Nanoparticles: the Trojan Horse of Cancer Treatment

Triskelis Therapeutics S.r.l. made its exhibition debut at this year’s CPHI in Milan, and, along with it, presented their innovative products, aimed at revolutionizing cancer treatment. Made up by a group of sixty-year-old managers, with other 40 years of experience each in various Pharma fields, this start-up is focusing its efforts and research on the discovery and development of innovative technologies to be applied in the field of oncology. The company has identified two platforms for the development of innovative products which utilize nanoparticles: the first one based on the use of human ferritin nanoparticles associated with toxins, to target and eliminate cancer cells, minimizing damage to healthy tissues as much as possible. The same platform can be used for the delivery of oncological diagnostics but also drugs intended for other therapeutic areas. The second platform uses new generation nanoparticles as a vehicle for both lipophilic and hydrophilic chemotherapies towards cancer cells. This new platform is the result of the most advanced research in the sector and will allow the possibility to offer safer and more effective treatments to doctors and patients.

Before delving more into this new type of technology, it is important to have an overall understanding of what nanoparticles are and how they work in order to better grasp this innovative concept and the nanoparticles’ role in it: 

Nanoparticles are ultrafine particles with dimensions ranging from 1 to 100 nanometers. Due to their small size, they exhibit unique physical and chemical properties that differ significantly from their bulk counterparts. These properties include increased surface area, enhanced reactivity, and the ability to penetrate biological barriers and they offer innovative solutions for cancer diagnosis, treatment, and prevention. Nanoparticles can be engineered to deliver therapeutic agents directly to tumor sites, minimizing damage to healthy tissues. This targeted delivery is primarily achieved through two mechanisms:

Passive Targeting: This relies on the enhanced permeability and retention (EPR) effect, where nanoparticles accumulate in tumor tissues due to their leaky vasculature. Tumors often have poorly formed blood vessels that allow nanoparticles to enter while preventing their exit.

Active Targeting: This involves modifying the surface of nanoparticles with ligands (such as antibodies or peptides) that specifically bind to receptors overexpressed on cancer cells. This approach enhances the selectivity of drug delivery, ensuring that therapeutic agents are released primarily at the tumor site.

Nanoparticles are utilized in various therapeutic modalities, including chemotherapy, radiotherapy, immunotherapy, and gene therapy.

Chemotherapy: Traditional chemotherapy often leads to systemic toxicity and resistance. Nanoparticle-based drug delivery systems can encapsulate chemotherapeutic agents, improving their solubility and stability.

Radiotherapy: Nanoparticles can enhance the effectiveness of radiotherapy by acting as radiosensitizers. They can absorb radiation and release it in a controlled manner, increasing the dose delivered to cancer cells while protecting surrounding healthy tissue..

Immunotherapy: Nanoparticles can also serve as adjuvants in cancer vaccines, enhancing the immune response against tumors. They can deliver tumor antigens and immune-stimulating agents, activating dendritic cells and promoting a robust anti-tumor immune response.

Gene Therapy: Nanoparticles facilitate the delivery of genetic material into cancer cells, allowing for targeted gene editing or the introduction of therapeutic genes. This approach holds potential for treating genetic mutations associated with various cancers.

The use of nanoparticles in oncology offers several advantages:

Increased Efficacy: By targeting cancer cells more effectively, nanoparticles can enhance the therapeutic index of drugs, leading to better treatment outcomes.

Reduced Toxicity: Targeted delivery minimizes exposure of healthy tissues to toxic agents, reducing side effects and improving patient quality of life.

Overcoming Drug Resistance: Nanoparticles can be designed to bypass mechanisms of drug resistance, making previously ineffective therapies viable options.

Multimodal Treatment: Nanoparticles can be engineered to carry multiple therapeutic agents, allowing for combination therapies that can attack tumors through different mechanisms simultaneously.

Despite their potential, the use of nanoparticles in oncology faces several challenges:

Safety and Toxicity: The long-term effects of nanoparticles in the body are not fully understood. Concerns about their biocompatibility and potential toxicity must be addressed through rigorous testing.

Manufacturing and Scalability: Producing nanoparticles consistently and at scale remains a challenge. Variability in size, shape, and surface properties can affect their performance and safety.

