Gene therapy using small interfering RNA(siRNA)is emerging as a novel therapeutic approach to treat various diseases.However,safe and efficient siRNA delivery still constitutes the major obstacle for clinical implemen...Gene therapy using small interfering RNA(siRNA)is emerging as a novel therapeutic approach to treat various diseases.However,safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics.Here we report an ionizable supramolecular dendrimer vector,formed via self-assembly of a small amphiphilic dendrimer,as an effective siRNA delivery system with a favorable safety profile.By virtue of the ionizable tertiary amine terminals,the supramolecular dendrimer has a low positively charged surface potential and no notable cytotoxicity at physiological pH.Nonetheless,this ionizable feature imparted sufficient surface charge to the supramolecular dendrimer to enable formation of a stable complex with siRNA via electrostatic interactions.The resulting siRNA/dendrimer delivery system had a surface charge that was neither neutral,thus avoiding aggregation,nor too high,thus avoiding cytotoxicity,but was sufficient for favorable cellular uptake and endosomal release of the siRNA.When tested in different cancer cell lines and patient-derived cancer organoids,this dendrimer-mediated siRNA delivery system effectively silenced the oncogenes Myc and Akt2 with a potent antiproliferative effect,outperforming the gold standard vector,Lipofectamine 2000.Therefore,this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery.The concept of supramolecular dendrimer nanovectors via self-assembly is new,yet easy to implement in practice,offering a new perspective for supramolecular chemistry in biomedical applications.展开更多
Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)is a dismal disease with a fast evolution and unpredictable treatment response.Nowadays,FOLFIRINOX[1]and gemcitabine[2]are the preferred treatments with a response rat...Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)is a dismal disease with a fast evolution and unpredictable treatment response.Nowadays,FOLFIRINOX[1]and gemcitabine[2]are the preferred treatments with a response rate of 33%and 11%,respectively.This poor patient response has been associated with an inefficient/non-personalized treatment allocation.Consequently,developing a rapid and efficient preclinical tool to test tumor drug sensitivity for each patient is hugely needed.Biopsy patient-derived organoid(PDO)appears to be a promising tool for developing individualized treatments for patients with PDAC.Several PDO-based platforms are in development worldwide as a guide to optimize therapy by directing tailored treatments.A critical point to consider PDO as promising is that it must represent the great clinical heterogeneity of PDAC as much as possible.Moreover,PDO has displayed histological features that mimic the PDAC phenotype.These characteristics make PDO an interesting option to obtaining reliable chemo-response profiles at a reasonable timeframe for most PDAC patients.展开更多
Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)treatment is focused on two regimens.The polychemotherapy,FOLFIRINOX(folinic acid,fluorouracil,irinotecan,oxali-platin),is used in patients with good health conditions...Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)treatment is focused on two regimens.The polychemotherapy,FOLFIRINOX(folinic acid,fluorouracil,irinotecan,oxali-platin),is used in patients with good health conditions[1],while gemcitabine,as monotherapy,in patients with poor health conditions[2–4].Gemcitabine resistance-associated pathways have been targeted to sensitize cancer cells,but the results were disappointing.Using a transcrip-tomic bioinformatics analysis combined with biological validation,we showed that glucuronidation was associ-ated with the gemcitabine resistance in PDAC,and its inhibition could switch tumors from resistant to sensitive.展开更多
基金This work was supported by the Ligue Nationale Contre le Cancer(L.P.,Z.L.)China Scholarship Council(W.L.,L.D.)+2 种基金Italian Association for Cancer Research(IG17413)(S.P.)the French National Research Agency under the frame of the H2020 Era-Net EURONANOMED European Research projects“Target4Cancer”,“NANOGLIO”,“TARBRAINFECT”,“NAN4-TUM”(L.P.),and H2020 NMBP“SAFE-N-MEDTECH”(L.P.)This article is based upon work from COST Action CA 17140“Cancer Nanomedicine from the Bench to the Bedside”supported by COST(European Cooperation in Science and Technology).
文摘Gene therapy using small interfering RNA(siRNA)is emerging as a novel therapeutic approach to treat various diseases.However,safe and efficient siRNA delivery still constitutes the major obstacle for clinical implementation of siRNA therapeutics.Here we report an ionizable supramolecular dendrimer vector,formed via self-assembly of a small amphiphilic dendrimer,as an effective siRNA delivery system with a favorable safety profile.By virtue of the ionizable tertiary amine terminals,the supramolecular dendrimer has a low positively charged surface potential and no notable cytotoxicity at physiological pH.Nonetheless,this ionizable feature imparted sufficient surface charge to the supramolecular dendrimer to enable formation of a stable complex with siRNA via electrostatic interactions.The resulting siRNA/dendrimer delivery system had a surface charge that was neither neutral,thus avoiding aggregation,nor too high,thus avoiding cytotoxicity,but was sufficient for favorable cellular uptake and endosomal release of the siRNA.When tested in different cancer cell lines and patient-derived cancer organoids,this dendrimer-mediated siRNA delivery system effectively silenced the oncogenes Myc and Akt2 with a potent antiproliferative effect,outperforming the gold standard vector,Lipofectamine 2000.Therefore,this ionizable supramolecular dendrimer represents a promising vector for siRNA delivery.The concept of supramolecular dendrimer nanovectors via self-assembly is new,yet easy to implement in practice,offering a new perspective for supramolecular chemistry in biomedical applications.
基金The PaCaOmics study was registered at www.clinicaltrials.gov with registration number NCT01692873PDAC samples were collected between January 2012 and December 2015.All experimental procedures on animals were approved by the Comitéd’éthique de Marseille numéro 14(C2EA-14).
文摘Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)is a dismal disease with a fast evolution and unpredictable treatment response.Nowadays,FOLFIRINOX[1]and gemcitabine[2]are the preferred treatments with a response rate of 33%and 11%,respectively.This poor patient response has been associated with an inefficient/non-personalized treatment allocation.Consequently,developing a rapid and efficient preclinical tool to test tumor drug sensitivity for each patient is hugely needed.Biopsy patient-derived organoid(PDO)appears to be a promising tool for developing individualized treatments for patients with PDAC.Several PDO-based platforms are in development worldwide as a guide to optimize therapy by directing tailored treatments.A critical point to consider PDO as promising is that it must represent the great clinical heterogeneity of PDAC as much as possible.Moreover,PDO has displayed histological features that mimic the PDAC phenotype.These characteristics make PDO an interesting option to obtaining reliable chemo-response profiles at a reasonable timeframe for most PDAC patients.
基金supported by the National Cancer Institute(Grants number 2018-078,2019-037, 2018-079),Canceropole Provence-Alpes-Côte d’Azur,Amidex Foundation and the national institute of health and medical research.
文摘Dear Editor,Pancreatic ductal adenocarcinoma(PDAC)treatment is focused on two regimens.The polychemotherapy,FOLFIRINOX(folinic acid,fluorouracil,irinotecan,oxali-platin),is used in patients with good health conditions[1],while gemcitabine,as monotherapy,in patients with poor health conditions[2–4].Gemcitabine resistance-associated pathways have been targeted to sensitize cancer cells,but the results were disappointing.Using a transcrip-tomic bioinformatics analysis combined with biological validation,we showed that glucuronidation was associ-ated with the gemcitabine resistance in PDAC,and its inhibition could switch tumors from resistant to sensitive.
