Conjugation with Cationic Cell-Penetrating Peptide Increases Pulmonary Absorption of Insulin

Patel, Leena N.; Wang, Jeffrey; Kim, Kwang‐Jin; Borok, Zea; Crandall, Edward D.; Shen, Wei‐Chiang

doi:10.1021/mp800174g

Cited by 55 publications

(36 citation statements)

References 48 publications

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“…As we know, cell penetration and cargo delivery properties of penetratin are well-known facts to scientists involved in the fields of cell permeation and peptide delivery. [12][13][14][15][16][17] According to the promising results reported for a special analog of penetratin in an intranasal insulin delivery (a physical mixture formulation), 18 this 16-amino-acid peptide sequence was synthesized in our peptide laboratory in Khaje Nasir University and purified to more than 95% purity. Table 1 provides the amino acid sequence of penetratin and the newly developed analog of penetratin (PenetraMax) investigated in this study.…”

Section: Methodsmentioning

confidence: 99%

“…This finding about the effect of l-penetratin (our CPP is a new analog of l-penetratin) on TEER values is in accordance with the results from other researchers. 37 Although for some kinds of CPPs such as poly-arginine, the reduction in TEER is proposed as a possible mechanism for enhancing the pulmonary absorption of insulin, 15 where other studies do not support the idea of TEER reduction for CPP. In a recent study carried out for elucidating the cell permeation mechanism of CPPs, such a mechanism was not proposed for CPPs and the effects of l-penetratin as well as poly-arginine on TEER values were not significant.…”

Section: Teer and Insulin Transport Studiesmentioning

confidence: 99%

“…Both cell culture and animal studies have shown that covalently, 15 and even physically, linking a CPP (eg, trans-activated-transcriptions [TAT]) to almost any type of drugs, including hydrophilic compounds and large proteins (molecular weight [Mw] .150 kDa), facilitates translocation of the attached species into the cells of all organ types, including the brain. 16 In this innovative study, a wise combination of the most successful and modern solutions to circumvent both the enzymatic situation and the mucosal barrier is reported.…”

Section: Introductionmentioning

confidence: 99%

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A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides

Barbari¹,

Dorkoosh²,

Amini³

et al. 2017

IJN

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A simple and reproducible water-in-oil (W/O) nanoemulsion technique for making ultrasmall (<15 nm), monodispersed and water-dispersible nanoparticles (NPs) from chitosan (CS) is reported. The nano-sized (50 nm) water pools of the W/O nanoemulsion serve as “nano-containers and nano-reactors”. The entrapped polymer chains of CS inside these “nano-reactors” are covalently cross-linked with the chains of polyethylene glycol (PEG), leading to rigidification and formation of NPs. These NPs possess excessive swelling properties in aqueous medium and preserve integrity in all pH ranges due to chemical cross-linking with PEG. A potent and newly developed cell-penetrating peptide (CPP) is further chemically conjugated to the surface of the NPs, leading to development of a novel peptide-conjugated derivative of CS with profound tight-junction opening properties. The CPP-conjugated NPs can easily be loaded with almost all kinds of proteins, peptides and nucleotides for oral delivery applications. Feasibility of this nanoparticulate system for oral delivery of a model peptide (insulin) is investigated in Caco-2 cell line. The cell culture results for translocation of insulin across the cell monolayer are very promising (15%–19% increase), and animal studies are actively under progress and will be published separately.

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Section: Methodsmentioning

confidence: 99%

Section: Teer and Insulin Transport Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides

Barbari¹,

Dorkoosh²,

Amini³

et al. 2017

IJN

View full text Add to dashboard Cite

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“…Cell-penetrating peptides have showed remarkable ability to transport a wide variety of therapeutic macromolecules into the interior of cells owing to their high internalization efficiency and potential for structural modification (Patel et al, 2009;Desai et al, 2010;Lee et al, 2011;Mussbach et al, 2011). The cellular uptake mechanisms of CPPs have been widely studied by numerous investigations in recent years.…”

