<p>PAMAM Dendrimer Nanomolecules Utilized as Drug Delivery Systems for Potential Treatment of Glioblastoma: A Systematic Review</p>

Abstract

Glioblastoma (GB) is a grade IV astrocytoma that maintains a poor prognosis with respect to current treatment options. Despite major advancements in the fields of surgery and chemoradiotherapy over the last few decades, the life expectancy for someone with glioblastoma remains virtually unchanged and warrants a new approach for treatment. Poly(amidoamine) (PAMAM) dendrimers are a type of nanomolecule that ranges in size (between 1 and 100 nm) and shape and can offer a new viable solution for the treatment of intracranial tumors, including glioblastoma. Their ability to deliver a variety of therapeutic cargo and penetrate the blood-brain barrier (BBB), while preserving low cytotoxicity, make them a favorable candidate for further investigation into the treatment of glioblastoma. Here, we present a systematic review of the current advancements in PAMAM dendrimer technology, including the wide spectrum of dendrimer generations formulated, surface modifications, core modifications, and conjugations developed thus far to enhance tumor specificity and tumor penetration for treatment of glioblastoma. Furthermore, we highlight the extensive variety of therapeutics capable of delivery by PAMAM dendrimers for the treatment of glioblastoma, including cytokines, peptides, drugs, siRNAs, miRNAs, and organic polyphenols. While there have been prolific results stemming from aggressive research into the field of dendrimer technology, there remains a nearly inexhaustible amount of questions that remain unanswered. Nevertheless, this technology is rapidly developing and is nearing the cusp of use for aggressive tumor treatment. To that end, we further highlight future prospects in focus as researchers continue developing more optimal vehicles for the delivery of therapeutic cargo.

Smart Nanoparticles in Biomedicine: An Overview of Recent Developments and Applications

“…In this contest, they are amply used in the treatment of infectious diseases like malaria, leishmaniasis, schistosomiasis, toxoplasmosis, HIV, meningitis, hepatitis, herpes and especially in tumour therapy [168]- [170] (Table 1). Easy surface and core modifications with DNA, siRNA, plasmids, peptides, antibodies or drugs make them optimal candidates for drug delivery, especially for brain tumours like glioma, because they can cross the blood-brain barrier (BBB) and deliver biological molecules in a controlled way like proposed by Lu et al They had formulated PAMAM dendrimers conjugated with PEG, Arg-Gly-Asp (RGD) tripeptide for the tumour targeting and to the anticancer drug arsenic trioxide (ATO): the use of dendrimer vector permits to the dug to cross the BBB and enhance its antitumor effect glioma [171], [172]. The capability to incorporate many biological molecules and the ramified structure are optimal tissue engineering applications [173].…”

Dendrimers as Modulators of Brain Cells

“…Dendrimers can be constructed by divergent and convergent methodologies, pioneered by Tomalia and Frechét, in which the hyperbranched structure is either built from the core, in a layer-by-layer fashion, or through attaching dendrons to a central core [ 70 , 71 ]. Some well-known dendrimers include poly(amidoamine) (PAMAM), poly(propylene imine) (PPI), phosphorus, and bis-MPA-based dendrimers [ 72 , 73 , 74 , 75 ]. Dendrimers are classified by their generation, which is defined as the number of branched layers from a central core, such as G0, G1, G2 ( Figure 2 ).…”

“…Both endothelial cells and glioma cells express abundant receptors on their surface membrane, which facilitate transcytosis or endocytosis pathways. These receptors can be selectively targeted by the nano delivery systems conjugated to corresponding ligands, such as peptides, folate and carbohydrates [ 72 ]. Hence, different modes of BBB penetration and tumor cell uptake can be achieved by such targeted nanoparticles for drug delivery ( Figure 3 ).…”

Aging process of polyamidoamine dendrimers: Effect of pH and shaking in the fluorescence emission and aggregation‐state

“…In the 80s, Tomalia first synthesized dendrimers from an ethylenediamine core with polyamidoamine (PAMAM) branches, which converted in the most used up to date. Since that moment, PAMAM dendrimers emerged in the multiple fields of application of nanotechnology, especially as promising drug delivery systems [1][2][3][4][5][6], but also as a nanodrugs per se for their antibacterial, anti-prion, anti-viral, anti-coagulant, anti-oxidant, anti-inflammatory, and anti-aggregation proteins properties [7][8][9][10].…”