Physicochemical Characterization and Skin Permeation of Cationic Transfersomes Containing the Synthetic Peptide PnPP-19

Almeida, Flávia De Marco; Silva, Carolina Nunes; Lopes, Sérgio de Faria; Santos, Daniel Moreira dos; Torres, Fernanda Silva; Cardoso, Felipe Lima; Martinelli, Patrícia Massara; Silva, Elizabeth Ribeiro da; Lima, Maria Elena de; Miranda, Lucas Antonio Ferreira; Oliveira, Mônica Cristina

doi:10.2174/1567201815666180108170206

Cited by 11 publications

(6 citation statements)

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“…PnPP-19 was able to cross the skin, which allows its use in a formulation for topical application, and it reversed the erectile dysfunction phenotype presented by hypertensive and diabetic animals. However, the permeation was limited, but it still showed good efficacy ( De Marco Almeida et al, 2018 ; Silva et al, 2019 ). To improve the permeation, we are trying to develop other formulations and minimize the costs.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, topical formulations to treat ED is a strong tendency, as it allows the use of drugs comfortably with fewer systemic side effects ( Foldvari et al, 1998 ; Elnaggar et al, 2011 ). PnPP-19 was able to permeate human ( De Marco Almeida et al, 2018 ) and rat skin ( Silva et al, 2019 ), remaining active after skin permeation in both STZ-induced diabetic and healthy animals. The physicochemical properties of PnPP-19, which is amphipathic, contain a high percentage of cationic residues, an isoelectric point of about 10.16, and a net positive charge of 3.9 at pH 7, resulting in favorable conditions for the skin permeation ( De Marco Almeida et al, 2018 ).…”

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 99%

“…PnPP-19 was able to permeate human ( De Marco Almeida et al, 2018 ) and rat skin ( Silva et al, 2019 ), remaining active after skin permeation in both STZ-induced diabetic and healthy animals. The physicochemical properties of PnPP-19, which is amphipathic, contain a high percentage of cationic residues, an isoelectric point of about 10.16, and a net positive charge of 3.9 at pH 7, resulting in favorable conditions for the skin permeation ( De Marco Almeida et al, 2018 ). Therefore, transdermal administration of PnPP-19 can be an alternative to the oral route ( Cevc and Vierl, 2010 ; Silva et al, 2019 ).…”

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 99%

“…Therefore, transdermal administration of PnPP-19 can be an alternative to the oral route ( Cevc and Vierl, 2010 ; Silva et al, 2019 ). However, although PnPP-19 is very active by topical application, its permeation is not so high ( De Marco Almeida et al, 2018 ; Silva et al, 2019 ). Currently, new approaches are being developed by our group to improve the peptide permeability across the human skin.…”

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 99%

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From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

Silva

Nunes

Dourado

et al. 2022

Front. Mol. Biosci.

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The venom of the “armed” spider Phoneutria nigriventer comprises several potent toxins. One of the most toxic components from this venom is the neurotoxin PnTx2-6 (LD50 = ∼ 0.7 μg/mouse, 48 residues, five disulfide bridges, MW = 5,289.31 Da), which slows down the inactivation of various Na+ channels. In mice and rats, this toxin causes priapism, an involuntary and painful erection, similar to what is observed in humans bitten by P. nigriventer. While not completely elucidated, it is clear that PnTx2-6 potentiates erectile function via NO/cGMP signaling, but it has many off-target effects. Seeking to obtain a simpler and less toxic molecule able to retain the pharmacological properties of this toxin, we designed and synthesized the peptide PnPP-19 (19 residues, MW = 2,485.6 Da), representing a discontinuous epitope of PnTx2-6. This synthetic peptide also potentiates erectile function via NO/cGMP, but it does not target Na+ channels, and therefore, it displays nontoxic properties in animals even at high doses. PnPP-19 effectively potentiates erectile function not only after subcutaneous or intravenous administration but also following topical application. Surprisingly, PnPP-19 showed central and peripheral antinociceptive activity involving the opioid and cannabinoid systems, suggesting applicability in nociception. Furthermore, considering that PnPP-19 increases NO availability in the corpus cavernosum, this peptide was also tested in a model of induced intraocular hypertension, characterized by low NO levels, and it showed promising results by decreasing the intraocular pressure which prevents retinal damage. Herein, we discuss how was engineered this smaller active non-toxic peptide with promising results in the treatment of erectile dysfunction, nociception, and glaucoma from the noxious PnTx2-6, as well as the pitfalls of this ongoing journey.

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Section: Discussionmentioning

confidence: 99%

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 99%

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 99%

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 99%

See 2 more Smart Citations

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

Silva

Nunes

Dourado

et al. 2022

Front. Mol. Biosci.

