title: Poly(2-ethyl-2-oxazoline)-PLA-g-PEI amphiphilic triblock micelles for co-delivery of minicircle DNA and chemotherapeutics.
abstract: The design of nanocarriers for the delivery of drugs and nucleic-acids remains a very challenging goal due to their physicochemical differences. In addition, the reported accelerated clearance and immune response of pegylated nanomedicines highlight the necessity to develop carriers using new materials. Herein, we describe the synthesis of amphiphilic triblock poly(2-ethyl-2-oxazoline)-PLA-g-PEI (PEOz-PLA-g-PEI) micelles for the delivery of minicircle DNA (mcDNA) vectors. In this copolymer the generally used PEG moieties are replaced by the biocompatible PEOz polymer backbone that assembles the hydrophilic shell. The obtained results show that amphiphilic micelles have low critical micellar concentration, are hemocompatible and exhibit stability upon incubation in serum. The uptake in MCF-7 cells was efficient and the nanocarriers achieved 2.7 fold higher expression than control particles. Moreover, mcDNA-loaded micelleplexes penetrated into 3D multicellular spheroids and promoted widespread gene expression. Additionally, to prove the concept of co-delivery, mcDNA and doxorubicin (Dox) were simultaneously encapsulated in PEOz-PLA-g-PEI carriers, with high efficiency. Dox-mcDNA micelleplexes exhibited extensive cellular uptake and demonstrated anti-tumoral activity. These findings led us to conclude that this system has a potential not only for the delivery of novel mcDNA vectors, but also for the co-delivery of drug-mcDNA combinations without PEG functionalization.
authors.affiliation: CICS-UBI, Health Sciences Research Center, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: Vítor M
authors.initials: VM
authors.lastname: Gaspar
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR4301, Inserm et Université d'Orléans, 45071 Orléans cedex 02, France.
authors.forename: Cristine
authors.initials: C
authors.lastname: Gonçalves
authors.affiliation: CICS-UBI, Health Sciences Research Center, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: Duarte
authors.initials: D
authors.lastname: de Melo-Diogo
authors.affiliation: CICS-UBI, Health Sciences Research Center, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: Elisabete C
authors.initials: EC
authors.lastname: Costa
authors.affiliation: CICS-UBI, Health Sciences Research Center, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: João A
authors.initials: JA
authors.lastname: Queiroz
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR4301, Inserm et Université d'Orléans, 45071 Orléans cedex 02, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Pichon
authors.affiliation: CICS-UBI, Health Sciences Research Center, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: Fani
authors.initials: F
authors.lastname: Sousa
authors.affiliation: CICS-UBI, Health Sciences Research Center, University of Beira Interior, 6200-506 Covilhã, Portugal. Electronic address: icorreia@ubi.pt.
authors.forename: Ilídio J
authors.initials: IJ
authors.lastname: Correia
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004270:DNA, Circular / Q000008:administration & dosage* / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005347:Fibroblasts; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008823:Micelles; D011073:Polyamines / Q000737:chemistry; D011091:Polyesters; D011094:Polyethyleneimine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D017208:Rats, Wistar; D018874:Spheroids, Cellular / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004270:DNA, Circular; D004337:Drug Carriers; D008823:Micelles; D011073:Polyamines; D011091:Polyesters; D011108:Polymers; C511916:poly(2-ethyl-2-oxazoline); D049452:Green Fluorescent Proteins; D019344:Lactic Acid; C033616:poly(lactide); D004317:Doxorubicin; D011094:Polyethyleneimine
keywords: Anti-tumoral drugs; Cancer therapy; Co-delivery; Micellar carriers; Minicircle DNA