CYCLOSERT™ TECHNOLOGY PLATFORM

The Cyclosert technology links drugs to linear, cyclodextrin-based polymers to generate macromolecular prodrugs.  Cyclodextrins are cyclical sugars that are highly water soluble but contain a hydrophobic cavity enabling the formation of complexes with insoluble molecules.  Functionalized cyclodextrins are biocompatible and non-immunogenic, resist degradation by human enzymes and are non-toxic, resulting in their use in many pharmaceutical formulations.  Preclinical and clinical studies show that Cyclosert retains all of these characteristics of cyclodextrin while providing unprecedented additional functionality:

• Increased solubility (approximately 1000-fold) without the need of toxic solubilizing agents such as Cremophor.
• Physiological stabilization and protection of active drug from enzymatic degradation.
• Linker library for drugs containing hydroxyls (primary, secondary, aliphatic, aromatic), sulfhydryls, amines, or carboxylic acids. 
• Innovative linker chemistries conferring plasma stability and disease / tissue specific release of the active drug through acid/base, oxido-reductive and enzymatic mechanisms. 
• Highly reproducible, proprietary self-assembly process resulting in sub-100 nm size nanoparticles with close to neutral surface charge.  This assembly is mediated by the presence of the drug on the polymer.
• After release of the drug, nanoparticles disassemble into single polymer strands, which are cleared from the body by excretion in the urine.

Nanoparticle drug advantages

Cyclosert nanoparticles are typically between 30 and 60 nm in diameter, avoiding rapid kidney clearance.  Their hydrophilic character and close to neutral surface charge allows them to evade uptake by macrophages, which do not recognize them as foreign entities.  Taken together this allows them to circulate for extended times in the blood stream.  A long circulation half-life leads to a preferential accumulation of Cyclosert nanoparticles in diseased tissues with abnormally leaky vasculature.  Unlike vessels in healthy tissue, blood vessels in tumors and other tissues with abnormal neovascularization, such as in autoinflammatory diseases have large openings that make them permeable to nanoparticles (EPR Effect ).  In mouse models, Cyclosert nanoparticles have been shown to preferentially accumulate in tumor tissue over time. 

PET study of Cu64 labeled IT-101 nanoparticles injected intravenously in mice bearing subcutaneous Neuro 2A tumors.  At 3 hours post injection (left), a high concentration of IT-101 remains in the blood stream, indicated by a high signal from the central chest cavity.  At 24 hours post injection, drug accumulation is seen in the tumor implanted in the left flank. 

Tumor accumulation combined with low levels of free circulating drug contribute to the improved safety and efficacy of the Cyclosert nanoparticles compared to the drug molecule alone.

Another advantage of Cyclosert nanoparticles is that they are taken up by cancer cells through a cellular process called endocytosis, leading to the intracellular accumulation of drug conjugates in vesicles called endosomes.  Intracellular release of cytotoxic drugs is especially useful for tumors which have developed resistance to chemotherapeutics by over-expression of surface pumps (such as P-Glycoprotein or multidrug resistance protein).  Bypassing these surface pumps resulted in enhanced antitumor activity of Cyclosert conjugates in preclinical models resistant to treatment with small molecule cancer drugs. 

Preclinical and Clinical Development

Calando has applied it’s expertise in polymer chemistry, chemical synthesis, and preclinical screening to generate Cyclosert conjugates of multiple compounds.  The lead compound IT-101, a conjugate with camptothecin, is currently undergoing clinical testing.  Data resulting from Calando’s preclinical as well as clinical research indicate that Cyclosert may offer the following advantages over traditional drugs:

• Non-toxic polymer carrier:  GLP toxicology studies in rats and dogs did not show any significant toxicity caused by the polymer alone.  Animal studies show that after release of its payload the polymer is mostly excreted in the urine.
• Significant improvement in therapeutic index compared to the active molecule alone.  This may result in improved quality of life and better efficacy due to on-time administration with fewer dose reductions or limitations on the optimal number of therapy cycles.
• Prolonged plasma half-life of polymer conjugates compared to small molecules.  This may benefit drugs that rely on a cell-cycle specific mechanism of action or that have reversible interactions with their cellular target.
• Dose-linear pharmacokinetics (AUC, cmax) for polymer prodrug and free drug in animals and humans.  This allows for more predictable dose and schedule finding studies in clinical development.