Cell penetrating peptides as an innovative approach for drug delivery; then, present and the future

Bashyal, Santosh; Noh, Gyubin; Keum, Taekwang; Choi, Young Wook; Lee, Sang Kil

doi:10.1007/s40005-016-0253-0

Cited by 36 publications

(26 citation statements)

References 100 publications

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“…For this purpose, protein-transduction domains, also known as cell-penetrating peptides (CPP) that are small sequences of peptides, have demonstrated ability to transport cargo into cells in a non-invasive manner. These peptides have been widely used in the delivery of a variety of molecules across the cell membrane [25,26]. Cationic CPP, such as penetratin (Pen), have demonstrated other biological activity besides efficient cellular uptake, including facilitating intracellular delivery and endosomal escape [26,27].…”

Section: Introductionmentioning

confidence: 99%

Dual functionalized liposome-mediated gene delivery across triple co-culture blood brain barrier model and specific in vivo neuronal transfection

Rodrigues

Oue

Banerjee

et al. 2018

Journal of Controlled Release

100

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Gene therapy has become a promising approach for neurodegenerative disease treatment, however there is an urgent need to develop an efficient gene carrier to transport gene across the blood brain barrier (BBB). In this study, we strategically designed dual functionalized liposomes for efficient neuronal transfection by combining transferrin (Tf) receptor targeting and enhanced cell penetration utilizing penetratin (Pen). A triple cell co-culture model of BBB confirmed the ability of the liposomes to cross the barrier layer and transfect primary neuronal cells. In vivo quantification of PenTf-liposomes demonstrated expressive accumulation in the brain (12%), without any detectable cellular damage or morphological change. The efficacy of these nanoparticles containing plasmid β-galactosidase in modulating transfection was assessed by β-galactosidase expression in vivo. As a consequence of accumulation in the brain, PenTf-liposomes significantly induced gene expression in mice. Immunofluorescence studies of brain sections of mice after tail vein injection of liposomes encapsulating pDNA encoding GFP (pGFP) illustrate the superior ability of dual-functionalized liposomes to accumulate in the brain and transfect neurons. Taken together, the multifunctional liposomes provide an excellent gene delivery platform for neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

Dual functionalized liposome-mediated gene delivery across triple co-culture blood brain barrier model and specific in vivo neuronal transfection

Rodrigues

Oue

Banerjee

et al. 2018

Journal of Controlled Release

100

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“…As the cytosolic internalization of DiI-RIPL-NLC was time-dependent, it can be concluded that the RIPL peptide enhanced the translocation of NLC by the internalization mechanisms of polyarginine such as direct penetration or macropinocytosis. 46,47 In addition, DiI-RIPL-NLC was internalized into the intracellular region after exposure to SKOV3 cells for a relatively short period of time. This observation supports the flow cytometry results, indicating that DiI-RIPL-NLC selectively binds to Hpn-expressing cells and enhances cellular uptake.…”

Section: Assessment Of Translocational Behavior Of Ripl-nlcsmentioning

confidence: 99%

RIPL peptide-conjugated nanostructured lipid carriers for enhanced intracellular drug delivery to hepsin-expressing cancer cells

