Microscopic Cubes Safely Deliver Toxic Drugs to Cancer Cells
By LabMedica International staff writers
Posted on 11 Jul 2017
Microscopic hydrogel cubes have proven to be an effective system for the delivery of toxic chemotherapeutic agents to cancer cells growing in culture.Posted on 11 Jul 2017
Many potent anticancer drugs are hydrophobic and lack tumor selectivity, which limits their application in cancer therapy. Although cubical hydrogels of poly(methacrylic acid) have been shown to exhibit excellent biocompatibility and versatility, they have not been investigated for hydrophobic drug delivery due to poor mechanical stability and incompatibility between hydrophobic drugs and a hydrophilic hydrogel network.
Image: Researchers have developed micro-cubes that can sponge up a hydrophobic anti-cancer drug and safely deliver it to cancer cells. Tissue culture tests show these tiny, porous cubes are more potent against liver cancer cells and less harmful to normal liver cells, compared to the drug alone (Photo courtesy of the University of Alabama).
To overcome these limitations, investigators at the University of Alabama (Birmingham, USA) and Texas Tech University (Lubbock, USA) developed a method for preparing a multilayer hydrogel-based platform with controlled nanostructure, cubical shape, and redox-responsiveness for delivery of highly potent anticancer therapeutics such as the hydrophobic drug BA-TPQ (7-(benzylamino)-3,4-dihydro-pyrrolo[4,3,2-de]quinolin-8(1H)-one). BA-TPQ is an iminoquinone derivative and one of the most potent analogs of natural anti-cancer compounds discovered in the Philippine sponge Zyzzya fuliginosa. This drug demonstrates high potency against human breast and prostate cancer cell lines, but its use has been limited by poor solubility, low bioavailability, and undesirable toxicity.
The investigators prepared two-micrometer hydrogel cubes from layers of nontoxic cross-linked poly(methacrylic acid) formed on a removable porous scaffold. The BA-TPQ drug was absorbed into the cubes, which were then reduced to a powder by freeze-drying (lyophilization).
The investigators reported in the June 3, 2017, online edition of the journal Acta Biomaterialia that the BA-TPQ-loaded hydrogels maintained their cubical shape and pH-sensitivity after lyophilization, which would be advantageous for long-term storage. Conversely, the particles degraded in vitro in the presence of five-millimolar glutathione providing 80% drug release within 24 hours. Encapsulating BA-TPQ into hydrogels significantly increased its transport via Caco-2 cell monolayers used as a model for oral delivery where the apparent permeability of BA-TPQ-hydrogel cubes was approximately two-fold higher than that of BA-TPQ alone. BA-TPQ-hydrogel cubes exhibited better anticancer activity against HepG2 and Huh7 hepatoma cells compared to the non-encapsulated drug.
Surprisingly, normal liver cells had a lower sensitivity to BA-TPQ-hydrogel cubes compared to those of cancer cells. In addition, encapsulating BA-TPQ in the hydrogels amplified the potency of the drug via down-regulation of MDM2 (Mouse double minute 2 homolog) oncogenic protein and upregulation of p53 (a tumor suppressor) and p21 (cell proliferation suppressor) expression in HepG2 liver cancer cells.
The results obtained in this study led the investigators to say that, "We believe that our novel drug-delivery platform for the highly potent anti-cancer drug BA-TPQ provides a facile method for encapsulation of hydrophobic drugs and can facilitate enhanced efficacy for liver cancer therapy."
Related Links:
University of Alabama
Texas Tech University