Anionic Amino Acid Dendrimer−Trastuzumab Conjugates for Specific Internalization in HER2-Positive Cancer Cells

Abstract

Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2), offers a promising strategy of anticancer drug targeting to HER2-expressing cancer cells. Conjugation of trastuzumab to dendrimers, repeatedly branched polymers with a highly functionalized surface, can enhance the drug loading capacity. However, typical dendrimers such as cationic polyamidoamine dendrimers have exhibited a nonspecific cytotoxicity. In the present study, we developed a novel biocompatible amino acid dendrimer with potentially less toxicity by surface modification of the sixth generation lysine dendrimer with glutamate (KG6E). The synthesized KG6E showed a well-controlled particle size around 5-6 nm with low polydispersibility and negative surface potentials for negligible cytotoxicity. Next, the targeting efficiency of the fluorescent-labeled KG6E-trastuzumab conjugate was evaluated in HER2-positive (SKBR3) and -negative (MCF7) human breast cancer cell lines compared to free trastuzumab and KG6E dendrimers. The KG6E-trastuzumab conjugate was specifically bound to SKBR3 cells in a dose-dependent manner with low binding affinity to MCF7 cells. Furthermore, the conjugate was significantly internalized in SKBR3 cells and then trafficked to lysosomes. These results indicate the potential of KG6E-trastuzumab conjugates as HER2-targeting carriers for therapeutic and diagnostic approaches to cancer therapy.

Novel water soluble dendrimer nanocarrier for enhanced photodynamic efficacy of protoporphyrin IX

“…Biocompatibility of the most PAMAM, Poly(lysine) dendrimers with cytotoxic (cationic) surface charged groups are improved to anionic surface with the aid of PEGylation, anionic amino acid such as glutamate over their cationic surface functionalities [22][23][24]. Despite successful talk on drug encapsulation and the biocompatibility of dendrimers, the fate of dendrimer is to readily degrade from the body as a non-toxic product after its administration [25].…”

Dendrimers and miktoarm polymers based multivalent nanocarriers for efficient and targeted drug delivery

“…folic acid (FA), 72,158,159,204,213,214 biotin, 177,215 or macromolecules, for example, cell penetrating peptides, [216][217][218] or antibodies. 151,219,220 FA has affinity towards receptors expressed on tumors. FA-bound dendrimer-drug conjugates largely accumulated in the tumor cells, as compared to the free drug, 217,221 or the dendrimer-drug conjugates without a targeting agent.…”

Glycosylation-mediated targeting of carriers

“…So far, galactose, mannose, fucose, mannose-6-phosphate, sialyl Lewis x, peptides, and proteins (i.e., transferrin, epidermal growth factor, and anti-human epidermal growth factor receptor 2 antibodies) have been used as ligands [3][4][5][6][7][8][9][10]. Among the various ligands reported, sugar recognition mechanisms are a promising approach for active targeting because of their high affinity and expression.…”