2020-07-015 - SMARTY - SMARTY: A nanodelivery tool for the clinical administration of miRNAs

SMARTY

2020-07-015

Quatsomes (QS): Engineered non-liposomal nanovesicles for in vivo nucleic acid delivery. Develop an optimal QS formulation to use them as an enabling technology for the application of RNA-based therapies against cancer

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Consequently, the potential of this innovative nanomedicine for the treatment of neuroblastoma tumors is not only at the scientific-technological level but also has significant societal impact. First, it has the potential to establish a new class of personalized therapies for pediatric cancer patients through RNA-based treatments tailored to their unique needs, genetics and tumor characteristics, as RNA therapies currently require a reference formulation to be effectively administered. In addition, this nanomedicine may benefit patients who lack effective treatment options and have a low life expectancy, particularly those with advanced disease or metastases. Compared to chemotherapy, which has long-lasting side effects, this asset can improve quality of life by targeting tumor cells without damaging healthy ones and eliciting an antitumor response without damaging DNA. In addition, the development of a more effective nanomedicine can contribute to social progress by improving the accessibility and affordability of medical care. The development of a more effective drug can reduce the frequency and dose of administration, resulting in fewer adverse effects, shorter hospital stays, reduced patient complications and potential economic costs to the National Health System.

Cancer is currently one of the leading causes of death worldwide, with approximately 9.6 million deaths, and its incidence is expected to increase by ~70% over the next 15 years. Specifically, pediatric cancer accounts for less than 1% of cancer cases, but 400,000 new cases are diagnosed annually. Although the prognosis for these patients has improved over the past 30 years, the overall 5-year survival rate for childhood cancers is around 80%. However, for children with metastatic cancer, it decreases to 30%. In particular, neuroblastoma (NB) is the most common pediatric solid tumor in children, accounting for ~ 8-10% of cases and ~ 15% of pediatric cancer deaths. Patients with high-risk NB have a survival of less than 40%. However, as with many other tumors, the most aggressive form is metastatic neuroblastoma, which often spreads to the liver, bone marrow, bone, lymph nodes and lungs. This occurs in 50% of patients who become resistant to conventional therapies. Furthermore, despite intensive multimodality therapies, less than 40% of patients with high-risk NB survive, and two-thirds of these survivors experience lasting side effects. The present patented active consists of a family of nanovesicles, called Quatsomes (QS), which act as nanotransporters and protect conjugated RNAs, e.g. microRNAs, from degradation by nucleases, thus increasing their circulation time in blood and the possibility of reaching and penetrating tumor cells. In the present patent, it is shown that the release of these RNAs from the nanovesicles occurs more effectively depending on the components that are part of the formulation. Specifically, the patented nanovesicles are composed of a quaternary ammonium surfactant, which gives them the positive charge necessary to conjugate the nucleic acids, and a mixture of sterols, mainly derived from cholesterol, which, apart from giving greater stability to the membrane of the nanovesicles, give them the ability to release the conjugated RNA depending on the pH. This is because the cholesterol molecules are partially substituted by a pH-sensitive sterol, DC-Cholesterol, which contains a pH-protonable tertiary amine that plays a key role in the conjugation of RNA molecules at acidic or neutral pHs and induces the release of the therapeutic active at basic pHs (e.g., at intracellular pHs of tumor cells).

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Grant a license to Nanomol Tehcnologies to exploit our technology.

Cancer is currently one of the leading causes of death worldwide, with approximately 9.6 million deaths, and its incidence is expected to increase by ~70% over the next 15 years. Specifically, pediatric cancer accounts for less than 1% of cancer cases, but 400,000 new cases are diagnosed annually

Pharmacautical companies, Australia, Canada, Europe, Japan and United States of America.

Nanovesicles, called Quatsomes (QS), which act as nanotransporters and protect the conjugated RNAs, e.g. microRNAs, from degradation by nucleases, thus increasing their circulation time in the blood and the possibility of reaching and penetrating tumor cells. In the present patent, it is shown that the release of these RNAs from the nanovesicles occurs more effectively depending on the components that are part of the formulation. Specifically, the patented nanovesicles are composed of a quaternary ammonium surfactant, which gives them the positive charge necessary to conjugate the nucleic acids, and a mixture of sterols, mainly derived from cholesterol, which, apart from giving greater stability to the membrane of the nanovesicles, give them the ability to release the conjugated RNA depending on the pH. This is because the cholesterol molecules are partially substituted by a pH-sensitive sterol, DC-Cholesterol, which contains a pH-protonable tertiary amine that plays a key role in the conjugation of RNA molecules at acidic or neutral pHs and induces the release of the therapeutic active at basic pHs (e.g., at intracellular pHs of tumor cells).

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More experimental research is needed. Preclinical experiments and Quatsomes optimization and validation is required.

• EP19382372.1; NANOVESICLES AND ITS USE FOR NUCLEIC ACID DELIVERY; 13May2019 • PCTEP2020063195; 12 May 2020 Entered into National Phases on November 13, 2021 in: Australia, Canada, Europe, Japan and United States of America.

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QS show high colloidal stability upon storage, and show outstanding vesicle homogeneity regarding size, lamellarity and membrane supramolecular organization. QS are prepared by a one-step, efficient/reproducible, patented CO2-based manufacturing process, which ensure a high “batch-to-batch” consistency and allow the preparation of nanomedicines in sufficient quantities for both preclinical and clinical testing. The positive charges of QS allow the formation of complexes with negatively charged biomolecules, such as microRNAs. QS can be efficiently functionalized either with targeting units, such as peptides, to promote “selective” delivery to specific target site; or with stealth polymers, like poly-(ethylene glycol) (PEG), to avoid protein corona formation and to increase blood-circulation time