title: Gas-generating TPGS-PLGA microspheres loaded with nanoparticles (NIMPS) for co-delivery of minicircle DNA and anti-tumoral drugs.
abstract: Drug-DNA combination therapies are receiving an ever growing focus due to their potential for improving cancer treatment. However, such approaches are still limited by the lack of multipurpose delivery systems that encapsulate drugs and condense DNA simultaneously. In this study, we describe the successful formulation of gas-generating pH-responsive D-α-tocopherol PEG succinate-poly(D,L-lactic-co-glycolic acid) (TPGS-PLGA) hollow microspheres loaded with both Doxorubicin (Dox) and minicircle DNA (mcDNA) nanoparticles as a strategy to co-deliver these therapeutics. For this study mcDNA vectors were chosen due to their increased therapeutic efficiency in comparison to standard plasmid DNA. The results demonstrate that TPGS-PLGA microcarriers can encapsulate Dox and chitosan nanoparticles completely condense mcDNA. The loading of mcDNA-nanoparticles into microspheres was confirmed by 3D confocal microscopy and co-localization analysis. The resulting TPGS-PLGA-Dox-mcDNA nanoparticle-in-microsphere hybrid carriers exhibit a well-defined spherical shape and neutral surface charge. Microcarriers incubation in acidic pH produced a gas-mediated Dox release, corroborating the microcarriers stimuli-responsive character. Also, the dual-loaded TPGS-PLGA particles achieved 5.2-fold higher cellular internalization in comparison with non-pegylated microspheres. This increased intracellular concentration resulted in a higher cytotoxic effect. Successful transgene expression was obtained after nanoparticle-mcDNA co-delivery in the microspheres. Overall these findings support the concept of using nanoparticle-microsphere multipart systems to achieve efficient co-delivery of various drug-mcDNA combinations.
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: CICS-UBI-Health Sciences Research Center, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: André F
authors.initials: AF
authors.lastname: Moreira
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: 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: Centre de Biophysique Moléculaire, CNRS UPR4301, Inserm and University of 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. Electronic address: icorreia@ubi.pt.
authors.forename: Ilídio J
authors.initials: IJ
authors.lastname: Correia
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D004270:DNA, Circular / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers; D005740:Gases; D015870:Gene Expression; D019344:Lactic Acid / Q000008:administration & dosage*; D008863:Microspheres; D053758:Nanoparticles; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D000903:Antibiotics, Antineoplastic; D004270:DNA, Circular; D004337:Drug Carriers; D005740:Gases; D014810:Vitamin E; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D004317:Doxorubicin; C014225:tocophersolan
keywords: Co-delivery; Drugs; Microspheres; Minicircle DNA; Nanoparticles