Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Khafagy, El-Sayed; Iwamae, Ruisha; Kamei, Noriyasu; Takeda‐Morishita, Mariko

doi:10.1208/s12248-015-9804-y

Cited by 28 publications

(16 citation statements)

References 55 publications

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“…There were clear differences in the absorption-enhancing efficiency between L-and D-penetratin; by contrast, the chiral effect was unexpectedly much smaller for PenetraMax than for penetratin. This minimal chiral effect for PenetraMax was consistent with our earlier publication, 18 in which coadministration with L-or D-PenetraMax greatly increased the intestinal absorption of insulin with only a slight chiral effect for PenetraMax. This might also reflect the stabilizing effect of PenetraMax because it has a stronger intermolecular binding with insulin than does penetratin.…”

Section: Effect Of Cpps On the Intestinal Absorption Of Dextransupporting

confidence: 91%

Applicability and Limitations of Cell-Penetrating Peptides in Noncovalent Mucosal Drug or Carrier Delivery Systems

Kamei

Nielsen

Nakakubo

et al. 2016

Journal of Pharmaceutical Sciences

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Our recent studies show that cell-penetrating peptides (CPPs) have potential to improve the intestinal absorption of peptide and protein drugs safely and effectively when used in the noncovalent drug--CPP approach. To clarify the applicability and limitations of this strategy, the present study examined the effects of cargo size on the absorption-stimulatory effect of CPPs. Different sizes of hydrophilic macromolecular dextran (4.4, 10, and 70 kDa) and polystyrene-based nanoparticles (20, 100, and 200 nm) were chosen as the model cargos in this study. In an in situ rat intestinal absorption study, CPPs (octaarginine, Tat, penetratin, and PenetraMax) increased the intestinal absorption of dextran, and the efficiency varied according to the molecular size of dextran. Among the CPPs, D-penetratin showed an enhancing effect even when coadministered with the largest dextran (70 kDa). By contrast, an in vitro study of Caco-2 cell uptake showed that the ability of CPPs to deliver nanoparticles into epithelial cells was dependent on their particle size and that the relatively poor internalization of 200-nm nanoparticles could be facilitated by coincubation with CPPs. These findings suggest that the intrinsic uptake properties of macromolecules and particulate cargos determine the effectiveness of their intestinal mucosal delivery using the noncovalent CPP method.

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Section: Effect Of Cpps On the Intestinal Absorption Of Dextransupporting

confidence: 91%

Applicability and Limitations of Cell-Penetrating Peptides in Noncovalent Mucosal Drug or Carrier Delivery Systems

Kamei

Nielsen

Nakakubo

et al. 2016

Journal of Pharmaceutical Sciences

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“…injection. More recently, a modified form of penetratin, labeled PenetraMax, was able to facilitate transport across the small intestine into the blood stream . Thus, with additional modifications, it may be possible to deliver the scFv orally for delivery across the intestinal epithelium, through the blood stream and finally across the blood–brain barrier for action in the CNS.…”

Section: Discussionmentioning

confidence: 99%

α‐synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease

Spencer

Williams

Rockenstein

et al. 2016

Ann Clin Transl Neurol

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ObjectiveProgressive accumulation of α‐synuclein (α‐syn) has been associated with Parkinson's disease (PD) and Dementia with Lewy body (DLB). The mechanisms through which α‐syn leads to neurodegeneration are not completely clear; however, the formation of various oligomeric species have been proposed to play a role. Antibody therapy has shown effectiveness at reducing α‐syn accumulation in the central nervous system (CNS); however, most of these studies have been conducted utilizing antibodies that recognize both monomeric and higher molecular weight α‐syn. In this context, the main objective of this study was to investigate the efficacy of immunotherapy with single‐chain antibodies (scFVs) against specific conformational forms of α‐syn fused to a novel brain penetrating sequence.MethodWe screened various scFVs against α‐syn expressed from lentiviral vectors by intracerebral injections in an α‐syn tg model. The most effective scFVs were fused to the cell‐penetrating peptide penetratin to enhance transport across the blood–brain barrier, and lentiviral vectors were constructed and tested for efficacy following systemic delivery intraperitoneal into α‐syn tg mice.ResultTwo scFVs (D5 and 10H) selectively targeted different α‐syn oligomers and reduced the accumulation of α‐syn and ameliorated functional deficits when delivered late in disease development; however, only one of the antibodies (D5) was also effective when delivered early in disease development. These scFVs were also utilized in an enzyme‐linked immunosorbent assay (ELISA) assay to monitor the effects of immunotherapy on α‐syn oligomers in brain and plasma.InterpretationThe design and targeting of antibodies for specific species of α‐syn oligomers is crucial for therapeutic immunotherapy and might be of relevance for the treatment of Lewy body disease.

