Improving Drug Potency and Efficacy by Nanocarrier-Mediated Subcellular Targeting

Polymeric micelles containing a chemotherapeutic drug carry it adjacent to the DNA target in tumor cells, enhancing the drug potency. Special Delivery to the Nucleus Micelles are useful in the washing machine, where they self-assemble from soaps, trap grease inside, and carry it away. These spheres, formed by linear molecules with hydrophobic tails that cluster in the core and hydrophilic heads sticking out, can carry cargo other than dirt. Micelles self-assembled in the presence of a chemotherapeutic drug can ensnare and carry it to tumors, where they are ingested by cells. By creating micelles that disperse in specific environment within the late endosome and lysosome, a region of the cell near the nucleus, Murakami et al. force these soapy spheres to release their deadly cargo—in this case a platinum-based drug called DACHPt [(1,2-diaminocyclohexane) platinum(II)]—right in the neighborhood of its target: DNA. This direct assault on the genome proves to be an effective antitumor strategy: Tumor cells growing in mice succumb more readily to a micelle-delivered derivative of platinum than they do to free drug. The authors’ micelle carriers are carefully assembled from block copolymers with properties suited to their task. A poly(ethylene glycol) polymer is linked to a string of glutamic acids, with a boron dipyrromethene at each end. By attaching fluorescent tags of different colors to the ends, the authors endowed their micelles with the ability to signal to an observer whether they are intact. When all the poly(glutamic acid) segments were clustered in the core, their red fluorescence was quenched and only the green surface dye on the poly(ethylene glycol) was visible. Once the micelle encountered specific conditions in the late endosome and lysosome, the core dispersed, releasing the drug and dequenching the red dye. By taking advantage of these visible markers of the micelle state, the authors showed by time-lapse confocal laser scanning microscopy that the micelles were taken up into tumor cells by endocytosis and that they traveled to the late endosomal/lysosomal compartment, where the micelles dispersed and the drug was released. This color-coded behavior was apparent both in cultured tumor cells and in tumor cells growing subcutaneously in mice, which the authors monitored in the animals, also by confocal laser scanning microscopy. But does the direct delivery of DACHPt to the nuclear area improve its effectiveness? A comparison of free DACHPt to the micelle-carried drug shows that it can help with one serious problem of cancer therapeutics—tumors that become drug-resistant. After repeated exposure to DACHPt, tumor cells develop defensive proteins, such as metallothionein and methionine synthase, in their cytoplasm that inactivate the drug, protecting the tumor cell DNA from damage. Tumors that have become resistant to DACHPt grow well in the presence of the drug, but the micelle-delivered version effectively inhibited the tumors’ growth, most likely by bypassing the cells’ cytoplasmic defenses. Therefore, with appropriate chemical modifications, micelles can be used to carry medicinal cargo right where it is needed. Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.