Polymer gene delivery: overcoming the obstacles

Aied, Ahmed; Greiser, Udo; Pandit, Abhay; Wang, Wenxian

doi:10.1016/j.drudis.2013.06.014

Cited by 162 publications

(159 citation statements)

References 73 publications

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“…On one hand, this can reduce dendrimers' cytotoxicity since their surface functional groups might be shielded by proteins. On the other hand, proteins are often considered as an obstacle for transfection, raising an issue of serum stability: interactions with proteins can cause disassembly of dendriplexes, and aggregation with proteins can lead to rapid blood elimination [53]. In case of diethylamine-terminated CPD, the presence of serum contributed to more effective transfection and lowered dendrimers' cytotoxicity [13].…”

Section: Discussionmentioning

confidence: 99%

Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

Ihnatsyeu-Kachan

Dzmitruk

Apartsin

et al. 2017

Colloids and Interfaces

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Currently, RNAi based approaches for cancer treatment involving short double stranded RNA molecules (siRNA) are under vigorous scrutinization. Due to numerous biological obstacles, siRNA delivery into target cells requires protective escort. On the other hand, combining of siRNA-mediated gene silencing and action of conventional chemotherapeutics can propose additional enhancement of anticancer activity. In the present study, we investigated a siRNA cocktail able to downregulate anti-apoptotic genes (BCL-xL, BCL-2, MCL-1) and the chemotherapeutic agent 5-fluorouracil (5-FU) to evaluate multi-target cytotoxic effect on human cervical carcinoma cells (HeLa cell line). Novel phosphorus containing dendrimers of 3rd and 4th generations (namely AE2G3 and AE2G4) with voluminous piperidine terminal cationic groups were designed and tested as siRNA carriers. Dendrimers of both generations showed remarkable ability to bind pro-apoptotic siRNAs and provided 80-100% siRNA uptake by HeLa cells in the serum containing medium, while the widespread transfection agent Lipofectamine showed only~40% uptake. SiRNA cocktail (in low concentrations 50 and 100 nM) delivered by AE2G3 dendrimer caused almost complete elimination of cancer cells. We have discovered considerable increase of 5-FU cytotoxic effect by addition of AE2G3/siRNA cocktail complexes in low doses. Thus, we demonstrated the effectiveness of combined multi-target siRNA anticancer approach and described new highly effective serum stable nanomaterial vehicle for gene-based drugs.

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Section: Discussionmentioning

confidence: 99%

Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

Ihnatsyeu-Kachan

Dzmitruk

Apartsin

et al. 2017

Colloids and Interfaces

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“…The polymer type, the surface decoration of the particles, as well as further excipients and adjuvants all represent factors that enable the modulation of the immunological properties of a particle-based Ag delivery system (35,(46)(47)(48)(49)(50)(51)(52). In studies in which PLGA microparticles were shown to stimulate APCs associated with the release of Ags into the cytosol as consequence of destabilization of the endosomal membrane (53)(54)(55). Although this destabilization was produced by the polymer itself, we show that a photosensitizer can be included in the particles for the purpose of destabilizing the endosomes, targeting of Ag to cytosol and MHCI, and generation of high numbers of CTLs.…”

Section: Discussionmentioning

confidence: 99%

Photosensitizer and Light Pave the Way for Cytosolic Targeting and Generation of Cytosolic CD8 T Cells Using PLGA Vaccine Particles

Bruno

Waeckerle-Men

Håkerud

et al. 2015

The Journal of Immunology

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The generation of CTLs is crucial in the immunological fight against cancer and many infectious diseases. To achieve this, vaccine Ags need to be targeted to the cytosol of dendritic cells, which can activate CD8 T cells via MHC class I (MHCI). Therefore, such targeting has become one of the major objectives of vaccine research. In this study, we aimed to bypass the unwanted and default MHC class II Ag presentation and trigger MHCI presentation by using a photosensitizer that, upon light activation, would facilitate cytosolic targeting of codelivered Ag. Poly(lactide-co-glycolide) microparticles ∼1 μm size were loaded with OVA and the photosensitizer tetraphenyl chlorine disulphonate (TPCS2a) and administered intradermally in mice, which were illuminated 1 d later for activation of the photosensitizer. Immunization in the presence of TPCS2a significantly increased activation of CD8 T cells compared with immunization without TPCS2a and as measured by CD8 T cell proliferation, production of proinflammatory IFN-γ, TNF-α, and IL-2, and prevention of tumor growth. Cytotoxicity was demonstrated by granzyme B production in vitro and by in vivo killing of CFSE-labeled targets. CD4-dependent Ab responses were abrogated in mice immunized with TPCS2a-containing particles, suggesting that photosensitization facilitated a shift from default MHC class II toward MHCI Ag presentation. Hence, vaccine particles with Ag and photosensitizers proved an effective vehicle or adjuvant for stimulation of CTLs, and they may find potential application in therapeutic cancer vaccination and in prophylactic and therapeutic vaccination against intracellular infections.

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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: 98%