Technology
CriPec® technology platform
An improved disposition resulting in higher concentrations at the target site.
Our CriPec® technology platform is a pioneering approach to transform the efficacy and side-effect profiles of therapeutic candidates by creating tailor-made nanoparticles.
The treatment of various diseases is often hampered by limited efficacy and serious toxicity symptoms as a result of an unfavourable distribution of the drug within the patient’s body.
We are leveraging the technologies in our proprietary CriPec® platform to enable the rational design of unique nanomedicines with superior therapeutic profiles. The highly tuneable polymers and biodegradable drug linkers in our CriPec® platform are combined with the therapeutic of interest to create customized nanomedicines. If active targeting is required then a targeting ligand can be added to further tune the nanomedicine.
CriPec® nanoparticle: rational design using proprietary processes
- Covalent attachment (derivatization) of a drug molecule with a linker.
- Tailor-made CriPec® polymer.
- Self-assembly of drug-linker with CriPec® polymer into polymeric micelles.
- Immediate crosslinking of both the CriPec® polymer and the drug-linker results in transiently stable nanoparticles.
- Optional covalent conjugation of ligands for active targeting and/or labels for imaging.
- Purification via a straightforward process.
Advantages of the CriPec® platform:
Size
Tailor made, uniform nanoparticle size between 30 to 100 nm (PDI< 0.2).
Broad applicability
CriPec®can be used with many different therapeutic modalities including small molecules, steroids, peptides, oligonucleotides as well as combinations thereof in an approach known as CriPec®-DUO. This approach has the potential to enable the generation of synergistic combination therapies that were previously not possible, or to overcome the shortcomings of current combination therapies, which can include disparate biodistribution, short half-life and high toxicity.
Prolonged circulation
The surface polyethylene glycol (PEG) stealth layer of the nanoparticle prevents its rapid elimination from the bloodstream and results in a really prolonged systemic circulation, thereby facilitating a higher accumulation at the diseased tissue.
Predictable behaviour
The biological behaviour of CriPec® nanomedicines is predictable as it is dependent on the conformation of the nanoparticle itself and not affected by the type of entrapped drug molecules.
Customized, tuneable drug release
The linkers that temporarily entrap the drug within the CriPec® nanoparticle determine the site and rate of release of the native drug molecule i.e. hours – days.
Importantly, drug release can be customized and it is driven by (purely) chemically-induced cleavage.
Release profiles in both in vitro and in vivo are anticipated to closely match due to the absence of enzymes in the process. With CriPec®-DUO, 2 different APIs with completely dissimilar release profiles can be generated with the aim of producing synergistic therapeutic effects.
Manufacturing
A straightforward cGMP manufacturing process generates excellent yield and high drug loading that is independent of the entrapped therapeutic type.
Conjugation of a compound to the surface involves a very efficient single synthesis step and purification is easily performed using tangential flow filtration.
The resulting nanoparticles can be sterilized by aseptic filtration.
Nanoparticles can be successfully scaled up to clinical batches whilst retaining all their pharmaceutical properties.
Administration
Excellent nanoparticle stability means that CriPec® nanomedicines can be administered intravenously and subcutaneously (s.c). Since the drug is conjugated to the nanoparticle, no local side effects are anticipated following s.c. injection.
Cellular targeting (optional)
CriPec® nanoparticles can be combined with targeting ligands such as antibodies, antibody fragments, peptides or other small molecular weight compounds.
Ligand selection is driven by the target tissue-type and cell characteristics. The goal is to achieve the highest specificity, selective binding and maximum cellular internalisation.
Labelling (optional)
Labels can be embedded in the nanaoparticle to enable (non-)invasive trafficking and monitoring through biological matrices
CriPec®-based nanomedicines
Applying the CriPec® platform results in nanomedicines with a superior therapeutic profile as compared to the native drug molecule due to:
A prolonged circulation.
A controlled release of the drug at the target site.
Delivery of 100-1000’s active molecules per nanoparticle to the target.
These properties have the potential to translate into a higher efficacy, lower off-target toxicity and an improved safety profile.
CriPec® nanoparticles mode of action – passive versus cellular targeting
CriPec® nanoparticles exhibits prolonged circulation in the blood stream, allowing them to passively target the diseased tissue of interest through the so-called enhanced permeability and retention (EPR) effect. It is hypothesized that the nanomedicine tends to accumulate in tumour or chronically inflamed tissue more readily than in normal tissue.
In the case of specifically targeted CriPec® nanoparticles, their targeting ligand directs the particle to the relevant cellular and intracellular molecular targets which:
- Further increases efficacy and lowers off-target toxicity.
- Increases selective tissue and cellular interaction.
- Enhances cellular internalisation, resulting in higher drug levels at the intracellular site of action.
Assessing the distribution of CriPec®-based nanomedicines in vivo
The biological fate of CriPec® based candidates can be tracked in vivo by directly combining an imaging agent, such as a fluorescent dye, a NIR label, and/or a PET radiotracer, to the CriPec® candidate.
Accumulation of CriPec® in antigen presenting cells
In vitro studies with rhodamine labelled CriPec® showed good uptake in antigen presenting cells like macrophages and dendritic cells. This opens up therapeutics opportunities in the immuno-oncology field.
Uptake of CriPec® in Raw Blue macrophages (A) and mouse dendritic cells (B).
© Cristal Therapeutics
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6229 EV Maastricht
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