The Dendrimer SEALs: Infiltrate, Search and Destroy

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Science Translational Medicine  17 Apr 2013:
Vol. 5, Issue 181, pp. 181ec64
DOI: 10.1126/scitranslmed.3006315

A biomaterial that can reach a specific location, selectively target diseased cells while sparing healthy ones, display extended circulation time, and metamorphose when internalized into cells to enable efficient cargo release: Is this science fiction or are we already there? Medina et al. show that dendrimer-based materials can be decorated with multiple bioactive molecules and do it all: selectively target liver cancer cells, maintain the function of healthy cells, and release their cargo locally and in a controlled fashion.

Systemic cancer therapy is suboptimal as a life-saving treatment. This deficiency is the result of nonspecific high dosing that results in extremely deleterious side effects. Local therapy can prevent systemic toxicity while enabling effective and confined concentration and retention of the therapeutic agent. However, the means by which to attain ideal release kinetics, targeting, and penetration remain elusive. A range of materials and active molecules has been used to achieve targeting, enhanced circulation time, and selectivity. However, there has been no single material that has achieved all of these objectives.

Dendrimers are a family of materials characterized by a distinct chemical tree-like branching architecture, with a large number of amine groups that can immobilize agents. The authors use several interesting strategies that combined dendrimers with chemotherapeutic drugs in order to deliver a large dose of chemotherapeutic agent selectively into the cytoplasm of hepatic cancer cells while escaping recognition and internalization by hepatic macrophages and avoiding neighboring normal hepatocytes. Particle uptake and selectivity were examined in vitro by using healthy or malignant human hepatic cells, in the presence of liver macrophages, followed by in vivo examination of particles’ efficacy in a mouse model of liver cancer. Covalent coupling of N-acetyl-galactosamine to dendrimers proved to selectively bind to the asialoglycoprotein receptor expressed on the surface of liver cancer cells, thus allowing selective targeting of malignant cells. In addition, suppression of nonspecific protein adsorption—achieved by the neutralization of the dendritic primary amine charge by acetylation—was evident by the extent of in vitro bovine serum albumin binding. This led to an in vivo reduction of particle clearance and minimized nonspecific distribution to the liver, kidneys, and spleen. PEGylation using polyethylene glycol (PEG) conjugation prevented particle opsonization—that is, protein adsorption—and hence phagocytosis by macrophages. However, PEGylation also reduced cellular uptake and inhibited endosomal escape, thus decreasing delivery efficiency. The authors elegantly bypassed this obstacle by using a degradable linkage between the PEG moiety and the dendrimer, which protected the material from opsonization while circulating. Once in acidic endosomes of cancer cells, the PEG moiety was shed, enabling enhanced cargo release intracellularly.

We are at the advent of targeted rather than systemic treatment of cancers. As shown by Medina et al., combining state-of-the-art material design with targeted therapeutics into one platform can result in intelligent therapies that are more effective in combatting multiple types of cancer with minimal toxic side effects. The described principles are sound and can be rapidly moved from bench to bedside to allow a new and improved toolbox for treating cancer.

S. H. Medina et al., Targeting hepatic cancer cells with PEGylated Dendrimers Displaying N-acetylgalactosamine and SP94 peptide ligands. Adv. Healthcare Mater., published online 3 April 2013 (10.1002/adhm.201200406). [Abstract]

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