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“…Phosphatidylcholine and Tween 20 are classic transfersomal ingredients [ 26 , 27 , 28 , 29 , 30 ]. In addition to Tween 20, other non-ionic surfactants can also be included in the transfersome composition: sodium deoxycholate, sorbitan monooleate (Span 80), polysorbate 80 (Tween 80) [ 31 , 32 , 33 ], etc.…”

Section: Discussionmentioning

confidence: 99%

Transdermal Delivery of 2-PAM as a Tool to Increase the Effectiveness of Traditional Treatment of Organophosphate Poisoning

Васильева

Gaynanova

Zueva

et al. 2022

IJMS

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For the first time, the efficacy of post-exposure treatment of organophosphate (OP) poisoning was increased by transdermal delivery of acetylcholinesterase (AChE) reactivator pyridine-2-aldoxime methochloride (2-PAM) as a preventive countermeasure. By selecting the optimal ratio of components, classical transfersomes (based on soybean phosphatidylcholine and Tween 20) and modified transfersomes (based on soybean phosphatidylcholine, Tween 20 and pyrrolidinium cationic surfactants with different hydrocarbon tail lengths) were obtained for 2-PAM encapsulation. Transfersomes modified with tetradecylpyrrolidinium bromide showed the best results in encapsulation efficiency and sustained release of 2-PAM from vesicles. Using Franz cells, it was found that the incorporation of surfactants into PC liposomes results in a more prolonged release of 2-PAM through the rat skin. Transfersomes containing 2-PAM, after exhaustive physical and chemical characterization, were embedded in a gel based on Carbopol® 940. A significantly high degree of erythrocyte AChE reactivation (23 ± 7%) was shown for 2-PAM in unmodified transfersomes in vivo. Preliminary transdermal administration of 2-PAM 24 h before emergency post-exposure treatment of OP poisoning leads to an increase in the survival rate of rats from 55% to 90%.

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PnPP-19 Peptide Restores Erectile Function in Hypertensive and Diabetic Animals Through Intravenous and Topical Administration

Silva

Nunes

Almeida

et al. 2019

The Journal of Sexual Medicine

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Introduction With the aim of overcoming the high toxicity of PnTx2-6 (or δ-CNTX-Pn2a), a toxin from the venom of the armed spider (Phoneutria nigriventer), the 19-aminoacid peptide, PnPP-19 (P nigriventer potentiator peptide), was synthesized based on molecular modeling studies of PnTx2-6. PnPP-19 improved the erectile function of normotensive rats and mice, without eliciting side effects, and no signs of toxicity were observed. In addition, PnPP-19 was able to potentiate the effect of sildenafil. Aim To evaluate the efficacy of PnPP-19 in hypertensive and diabetic mouse/rat models in restoring erectile function, after topical administration; verify the biodistribution of PnPP-19 administration (topical and intravenous), permeation, and cyclic guanosine monophosphate (cGMP)/nitric oxide via implication. Methods Corpus cavernosum relaxation was evaluated using cavernous strips from male spontaneous hypertensive rats (SHR) and from streptozotocin (STZ)-diabetic mice contracted with phenylephrine and submitted to electrical field stimulation before and after incubation with PnPP-19 (10−8 mol/L, 10 minutes) or vehicle. This procedure was also used to determine cGMP/nitric oxide levels, at 8 Hz and to check the effect of PnPP-19 with sildenafil citrate. Biodistribution assays were performed using iodine 123–radiolabeled PnPP-19. In vivo erectile function was evaluated using intracavernosal pressure/main arterial pressure ratio in STZ-diabetic rats after PnPP-19 topical administration. Main Outcome Measures PnPP-19 may become a new drug able to fill the gap in the pharmacologic treatment of erectile dysfunction, especially for hypertensive and diabetic individuals Results PnPP-19 potentiated corpus cavernosum relaxation, in both control and SHR rats. SHR-cavernosal tissue treated with PnPP-19 (1–32 Hz) reached the same relaxation levels as control Wistar rats (16 and 32 Hz). PnPP-19 treatment improved cavernosal tissue relaxation in STZ-diabetic mice and rats. PnPP-19 enhanced cGMP levels in STZ-diabetic mice corpus cavernosum strips. After topical or intravenous administration in rats, 123I-PnPP-19 was mainly recruited to the penis. When topically administered (400 μg/rat), PnPP-19 restores erectile function in STZ-diabetic rats, also improving it in healthy rats by increasing the intracavernosal pressure/main arterial pressure ratio. PnPP-19 exhibited an additive effect when co-administered with sildenafil, showing a novel mode of action regardless of phosphodiesterase type 5 inhibition. Clinical Implications PnPP-19 seems to be an indicated drug to be tested to treat ED in diabetic and hypertensive patients. Strength & Limitations PnPP-19, although active by topical application and showing safety to human beings (not shown), has low permeability, about 10% of the applied dose. Conclusion Our results showed that PnPP-19 may emerge as a potent new drug that can be topically administered, becoming a promising alternative for erectile dysfunction treatment.

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Physicochemical Characterization and Skin Permeation of Cationic Transfersomes Containing the Synthetic Peptide PnPP-19

Abstract: The encapsulation of PnPP-19 in cationic transfersomes protected the peptide from degradation, favoring its topical administration.

Cited by 11 publications

References 0 publications

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

Transdermal Delivery of 2-PAM as a Tool to Increase the Effectiveness of Traditional Treatment of Organophosphate Poisoning

PnPP-19 Peptide Restores Erectile Function in Hypertensive and Diabetic Animals Through Intravenous and Topical Administration

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