The mechanism of selective transfection mediated by pentablock copolymers; Part I: Investigation of cellular uptake

Zhang, Bingqi; Mallapragada, Surya K.

doi:10.1016/j.actbio.2010.11.032

Cited by 14 publications

(13 citation statements)

References 36 publications

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“…The enhanced cellular uptake was due to the presence hydrophobic PPO groups, which are capable of promoting cell membrane internalization through thermoreversible micellization and hydrophobic interactions [51,52,[57][58][59]69]. On the other hand, the PDEAEM endblocks enhanced the endosomal escape through protonated tertiary amine groups by pH buffering (Figure 4) [57,59,61].…”

Section: Resultsmentioning

confidence: 99%

Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer

Kalaga

Pothuraju

et al. 2019

Journal of Controlled Release

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A polymeric dual delivery nanoscale device (DDND) was designed for combined delivery of micro RNA (miR-345) and gemcitabine (GEM) to treat pancreatic cancer (PC). This temperature and pH-responsive pentablock copolymer system was able to restore miR-345, making xenograft tumors more susceptible to GEM, the standard therapy for PC. Restoration using DDND treatment results in sonic hedgehog signaling down regulation, which decreases desmoplasia, thereby resulting in improved GEM perfusion to the tumor and better therapeutic outcomes. The release of miR-345 and GEM could be tuned by using the DDND in the form of micelles or in the form of thermoreversible gels, based on polymer concentration. The DDNDs enabled miR-345 stability and sustained co-release of miR-345 and GEM, thereby facilitating dose-sparing use of GEM. Further, enhanced in vitro cellular uptake due to amphiphilic character, and endosomal escape because of the cationic end blocks led to efficient transfection with DDNDs. The combined DDND treatment enabled efficient reduction in cell viability of Capan-1 and CD18/HPAF cells in vitro compared with either GEM or miR-345 treatment alone. Mice carrying xenograft tumors treated with DDNDs carrying both miR-345 and GEM combination therapy displayed reduced tumor growth and less metastasis in distant organs compared to individual drug treatments.

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Section: Resultsmentioning

confidence: 99%

Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer

Kalaga

Pothuraju

et al. 2019

Journal of Controlled Release

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“…Whereas, many tumor cells have an acidified cytosol and more alkaline endosomes/lysosomes with both pH values is around 6.7 [ 21 , 22 , 23 ]. Although the reason for alkalinization of the endosomal and lysosomal compartments remains elusive, the elevated organelle pH in tumor cells has been confirmed in many reports [ 21 , 23 , 24 , 25 ] and proved to dramatically reduce the transfection efficiency of non-viral vectors in tumor cells [ 26 ]. Similarly, low GAPDH knockdown in UM-SCC-17B cancer cells can be attributed to endosomal alkalinization, which will reduce the hydrolysis of the hydrazone linkages connecting the membrane-active P(HMA- co -TMAEMA) grafts to the polymer backbone.…”

Section: Resultsmentioning

confidence: 99%

Silencing Bcl-2 Expression in Epithelial Cancer Cells Using “Smart” Particles

Lin

Jiang

Zhang

et al. 2014

JFB

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Short interfering RNA (siRNA) targeted against anti-apoptotic Bcl-2 protein proved to knockdown its expression and trigger cancer cell death. We used degradable, pH-sensitive, comb-like [P(EAA-co-BMA)-b-PNASI-g-P(HMA-co-TMAEMA)] polymer to condense anti-Bcl-2 siRNA into “smart” particles, which proved to shuttle their cargo past the endosomal membrane and into the cytoplasm of HeLa and UM-SCC-17B cancer cells. HeLa and UM-SCC-17B cancer cells were treated with anti-Bcl-2 particles followed by quantifying Bcl-2 mRNA and protein levels using qRT-PCR and western blotting, respectively. “Smart” anti-Bcl-2 particles selectively suppress Bcl-2 mRNA and protein levels in HeLa cells by 50%–60% and 79%–81%, respectively. Similarly, “smart” anti-Bcl-2 particles inhibited Bcl-2 mRNA levels by 30%, 40%, and 20% upon incubation with UM-SCC-17B cancer cells for 48, 72, and 96 h, respectively. Bcl-2 protein expression in UM-SCC-17B cancer cells was inhibited by 30% after treatment for 72 h. Results show that pH-sensitive comb-like polymer complex anti-Bcl-2 siRNA forming “smart” nanoparticles that deliver their cargo into the cytoplasm of HeLa and UM-SCC-17B cancer cells causing Bcl-2 knockdown at the mRNA and protein levels.

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“…It is worth emphasizing that the contribution of nonspecific pathways comprises from 30–40% to 90% of the total transfection effect of targeted polyplexes (e.g. for polyplexes with such receptor ligands as EGF [50,51], transferrin [52,53], folate [54], and pentacyclic RDG-mimetic [55]), so understanding of these pathways and minimization of their contribution are the major requirements for amendment of polyplexes.…”

Section: Discussionmentioning

confidence: 99%

Subcellular trafficking and transfection efficacy of polyethylenimine–polyethylene glycol polyplex nanoparticles with a ligand to melanocortin receptor-1

Durymanov

Beletkaia

Ulasov

et al. 2012

Journal of Controlled Release

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We have synthesized and investigated properties of new PEI-PEG-based polyplexes containing MC1SP-peptide, a ligand specific for melanocortin receptor-1 (targeted polyplexes), and control polyplexes without this ligand peptide (non-targeted polyplexes). The targeted polyplexes demonstrated receptor-mediated transfection of Cloudman S91 (clone M-3) murine melanoma cells that was more efficient than with the non-targeted ones. Transfection with the targeted polyplexes was inhibited by chlorpromazine, an inhibitor of the clathrin-mediated endocytosis pathway, and, to a lesser extent, by filipin III or nystatin, inhibitors of the lipid-raft endocytosis pathway, whereas transfection with the non-targeted polyplexes was inhibited mainly by nystatin or filipin III. The targeted polyplexes caused significantly higher in vivo transfection of melanoma tumor cells after intratumoral administration compared to the non-targeted control. The targeted polyplexes carrying the HSVtk gene, after ganciclovir administration, more efficiently inhibited melanoma tumor growth and prolonged the lifespan of DBA/2 tumor-bearing mice compared to the non-targeted ones. Packed targeted polyplexes appeared and accumulated in the melanoma cells six hours earlier than the non-targeted ones. The targeted polyplexes enter into the nuclei of the melanoma cells more rapidly than the non-targeted control, and this difference may also be attributed to processes of receptor-mediated endocytosis. We believe that these data may be useful for the optimization of polyplex systems.

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The mechanism of selective transfection mediated by pentablock copolymers; Part I: Investigation of cellular uptake

Cited by 14 publications

References 36 publications

Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer

Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer

Silencing Bcl-2 Expression in Epithelial Cancer Cells Using “Smart” Particles

Subcellular trafficking and transfection efficacy of polyethylenimine–polyethylene glycol polyplex nanoparticles with a ligand to melanocortin receptor-1

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