drug brain-tumor exposure, for review see Raucher et al 2018 [68].…”

One-Step Soft Chemical Synthesis of Magnetite Nanoparticles under Inert Gas Atmosphere. Magnetic Properties and In Vitro Study

“…Iron oxide based magnetic nanoparticles (IONPs) have received remarkable attention in a wide range of applications because of their unique physicochemical properties inherent to the nanoscale. Small size, high surface area, quantum confinement, and novel magnetic and optical effects open up new fields for application of iron oxides [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15].…”

“…The IONPs show ability for the biomedical application; they need to possess suitable core size and monodispersity, acceptable hydrodynamic diameter, high saturation magnetization (Ms), high stability in biological fluid media, to be biocompatible and degradable with reduced toxicity over a large time scale, capable of clearance from the body post imaging [1][2][3][4][5][6][7]9,11]. Critical requirements for biomedical related fields are good values of magnetization and ability to form stable aqueous dispersions.…”

Synthesis, Characterization, and In Vitro Studies of an Reactive Oxygen Species (ROS)-Responsive Methoxy Polyethylene Glycol-Thioketal-Melphalan Prodrug for Glioblastoma Treatment

“…Nevertheless, standard therapy with TMZ only increases survival for 2.5 months (Resende et al, 2018). This is probably due to the aggressiveness of recurrent tumors, the antitumoral drug resistance frequently observed (Raucher et al, 2018), and the often low selectivity of chemotherapeutics (Hagen et al, 2012), with frequent administrations (Farokhzad and Langer, 2006) leading to decreased patient compliance and increase in drug resistance (Yang et al, 2016). Hence, the design of new therapies against GBM that prolong survival or cure the disease are strongly needed.…”