Technology
CriPec® technology platform
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 customised nanomedicines. If active targeting is required then a targeting ligand can be added to further tune the nanomedicine.
Tailor made, uniform nanoparticle size between 30 to 100 nm (PDI< 0.2).
CriPec®can be used with many different therapeutic modalities including small molecules, steroids, peptides, oligonucleotides and combinations thereof. 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.
The surface polyethylene glycol (PEG) stealth layer of the nanoparticle prevents its rapid elimination from the bloodstream and results in substantially prolonged systemic circulation, thereby facilitating a higher accumulation at the diseased tissue.
The biological behaviour of CriPec® nanomedicines is predictable as it is dependent on the conformation of the nanoparticle itself and not affected by the entrapped drug molecules.
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 customised and it is driven by (purely) chemically-induced cleavage.
Release profiles in vitro and in vivo are anticipated to match closely, due to the absence of enzymes in the process.
Using CriPec®-DUO, two different active pharmaceutical ingredients with completely dissimilar release profiles can be generated, with the aim of producing synergistic therapeutic effects.
A straightforward cGMP manufacturing process generates excellent yield and high drug loading that is independent of the entrapped therapeutic.
Conjugation of a compound to the surface involves a very efficient single-step synthesis, and purification is easily performed using tangential flow filtration.
The resulting nanoparticles can be sterilised by aseptic filtration.
Nanoparticles can be successfully scaled up to clinical batches whilst retaining all their pharmaceutical properties.
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.
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.
Labels can be embedded in the nanoparticle to enable (non-)invasive trafficking and monitoring through biological matrices
Applying the CriPec® platform results in nanomedicines with a superior therapeutic profile as compared to the native drug molecule due to:
An improved disposition resulting in higher concentrations at the target site.
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 exhibit 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 hypothesised that the nanomedicine tends to accumulate in the tumour or chronically inflamed tissue more readily than in normal tissue. This has been validated in the clinic by our lead candidate CPC634, where a 4-fold increase in tumour accumulation was observed compared to free docetaxel.
In the case of specifically targeted CriPec® nanoparticles, their targeting ligand directs the particle to the relevant cellular and intracellular molecular targets which:
The biological fate of CriPec®-based candidates can be tracked in vivo by directly combining an imaging agent, such as a fluorescent dye, NIR label, and/or PET radiotracer, to the CriPec® candidate.
CPC205, the radiolabelled derivative of CPC634 (89Zr-CPC634), is used in combination with PET imaging as a tool to examine drug distribution across the body. This technique can also be used to non-invasively measure the uptake of CPC634 by a tumour, to determine whether the nanomedicine is a suitable targeted treatment option for an individual patient. Radiolabelled derivatives therefore have the potential to be utilised in developing CriPec® companion diagnostics.
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).
CriPec®-oligonucleotides are CriPec®-based nanoparticles incorporating therapeutic oligonucleotides such as siRNA and antisense RNA, which are able to regulate the expression of genes.
CriPec®-oligonucleotides are designed to overcome the major shortcomings of current oligonucleotide therapies, including poor biodistribution, ineffective tissue targeting and inappropriate cellular processing, which result from endosomal uptake and subsequent lysosomal degradation. CriPec®-oligonucleotides aim to selectively and effectively target the correct subcellular compartment in the diseased tissue.
Accumulation of CriPec®-siRNA in a human prostate cancer (PC3) cell model in vitro. Confocal imaging shows presence of CriPec® (A) and siRNA (B) in the cells.
siRNA levels in blood (A) and tumour tissue (B) upon intravenous injection in the PC3 in vivo model.