PEG shielded MMP sensitive CPPs for efficient and tumor specific gene delivery in vivo.
Gene therapy has great potential to treat a range of different diseases, such as cancer. For that therapeutic gene can be inserted into a plasmid vector and delivered specifically to tumor cells. The most frequently used applications utilize lipoplex and polyplex approaches where DNA is non-covalently condensed into nanoparticles. However, lack of in vivo efficacy is the major concern that hinders translation of such gene therapeutic applications into clinics. In this work we introduce a novel method for in vivo delivery of plasmid DNA (pDNA) and efficient tumor-specific gene induction using intravenous (i.v) administration route. To achieve this, we utilize a cell penetrating peptide (CPP), PepFect14 (PF14), double functionalized with polyethylene glycol (PEG) and a matrix metalloprotease (MMP) substrate. We show that this delivery vector effectively forms nanoparticles, where the condensed CPP and pDNA are shielded by the PEG, in an MMP-reversible manner. Administration of the complexes results in efficient induction of gene expression specifically in tumors, avoiding normal tissues. This strategy is a potent gene delivery platform that can be used for tumor-specific induction of a therapeutic gene.
Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia. Electronic address: kadi-liis.veiman@ut.ee.
Kadi-Liis
KL
Veiman
Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
Kadri
K
Künnapuu
Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia; Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences, Stockholm University, SE-10691 Stockholm, Sweden.
Tõnis
T
Lehto
Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
Kristina
K
Kiisholts
Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
Kalle
K
Pärn
Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia; Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences, Stockholm University, SE-10691 Stockholm, Sweden.
Ülo
Ü
Langel
Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
Kaido
K
Kurrikoff
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006801:Humans; D055666:Lipopeptides / Q000008:administration & dosage* / Q000737:chemistry; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010957:Plasmids; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects
D057846:Cell-Penetrating Peptides; D055666:Lipopeptides; C560878:PepFect14 peptide; D011092:Polyethylene Glycols; D004247:DNA; D008156:Luciferases; D020778:Matrix Metalloproteinase 2
Cell-penetrating peptide; Gene delivery; Matrix metalloprotease; Non-covalent complexes; PEGylation; Tumor