Catechol Polymers for pH-Responsive, Targeted Drug Delivery to Cancer Cells

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug–polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug–polymer conjugates. The pH-sensitive catechol–boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases

Coassembled Cytotoxic and Pegylated Peptide Amphiphiles Form Filamentous Nanostructures with Potent Antitumor Activity in Models of Breast Cancer

Self-assembled peptide amphiphiles (PAs) consisting of hydrophobic, hydvrogen-bonding, and charged hydrophilic domains form cylindrical nanofibers in physiological conditions and allow for the presentation of a high density of bioactive epitopes on the nanofiber surface. We report here on the use of PAs to form multifunctional nanostructures with tumoricidal activity. The combination of a cationic, membrane-lytic PA coassembled with a serum-protective, pegylated PA was shown to self-assemble into nanofibers. Addition of the pegylated PA to the nanostructure substantially limited degradation of the cytolytic PA by the protease trypsin, with an 8-fold increase in the amount of intact PA observed after digestion. At the same time, addition of up to 50% pegylated PA to the nanofibers did not decrease the <i>in vitro</i> cytotoxicity of the cytolytic PA. Using a fluorescent tag covalently attached to PA nanofibers we were able to track the biodistribution in plasma and tissues of tumor-bearing mice over time after intraperitoneal administration of the nanoscale filaments. Using an orthotopic mouse xenograft model of breast cancer, systemic administration of the cytotoxic pegylated nanostructures significantly reduced tumor cell proliferation and overall tumor growth, demonstrating the potential of multifunctional PA nanostructures as versatile cancer therapeutics

Photoexpulsion of Surface-Grafted Ruthenium Complexes and Subsequent Release of Cytotoxic Cargos to Cancer Cells from Mesoporous Silica Nanoparticles

Ruthenium­(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium­(II) dipyridophenazine (dppz) complexes. This hybrid nanomaterial displays enhanced luminescent properties relative to that of the ruthenium­(II) dppz complex in a homogeneous phase. Since the coordination between the ruthenium­(II) complex and a monodentate ligand linked covalently to the nanoparticles can be cleaved under irradiation with visible light, the ruthenium complex can be released from the surface of the nanoparticles by selective substitution of this ligand with a water molecule. Indeed, the modified MSNPs undergo rapid cellular uptake, and after activation with light, the release of an aqua ruthenium­(II) complex is observed. We have delivered, in combination, the ruthenium­(II) complex and paclitaxel, loaded in the mesoporous structure, to breast cancer cells. This hybrid material represents a promising candidate as one of the so-called theranostic agents that possess both diagnostic and therapeutic functions

Photoexpulsion of Surface-Grafted Ruthenium Complexes and Subsequent Release of Cytotoxic Cargos to Cancer Cells from Mesoporous Silica Nanoparticles

Ruthenium­(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium­(II) dipyridophenazine (dppz) complexes. This hybrid nanomaterial displays enhanced luminescent properties relative to that of the ruthenium­(II) dppz complex in a homogeneous phase. Since the coordination between the ruthenium­(II) complex and a monodentate ligand linked covalently to the nanoparticles can be cleaved under irradiation with visible light, the ruthenium complex can be released from the surface of the nanoparticles by selective substitution of this ligand with a water molecule. Indeed, the modified MSNPs undergo rapid cellular uptake, and after activation with light, the release of an aqua ruthenium­(II) complex is observed. We have delivered, in combination, the ruthenium­(II) complex and paclitaxel, loaded in the mesoporous structure, to breast cancer cells. This hybrid material represents a promising candidate as one of the so-called theranostic agents that possess both diagnostic and therapeutic functions

Photoexpulsion of Surface-Grafted Ruthenium Complexes and Subsequent Release of Cytotoxic Cargos to Cancer Cells from Mesoporous Silica Nanoparticles

Ruthenium­(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium­(II) dipyridophenazine (dppz) complexes. This hybrid nanomaterial displays enhanced luminescent properties relative to that of the ruthenium­(II) dppz complex in a homogeneous phase. Since the coordination between the ruthenium­(II) complex and a monodentate ligand linked covalently to the nanoparticles can be cleaved under irradiation with visible light, the ruthenium complex can be released from the surface of the nanoparticles by selective substitution of this ligand with a water molecule. Indeed, the modified MSNPs undergo rapid cellular uptake, and after activation with light, the release of an aqua ruthenium­(II) complex is observed. We have delivered, in combination, the ruthenium­(II) complex and paclitaxel, loaded in the mesoporous structure, to breast cancer cells. This hybrid material represents a promising candidate as one of the so-called theranostic agents that possess both diagnostic and therapeutic functions