Nanoparticle Design and Development
The ability to optimize drug loading, particle size, particle components, conjugation linker chemistry and formulation process leads to tailored nanoparticles that have superior biological properties compared to the free drug they contain. The physical-chemical properties of the nanoparticle, such as surface charge and surface composition, affect the distribution of the particle in the body and are used to passively target the nanoparticle into target tissues. The composition and linker chemistry are chosen to optimize the release of the free drug, achieving a much improved pharmacokinetic profile and reducing systemic exposure. During the design of the nanoparticle, scale-up and manufacturing are considered, ensuring the production of nanoparticle populations of consistent physical characteristics at scale.

Cerulean has access to two complementary technologies within its nanoparticle platform. Both of these technologies provide for the formation of stable and consistent nanoparticles comprised of biocompatible components, which have high drug loading capacity, and are able to release active drug in a controlled fashion.

The Polymeric Nanoparticle Technology (PNP) allows for nanoparticle customization through conjugation chemistry, particle composition, formulation, and fine-tuning of nanoparticle size. This technology has produced product candidates with compelling pre-clinical validation.

The Cyclodextrin Nanoparticle Technology (CDP) produces self-assembled nanoparticles of a defined size range. The most advanced product (IT-101) from this technology is presently in Phase 1b/2a clinical development. This technology has been applied to several classes of molecules.

Biological Impact

When the Cerulean nanoparticles are administered in the bloodstream, they maintain their integrity in circulation, minimizing non-specific systemic drug dissemination and clearance. The size and surface properties of the nanoparticles favor extravasation through leaky vasculature, followed by deep penetration and retention at the tumor site. The physical properties of the nanoparticles facilitate endocytic intracellular uptake and help to avoid multi-drug resistance as the nanoparticles are not substrates of multi-drug transporters. The polymer-drug conjugation chemistry provides for controlled and sustained drug release, maximizing drug exposure to tumor target cells. The nanoparticles are made of biocompatible building blocks that allow for safe administration and excretion.

Our nanoparticles produce significant and prolonged tumor growth delay and improved tolerability compared to free drug in multiple mouse cancer models. Favorable drug distribution supports enhanced nanoparticle localization to the tumor and the improved pharmacokinetic profile demonstrate the advantages provided by the nanoparticles such as sustained release and shielding of the active drug.

Below is an example of nanoparticles produced with Cerulean’s PNP technology penetrating into tumor tissue far from blood vessels co-localizing with endosomes and demonstrating that these nanoparticles enter tumor cells as intact nanoparticles.

CRLX228, Cerulean’s preclinical lead candidate from the PNP technology contains a widely used oncology drug and is presently progressing into IND enabling studies. CRLX288 shows substantial efficacy and safety improvement over parent drug in validated pre-clinical models and offers the potential to dramatically improve the therapeutic index of the parent drug.

Profound Clinical Outcome

These highly optimized Cerulean nanoparticles produce a profound clinical outcome by allowing for high and sustained therapeutic drug levels at the target tissue and, in this way, maximizing therapeutic effects. The nanoparticles are active in drug-resistant diseases, are well tolerated, and enable full-course therapy with minimal toxicities. Because of these attributes, Cerulean's nanoparticles are highly compatible agents for combination therapies and provide for more effective disease management.

IT-101, Cerulean's lead product from the CDP technology (a nanoparticle containing a highly potent topoisomerase 1 inhibitor, camptothecin) is advancing in Phase 1 and is expected to begin testing in Phase 2 studies in 2010. This nanoparticle has shown enhanced localization of drug in tumor and superior activity in 10 xengraft mouse models spanning 7 cancer types. To date, it has also demonstrated promising safety and pharmacokinetic data in humans. IT-101 has the opportunity to address large unmet medical needs in difficult- to-treat tumor types.