High risk human papillomaviruses (HPVs) are responsible for over 70% of all cervical cancer cases worldwide, as well as other anogenital cancers in both women and men. The need remains for an efficient treatment of patients with HPV.
The nanotechnology applied to viral infection and cancer treatment has a tremendous potential for developing next-generation therapeutics. Specifically, DNA nano-based drug carriers for antiviral and/or anticancer drugs greatly enhance their bioavailability and increase their target specificity.
AS1411 is a G-quadruplex (G4)-forming DNA oligonucleotide that functions as an aptamer of nucleolin (NCL), a protein that is present at high levels on the surface of cancer cells. Clinical trials of AS1411 have indicated that it is well tolerated with evidence of therapeutic activity, but improved pharmacology and potency may be required for optimal efficacy. To this purpose, the production of AS1411 derivatives with chemical modifications (introduction of Locked Nucleic Acid and uracil derivatives) will be first addressed, aiming at improving the binding affinity to NCL and their pharmacological properties. To promote the endosomal escape and release of the ligands into the cytoplasm of cancer cells, the AS1411 derivatives will be conjugated to AuNP peptides known for causing endosome disruption.
DREAM seeks to use the actual lines of research of the national and international groups involved (which already have a strong background in the development of nanosystems), deepening it to develop a novel vehicle-ligand with antiviral and antitumoral effect in precancerous cells infected by HPV.
|Title||DREAM – Drug delivery nanosysteM for HPV infection therapy Nanotechnologies|
|Leading Institution||Universidade da Beira Interior (UBI)|
|Participating Institutions||The University of Austin at Texas (UT Austin)
Associação do Instituto Superior Técnico para a Investigação e Desenvolvimento (IST-ID)
Centro Hospitalar da Cova da Beira (CHCB)
Labfit – Health Products Research and Development Lda (HPRD Lda)
|Begin date||5th November, 2018|
|Key Words||AS1411 derivatives G-quadruplex, Nucleolin, Vehicles-drugs, HPV|
"DREAM intends to develop a novel vehicle-drug nanosystem based on DNA aptamer-functionalized nanoparticles with antitumoral effect in precancerous cells infected by Human Papillomavirus. The Portuguese team will develop the vehicles-drugs and will do preclinical evaluation in cellular and animal models. The UT-Austin team will measure the vehicles-drugs release from punctate endosomal compartments. The most promising nanoparticle will be formulated as a prototype for topical delivery of anticancer/antiviral drugs by HPRD Lda company, to control the HPV replication and/or treat precancerous lesions directly in the target basal cells potentiating the “bench-to-bedside” of the project outputs."