Regulatory Hurdles: The approval process for nanoparticle-based therapies can be complex, requiring extensive preclinical and clinical data to demonstrate safety and efficacy.

Cost: Developing and manufacturing nanoparticle-based therapies can be expensive, potentially limiting their accessibility to patients.

Regarding H-Ferritin, cancer cells exhibit an enhanced dependence on iron for growth and are dramatically more susceptible to iron depletion than non-cancer cells. Transferrin receptors (TfR) represent a membrane glycoprotein, (a molecule that includes protein and carbohydrate chains which, among others, is involved with the immune system), that has the ability to acquire iron by binding itself to another glycoprotein present in plasma, known as transferrin. TfR1 has been found to be abnormally expressed in various cancers. Engineered Human Heavy-Chain Ferritin (HFn) nanocarrier is emerging as a promising platform for tumor therapy, able to specifically target tumor cells by interaction with transferrin receptor 1 (TfR1), by binding itself to it. Without any ligand functionalization, HFn is able to specifically transport antitumor agents within cancer cells through TfR1-mediated targeting and the following receptor-mediated endocytosis. 

H-Ferratin Nanocages would basically function as a nano drug delivery system. This new platform has many appealing attributes to its functionality and creation: HFn can be “easily” produced as a recombinant protein in E.Coli and it has low immunogenicity since it is produced starting from human cNDA of H-ferritin; it provides thermal and chemical stability, as well as having high stability in biological fluids due to its protein nature.  This last points also leads to alternative active targeting moieties achieved by chemical functionalization or by protein engineering. The size of the nanoparticle cavity is certain and this allow you to calculate, exactly, how many anticancer drug molecules can be inserted and, furthermore, they are easily loadable with drugs exploiting a high concentration of drug content. Being that natural tumors overexpress ferritin receptors, this leads to a natural accumulation of these last on their membrane, making it easier for the ferratin to bypass natural barriers. Moreover, H-Ferratin nanocages give the possibility to overcome Multi Drug Resistance mechanisms, as well as being able to cross Blood-Brain barriers. 

Through various trials and experiments, Triskelis was able to produce compelling evidence of the safety and efficiency of engineered Human Heavy-chain Ferritin (HFn)-based exploited products for cancer treatment and diagnosis. To support this evidence, we can report that in terms of the production of H-Ferritin, low lipopolysaccharide (LPS) E. coli strain to produce human ferritin was successfully generated; low LPS strain was successfully cultivated in fermenter conditions; Human ferritin was successfully purified and LPS was successfully reduced below specifications = 200 EU/mL. both upstream and purification procedures has been effectively conducted, proving the efficiency of this new method of encapsulation and delivery. 

In regards to Glycopma, the second polymeric nanoplatform, the basic principle (GlycoNP) lies in a specific functionalization of a multidentate polymeric structure, poly [isobutene-alt-maleic anhydride] (PMA). This polymer and its branched derivatives, using dodecylamine or similar, are self-assembled in aqueous solution to form well-structured nanoparticles with intrinsic properties useful for drug delivery and nanomedicine. Glycopma has several main features, such as an excellent degree of biocompatibility both in vitro and in vivo, simple and tunable functionalization of the polymer for targeted purposes, excellent colloidal stability, ability to cross the blood-brain barrier and pH-dependent surface charge reversal, capable of actively promoting the exit from endosomes and the release of drugs into the cytosol. GlycoNP were tested to evaluate biodistribution in a subcutaneous human NSG TNBC mouse model (MDA-MB-231 cells), demonstrating spontaneous tropism, selectively accumulating to the tumor and rapidly eliminating excess nanoparticles through the liver. Isolation of cells from tumor extracts revealed that nanoparticles entered the cells and the related fluorescent signal was identified within the cell’s cytoplasm. 

Conclusion

Nanoparticles are undeniably an innovative new form of technology that deserve to be researched and explored. They have much undiscovered potential that could be essential in discovering new types of therapies. By extent, Human Ferritin Nanoparticles and Glycopma are the first step in what is sure to be a revolutionary new approach to cancer treatment and diagnosis; a creative solution that allows for a more targeted and controlled treatment of tumors. Should be interested in gaining more information on this topic or have any questions, please feel free to contact Triskelis at the following email addresses and they will be happy to get back to you with all the information you might need: info@triskelis.it and acolombo@triskelis.it