Dendrimer Technology in Glioma: Functional Design and Potential Applications

Abstract

Novel therapeutic and diagnostic methods are sorely needed for gliomas, which contribute yearly to hundreds of thousands of cancer deaths worldwide. Despite the outpouring of research efforts and funding aimed at improving clinical outcomes for patients with glioma, the prognosis for high-grade glioma, and especially glioblastoma, remains dire. One of the greatest obstacles to improving treatment efficacy and destroying cancer cells is the safe delivery of chemotherapeutic drugs and biologics to the tumor site at a high enough dose to be effective. Over the past few decades, a burst of research has leveraged nanotechnology to overcome this obstacle. There has been a renewed interest in adapting previously understudied dendrimer nanocarriers for this task. Dendrimers are small, highly modifiable, branched structures featuring binding sites for a variety of drugs and ligands. Recent studies have demonstrated the potential for dendrimers and dendrimer conjugates to effectively shuttle therapeutic cargo to the correct tumor location, permeate the tumor, and promote apoptosis of tumor cells while minimizing systemic toxicity and damage to surrounding healthy brain tissue. This review provides a primer on the properties of dendrimers; outlines the mechanisms by which they can target delivery of substances to the site of brain pathology; and delves into current trends in the application of dendrimers to drug and gene delivery, and diagnostic imaging, in glioma. Finally, future directions for translating these in vitro and in vivo findings to the clinic are discussed.

Keywords: dendrimers; drug delivery; gene therapy; glioblastoma; glioma; imaging; nanotechnology.

Figure 1

Schematics of dendrimers with one, two, and three generations. Each generation creates new moieties for attachment of functional ligands and therapeutics.

Figure 2

Dendrimer modifications and therapeutic attachments. Drugs can be encapsulated within the inner core or attached to surface functional groups. Dendrimers can carry a range of cargo, including DNA, siRNA, antibodies, and drugs. Addition of polyethylene glycol can improve dendrimer “stealth” and bioavailability. Fluorescence markers can be attached for drug tracking. Ligands can be attached that target specific receptors on the surfaces of cells of interest, improving specificity and minimizing side-effects.

Figure 3

Dendrimers can enter the target tissue via several mechanisms, including receptor-mediated endocytosis, as depicted. Once inside, dendrimers can exert a variety of effects depending on their associated functional groups. Dendrimers can release chemotherapeutic drugs encapsulated within their core or conjugated to their surface to promote apoptosis of tumor cells. Alternative uses of dendrimers include release of genetic material. Release of siRNA can allow for selective degradation and inhibition of mRNA involved in tumor development, proliferation, and survival. Dendriplexes release DNA that travels to the nucleus and undergoes transcription and translation to produce proteins, a novel form of gene therapy.

Figure 4

Potential applications of dendrimers in the treatment and diagnosis of glioma. Dendrimers and dendrimer conjugates with functional and targeting moieties attached have been used to deliver chemotherapeutic drugs directly to the tumor site when delivered systemically or intratumorally. Dendrimer conjugates can also be used to deliver biologics, including DNA- and RNA-based agents, to tumor sites for the purposes of gene therapy. In addition, dendrimers can be used for imaging and diagnostic purposes, including as agents for MRI/PET/SPECT modalities. Other novel applications of dendrimers in glioma include organelle-specific targeting, antimicrobial activity, and immunotherapy.