Combining poly-arginine with the hydrophobic counter-anion 4-(1-pyrenyl)-butyric acid for protein transduction in transdermal delivery

Abstract

Topical therapy is the most favored form of treatment for whitening against hyperpigmentation and sunburn because it lends itself to self-administration, patient compliance, and absence of systemic adverse effects. However, transdermal delivery of hydrophilic chemicals is difficult. The main purpose of this study is to develop a delivering system of hydrophilic drugs and proteins across the skin. Hydroquinone (HQ), a well-known tyrosinase inhibitor and antimelanogenesis compound, and enhanced green fluorescent protein (EGFP) were fused with eleven poly-arginine (11R). Both HQ-11R and EGFP-11R were efficiently delivered in B16 cells, a mouse melanoma cell line. HQ-11R was as effective as HQ alone at inhibiting melanin synthesis in B16 cells. EGFP-11R was efficiently delivered into cells of the epidermis with 4-(1-pyrenyl)-butyric acid (PB), a counteranion bearing an aromatic hydrophobic moiety, in vivo, but EGFP alone or EGFP-11R without PB was not. Finally, topical application of HQ-11R with PB significantly inhibited UV irradiationinduced pigmentation in guinea pigs compared with HQ alone. These results suggest that topical therapy using poly-arginine in combination with PB is useful for the delivery of hydrophilic drugs and proteins by the transdermal route . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Abstract Topical therapy is the most favored form of treatment for whitening against hyperpigmentation and sunburn because it lends itself to self-administration, patient compliance, and absence of systemic adverse effects. However, transdermal delivery of hydrophilic chemicals is difficult. The main purpose of this study is to develop a delivering system of hydrophilic drugs and proteins across the skin. Hydroquinone (HQ), a well-known tyrosinase inhibitor and antimelanogenesis compound, and enhanced green fluorescent protein (EGFP) were fused with eleven poly-arginine (11R).Both HQ-11R and EGFP-11R were efficiently delivered in B16 cells, a mouse melanoma cell line. HQ-11R was as effective as HQ alone at inhibiting melanin synthesis in B16 cells. EGFP-11R was efficiently delivered into cells of the epidermis with 4-(1-pyrenyl)-butyric acid (PB), a counteranion bearing an aromatic hydrophobic moiety, in vivo, but EGFP alone or EGFP-11R without PB was not. Finally, topical application of HQ-11R with PB significantly inhibited UV irradiation-induced pigmentation in guinea pigs compared with HQ alone. These results suggest that topical therapy using poly-arginine in combination with PB is useful for the delivery of hydrophilic drugs and proteins by the transdermal route. *Abstract1 2 3 4 5 6 7 8

Current Understanding of Direct Translocation of Arginine-Rich Cell-Penetrating Peptides and Its Internalization Mechanisms

“…We also found that pyrenebutyrate promotes translocation of enhanced green fluorescent protein (EGFP) conjugated with R8 into the cytosol of cultured cells such as HeLa cells and rat hippocampus primary neurons, suggesting applicability of this method to cytosolic delivery for exogenous molecules. So far, pyrenebutyrate-assisted translocation has been widely used for promoting the intracellular delivery of CPP-conjugated bioactive molecules including an apoptosis-inducing peptide PAD, 46) a tyrosinase inhibitor Hydroquinone, 47) a tumor suppressor p53, 48) and chemically modified fluorescent tags/proteins for fluorescent imaging 49,50) (Table 2). In-cell NMR spectroscopy is one of the prominent applications of pyrenebutyrate-assisted translocation.…”

Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines

“…Numerous studies have demonstrated that oligoarginine CPPs play an important role in overcoming both cellmembrane barriers 27 and tissue barriers. [54][55][56][57] Candan et al 53 developed a system to deliver hydrophilic drugs and proteins across the skin by employing polyarginine (R 11 ) and found that topical therapy using R 11 enhanced the delivery of hydrophilic cargo by the transdermal route through directed conjugation with payloads. Taking this strategy further, Shah et al 54 investigated the effect of polyarginine on topical delivery of surface-modified nanostructured lipid carriers containing spantide II/ketoprofen and demonstrated that the surface modification of these carriers with R 11 improved transport of drugs across the deeper skin layers.…”

Fabrication of Carboxylmethyl Chitosan Nanocarrier via Self-Assembly for Efficient Delivery of Phenylethyl Resorcinol in B16 Cells

“…Especially, hyperpigmentation is an important disease in the skin care industry, mainly due to prolonged exposure to ultraviolet light and excessive use of certain chemical drugs [3,4]. The common and effective treatments for all types of hyperpigmentary disorders are topical tyrosinase inhibitors and antimelanogenesis compounds, such as hydroquinone (HQ), kojic acid (KA), azelaic acid (AA), and phenylethyl resorcinol (PR) [5][6][7][8]. Specially, PR is an effective skin lightening agent compared with other commonly used skin lightening drugs and proved to be a highly safe ingredient [9].…”