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“…This is not consistent with our previous results of D-and L-form PenetraMax, which showed almost the same degree of absorption enhancement effects on insulin intestinal absorption. 17) This discrepancy could be a consequence of differences in absorption study methods (in situ versus in vivo studies). In this in vivo absorption study, the ability of L-form of PenetraMax was significantly diminished by the harsher environment of the entire gastrointestinal tract.…”

Section: Effect Of Penetratin and Penetramax On The In Vivomentioning

confidence: 99%

Exploration of the Key Factors for Optimizing the <i>in Vivo</i> Oral Delivery of Insulin by Using a Noncovalent Strategy with Cell-Penetrating Peptides

Kamei

Shigei

Hasegawa

et al. 2018

Biological & Pharmaceutical Bulletin

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This present study aimed to determine the optimal oral insulin delivery conditions that would maximize the utility of cell-penetrating peptides (CPPs) by using a noncovalent strategy. We first compared the effectiveness of two potential CPPs, penetratin and its analog PenetraMax, as absorption enhancers for insulin. The combined effect was evaluated under in vivo oral administration conditions. Both D-forms of CPPs were highly effective for increasing the oral absorption of insulin, and D-PenetraMax showed a more rapid onset of absorption enhancement effects compared with those of D-penetratin. However, synergistic absorption enhancement effects after combination treatment were not observed. Next, we tried a theoretical approach to establish optimized oral insulin delivery conditions. A surface plasmon resonance (SPR)-based analysis demonstrated that binding between insulin and penetratin (2 mM) might be saturated at 100-500 µM penetratin, while the bound concentration of penetratin could increase in accordance with an increased concentration of mixed insulin. To test this hypothesis, we investigated the effectiveness of different insulin doses in the gastric pH-neutralized mice. The results showed that the dissociation of noncovalent complexes of insulin and CPPs at the low gastric pH was prevented in these mice. Our findings clearly suggested that a noncovalent strategy with CPPs represents an effective approach for the L-form of CPP to increase the concentration of CPP-bound insulin to attain greater absorption of insulin, although this approach may not be appropriate for the D-form of CPP. Our findings will contribute to the development of oral dosage forms of insulin for noncovalent strategies involving CPP. Key words oral delivery; insulin; cell-penetrating peptide; penetratin; intermolecular interactionInsulin is the most important therapeutic agent for diabetes, even though there are now many other oral antidiabetic medicines available. Therefore, many types of insulin formulations, including rapid-and long-acting insulin as well as mixed type insulin, have been developed to date. 1-3) Diabetes patients can appropriately choose injectable types of insulin formulations; however, more convenient forms of insulin that can be administered via noninvasive routes, such as oral administration, have not yet been developed because of poor absorption through mucosal regions. [4][5][6][7] To further improve the QOL and compliance of patients, we aimed to develop a noninvasive form of insulin by using pharmaceutical technologies and drug delivery systems. Moreover, the oral route of insulin absorption has another advantage as insulin absorbed from the intestine first passes through the liver, similarly to endogenous insulin secreted to the portal vein; therefore, oral insulin can circumvent the risk of hypoglycemia.A major hurdle in the development of formulations for administration via noninvasive routes is the digestion and degradation in the harsh gastrointestinal environment. To protect biologics, such as insuli...

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Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Cited by 28 publications

References 55 publications

Applicability and Limitations of Cell-Penetrating Peptides in Noncovalent Mucosal Drug or Carrier Delivery Systems

Applicability and Limitations of Cell-Penetrating Peptides in Noncovalent Mucosal Drug or Carrier Delivery Systems

α‐synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease

Exploration of the Key Factors for Optimizing the <i>in Vivo</i> Oral Delivery of Insulin by Using a Noncovalent Strategy with Cell-Penetrating Peptides

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