Section: Pharmacodynamics and Pharmacokinetics In Vivomentioning

confidence: 99%

Enhanced oral bioavailability of insulin using PLGA nanoparticles co-modified with cell-penetrating peptides and Engrailed secretion peptide (Sec)

et al. 2015

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Biodegradable polymer nanoparticle drug carriers are an attractive strategy for oral delivery of peptide and protein drugs. However, their ability to cross the intestinal epithelium membrane is largely limited. Therefore, in the present study, cell-penetrating peptides (R8, Tat, penetratin) and a secretion peptide (Sec) with N-terminal stearylation were introduced to modify nanoparticles (NPs) on the surface to improve oral bioavailability of peptide and protein drugs. In vitro studies conducted in Caco-2 cells showed the value of the apparent permeability coefficient (Papp) of the nanoparticles co-modified with Sec and penetratin (Sec-Pen-NPs) was about two-times greater than that of the nanoparticles modified with only penetratin (Pen-NPs), while the increase of transcellular transport of nanoparticles modified together with Sec and R8 (Sec-R8-NPs), or Sec and Tat (Sec-Tat-NPs), was not significant compared with nanoparticles modified with only R8 (R8-NPs) or Tat (Tat-NPs). Using insulin as the model drug, in vivo studies performed on rats indicated that compared to Pen-NPs, the relative bioavailability of insulin for Sec-Pen-NPs was 1.71-times increased after ileal segments administration, and stronger hypoglycemic effects was also observed. Therefore, the nanoparticles co-modified with penetratin and Sec could act as attractive carriers for oral delivery of insulin.

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“…A combination of PDT and surgery, radiotherapy, or chemotherapy features low-or noninvasiveness, a low incidence of side effects, good compatibility with other treatments, fewer risks over repeated treatments, short treatment time, cost-effectiveness, and non-immunosuppression. 6,7 However, there were also several drawbacks to PDT, preventing it from being used as a major treatment modality: dependence on certain types of PSs and light sources (wavelength, time exposure, pulse duration, and pulse frequency), low delivery accuracy of the PSs, and limited treatment depth. 7,8 Therefore, to improve the efficiency of PDT and expand its applicability in the treatment of various cancers, the limitations regarding its clinical efficacy should be reduced.…”

Section: Introductionmentioning

confidence: 99%

Photodynamic therapy by conjugation of cell-penetrating peptide with fluorochrome

Kim¹,

Hwangbo²,

Cho³

2017

IJN

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Photodynamic therapy (PDT) is a promising alternative therapy that could be used as an adjunct to chemotherapy and surgery for cancer, and works by destroying tissue with visible light in the presence of a photosensitizer (PS) and oxygen. The PS should restrict tissue destruction only to the tumor and be activated by light of a specific wavelength; both of these properties are required. Arginine-rich peptides, such as cell-penetrating peptides, have membrane-translocating and nuclear-localizing activities, which have led to their application in various drug delivery modalities. Protamine (Pro) is an arginine-rich peptide with membrane-translocating and nuclear-localizing properties. The reaction of an N-hydroxysuccinimide (NHS) ester of rhodamine (Rho) and clinical Pro was carried out in this study to yield RhoPro, and a demonstration of its phototoxicity, wherein clinical Pro improved the effect of PDT, was performed. The reaction between Pro and the NHS ester of Rho is a solution-phase reaction that results in the complete modification of the Pro peptides, which feature a single reactive amine at the N-terminal proline and a single carboxyl group at the C-terminal arginine. This study aimed to identify a new type of PS for PDT by in vitro and in vivo experiments and to assess the antitumor effects of PDT, using the Pro-conjugated PS, on a cancer cell line. Photodynamic cell death studies showed that the RhoPro produced has more efficient photodynamic activities than Rho alone, causing rapid light-induced cell death. The attachment of clinical Pro to Rho, yielding RhoPro, confers the membrane-internalizing activity of its arginine-rich content on the fluorochrome Rho and can induce rapid photodynamic cell death, presumably owing to light-induced cell membrane rupture. PDT using RhoPro for HT-29 cells was very effective and these findings suggest that RhoPro is a suitable candidate as a PS for solid tumors.

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Conjugation with Cationic Cell-Penetrating Peptide Increases Pulmonary Absorption of Insulin

Cited by 55 publications

References 48 publications

A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides

A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides

Enhanced oral bioavailability of insulin using PLGA nanoparticles co-modified with cell-penetrating peptides and Engrailed secretion peptide (Sec)

Photodynamic therapy by conjugation of cell-penetrating peptide with fluorochrome

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