How RONDEL™ Works
Advanced Materials Engineering Meets Molecular Therapeutics
The RONDEL system takes advantage of molecular forces that generate self-assembly of an siRNA containing nanoparticle therapeutic. DNA and RNA are linear, negatively charged molecules. Component one of RONDEL is a linear polymer in which positively charged groups alternate with sugar molecules (cyclodextrin). Upon mixing with siRNA, the positively charged polymer associates with the negatively charged backbone of siRNAs. Several polymer/siRNA complexes self-assemble into a nanoparticle of less than 100nm in diameter that fully protects the siRNA from degradation in serum. This size is key to the delivery of the siRNA payload to tumor cells.
Each cyclodextrin molecule in the chain contains a hydrophobic core. Components two and three of the system contain adamantane covalently bound to polyethylene glycol (PEG). Adamantane is highly water insoluble. In aqueous solution, the adamantane end of the complex associates with the hydrophobic cores in the cyclodextrin polymer while the hydrophilic PEG extends from the hydrophobic core. The result is a siRNA containing nanoparticle coated with PEG, which acts to stabilize the nanoparticle and prevent aggregation under physiological conditions. A variety of targeting molecules that selectively attach to specified cell surface receptors can be covalently attached to the adamantane-PEG modifier, enabling the siRNA-containing particles to be coated with targeting molecules that address the nanoparticle to the tissue of interest.
The siRNA delivery system has been designed for intravenous injection. Upon delivery to the target cell, the targeting molecules bind to membrane receptors on the cell surface and the RNA-containing nanoparticle is taken into the cell by endocytosis. There, chemistry built into the polymer unpacks the siRNA from the delivery vehicle. The siRNA enters the cytoplasm where it can interact with the RNAi machinery of the cell.
CALAA-01, Calando's leading drug candidate, is a combination of RONDEL and a patented siRNA targeting the M2 subunit of ribonucleotide reductase, a clinically-validated cancer target. Ribonucleotide reductase catalyzes the conversion of ribonucleosides to deoxyribonucleosides and is necessary for DNA synthesis and replication; it is a critical component in the proliferation of cancer cells. Calando's siRNA and CALAA-01 have demonstrated potent anti-proliferative activity across multiple types of cancer cells.
CALAA-01 uses transferrin, a blood plasma protein for iron delivery, as its targeting agent. Many types of cancer cells have been shown to over produce transferring receptors.