Highly branched poly(β-amino ester)s for skin gene therapy

Zhou, Daohong; Gao, Yongsheng; Aied, Ahmed; Cutlar, Lara; Igoucheva, Olga; Newland, Ben; Alexeeve, Vitali; Greiser, Udo; Uitto, Jouni; Wang, Wenxian

doi:10.1016/j.jconrel.2016.06.014

Cited by 98 publications

(85 citation statements)

References 48 publications

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“…Such alternatives aim to achieve high transfection efficiency, and overcome virus drawbacks, such as their potential immune responses in therapeutic settings or their high production costs [5]. Most of these cationic polymeric vectors are polyamines, especially polyamines containing secondary and tertiary amino groups that can participate in a phenomenon known as 'proton-sponge' hypothesis for endosomal escape [6][7][8][9][10][11][12][13]. Paradoxically, this net positive charge is also one of their main drawbacks, as it is associated with their high cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Hydroxyl versus permethylated glycopolymers as gene carriers

Redondo

Martínez-Campos

Navarro

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

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Section: Introductionmentioning

confidence: 99%

Hydroxyl versus permethylated glycopolymers as gene carriers

Redondo

Martínez-Campos

Navarro

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

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“…Thus, synthesis of polymers for gene delivery is aimed on creation of structures showing a high buffer capacity in the neutral and slightly acidic range. Complex polymer structures containing high amounts of tertiary amine groups were recently obtained [45][46][47][48] and showed a high buffer capacity combined with enhanced transfection activity. Polymeric amines have been widely investigated as gene transfer agents [41,42].…”

Section: Resultsmentioning

confidence: 99%

Polymeric Amines and Ampholytes Derived from Poly(acryloyl chloride): Synthesis, Influence on Silicic Acid Condensation and Interaction with Nucleic Acid

et al. 2017

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Polymeric amines are intensively studied due to various valuable properties. This study describes the synthesis of new polymeric amines and ampholytes by the reaction of poly(acryloyl chloride) with trimethylene-based polyamines containing one secondary and several (1-3) tertiary amine groups. The polymers contain polyamine side chains and carboxylic groups when the polyamine was in deficiency. These polymers differ in structure of side groups, but they are identical in polymerization degree and polydispersity, which facilitates the study of composition-properties relationships. The structure of the obtained polymers was confirmed with 13 C nuclear magnetic resonance infrared spectroscopy, and acid-base properties were studied with potentiometry titration. Placement of the amine groups in the side chains influences their acid-base properties: protonation of the amine group exerts a larger impact on the amine in the same side chain than on the amines in the neighboring side chains. The obtained polymers are prone to aggregation in aqueous solutions tending to insolubility at definite pH values in the case of polyampholytes. Silicic acid condensation in the presence of new polymers results in soluble composite nanoparticles and composite materials which consist of ordered submicrometer particles according to dynamic light scattering and electron microscopy. Polymeric amines, ampholytes, and composite nanoparticles are capable of interacting with oligonucleotides, giving rise to complexes that hold promise for gene delivery applications.

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“…PBAE polymers (P1) were synthesized using a two-step Michael addition reaction as previously described [23,54,57,68–73]. Briefly, 1,4-butanediol diacrylate and 4-amino-1-butanol were reacted at molar ratios of 1.1:1 and 1.2:1 for 24 h at 90 °C to yield P1 of 6 kDa and 4 kDa, respectively.…”

Section: Methodsmentioning

confidence: 99%

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

Mastorakos

Zhang

Song

et al. 2017

Journal of Controlled Release

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The discovery of powerful genetic targets has spurred clinical development of gene therapy approaches to treat patients with malignant brain tumors. However, lack of success in the clinic has been attributed to the inability of conventional gene vectors to achieve gene transfer throughout highly disseminated primary brain tumors. Here, we demonstrate ex vivo that small nanocomplexes composed of DNA condensed by a blend of biodegradable polymer, poly(β-amino ester) (PBAE), with PBAE conjugated with 5 kDa polyethylene glycol (PEG) molecules (PBAE-PEG) rapidly penetrate healthy brain parenchyma and orthotopic brain tumor tissues in rats. Rapid diffusion of these DNA-loaded nanocomplexes observed in fresh tissues ex vivo demonstrated that they avoided adhesive trapping in the brain owing to their dense PEG coating, which was critical to achieving widespread transgene expression throughout orthotopic rat brain tumors in vivo following administration by convection enhanced delivery. Transgene expression with the PBAE/PBAE-PEG blended nanocomplexes (DNA-loaded brain-penetrating nanocomplexes, or DNA-BPN) was uniform throughout the tumor core compared to nanocomplexes composed of DNA with PBAE only (DNA-loaded conventional nanocomplexes, or DNA-CN), and transgene expression reached beyond the tumor edge, where infiltrative cancer cells are found, only for the DNA-BPN formulation. Finally, DNA-BPN loaded with anti-cancer plasmid DNA provided significantly enhanced survival compared to the same plasmid DNA loaded in DNA-CN in two aggressive orthotopic brain tumor models in rats. These findings underscore the importance of achieving widespread delivery of therapeutic nucleic acids within brain tumors and provide a promising new delivery platform for localized gene therapy in the brain.

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Highly branched poly(β-amino ester)s for skin gene therapy

Cited by 98 publications

References 48 publications

Hydroxyl versus permethylated glycopolymers as gene carriers

Hydroxyl versus permethylated glycopolymers as gene carriers

Polymeric Amines and Ampholytes Derived from Poly(acryloyl chloride): Synthesis, Influence on Silicic Acid Condensation and Interaction with Nucleic Acid

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

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