Lee¹,

Kim²,

Sung³

et al. 2018

IJN

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BackgroundTo facilitate selective and enhanced drug delivery to hepsin (Hpn)-expressing cancer cells, RIPL peptide (IPLVVPLRRRRRRRRC, 16-mer)-conjugated nanostructured lipid carriers (RIPL-NLCs) were developed.MethodsNLCs were prepared using a solvent emulsification-evaporation method and the RIPL peptide was conjugated to the maleimide-derivatized NLCs via the thiol-maleimide reaction. Employing a fluorescent probe (DiI), in vitro target-selective intracellular uptake behaviors were observed using fluorescence microscopy and flow cytometry. Separately, docetaxel (DTX) was encapsulated by pre-loading technique, then cytotoxicity and drug release were evaluated. In vivo antitumor efficacy was investigated in BALB/c nude mice with SKOV3 cell tumors after intratumoral injections of different DTX formulations at a dose equivalent to 10 mg/kg DTX.ResultsRIPL-NLCs showed positively charged nanodispersion, whereas NLCs were negatively charged. DTX was successfully encapsulated with an encapsulation efficiency and drug loading capacity of 95–98% and 44-46 µg/mg, respectively. DTX release was diffusion-controlled, revealing the best fit to the Higuchi equation. Cellular uptake of DiI-loaded RIPL-NLCs was 8.3- and 6.2-fold higher than that of DiI-loaded NLCs, in Hpn(+) SKOV3 and LNCaP cells, respectively. The translocation of RIPL-NLCs into SKOV3 cells was time-dependent with internalization within 1 h and distribution throughout the cytoplasm after 2 h. DTX-loaded RIPL-NLCs (DTX-RIPL-NLCs) revealed dose-dependent in vitro cytotoxicity, while drug-free formulations were non-cytotoxic. In SKOV3-bearing xenograft mouse model, DTX-RIPL-NLCs significantly inhibited tumor growth: the inhibition ratios of the DTX solution-treated and DTX-RIPL-NLC-treated groups were 61.4% and 91.2%, respectively, compared to those of the saline-treated group (control).ConclusionRIPL-NLCs are good candidates for Hpn-selective drug targeting with a high loading capacity of hydrophobic drug molecules.

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“…CPPs have been successfully applied in drug delivery amongst which penetratin (Pen), a CPP derived from Antennapedia homeodomain, has demonstrated capability to penetrate neurons and accumulate in the nucleus (Ramsey and Flynn, 2015). The cationic-amphiphilic character of Pen is involved in interaction with lipid components of cellular membrane and subsequent internalization into the cell (Bashyal et al, 2016;Zhang et al, 2016). Numerous studies have demonstrated the enhanced drug delivery abilities of Pen-modified liposomes (Chikh et al, 2001;Marty et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Functionalized liposomal nanoparticles for efficient gene delivery system to neuronal cell transfection

Rodrigues

Banerjee

Kanekiyo

et al. 2019

International Journal of Pharmaceutics

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Liposome based delivery systems provide a promising strategy for treatment of neurodegenerative diseases. A rational design of brain-targeted liposomes can support the development of more efficient treatments with drugs and gene materials. Here, we characterized surface modified liposomes with transferrin (Tf) protein and penetratin (Pen), a cell-penetrating peptide, for efficient and targeted gene delivery to brain cells. PenTf-liposomes efficiently encapsulated plasmid DNA, protected them against enzymatic degradation and exhibited a sustained in vitro release kinetics. The formulation demonstrated low cytotoxicity and was non-hemolytic. Liposomes were internalized into cells mainly through energy-dependent pathways especially clathrin-mediated endocytosis. Reporter gene transfection and consequent protein expression in different cell lines were significantly higher using PenTf-liposomes compared to unmodified liposomes. The ability of these liposome to escape from endosomes can be an important factor which may have likely contributed to the high transfection efficiency observed. Rationally designed bifunctional targeted-liposomes provide an efficient tool for improving the targetability and efficacy of synthesized delivery systems. This investigation of liposomal properties attempted to address cell differences, as well as, vector differences, in gene transfectability. The findings indicate that PenTf-liposomes can be a safe and non-invasive approach to transfect neuronal cells through multiple endocytosis pathways.

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Cell penetrating peptides as an innovative approach for drug delivery; then, present and the future

Cited by 36 publications

References 100 publications

Dual functionalized liposome-mediated gene delivery across triple co-culture blood brain barrier model and specific in vivo neuronal transfection

Dual functionalized liposome-mediated gene delivery across triple co-culture blood brain barrier model and specific in vivo neuronal transfection

RIPL peptide-conjugated nanostructured lipid carriers for enhanced intracellular drug delivery to hepsin-expressing cancer cells

Functionalized liposomal nanoparticles for efficient gene delivery system to neuronal cell transfection

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