Moreira Rute, Jervis Peter J, Carvalho André, Ferreira Paula M T, Martins José A, Valentão Patrícia, Andrade Paula B, Perreira David M
REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, R. Jorge Viterbo Ferreira, n 228, 4050-313 Porto, Portugal.
Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Pharmaceutics. 2020 Feb 3;12(2):122. doi: 10.3390/pharmaceutics12020122.
The use of peptide-drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen-dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition upon remote magnetic excitation. Thus, magnetic dehydrodipeptide-based hydrogels may find interesting applications as responsive Magnetic Resonance Imaging (MRI) contrast agents and for magnetic hyperthermia-triggered drug-release applications. Supramolecular hydrogels where the hydrogelator molecule is endowed with intrinsic pharmacological properties can potentially fulfill a dual function in drug delivery systems as (passive) nanocariers for incorporated drugs and as active drugs themselves. In this present study, we investigated the pharmacological activities of a panel of naproxen-dehydrodipeptide conjugates, previously studied for their hydrogelation ability and as nanocarriers for drug-delivery applications. A focused library of dehydrodipeptides, containing -terminal canonical amino acids (Phe, Tyr, Trp, Ala, Asp, Lys, Met) -capped with naproxen and linked to a -terminal dehydroaminoacid (ΔPhe, ΔAbu), were evaluated for their anti-inflammatory and anti-cancer activities, as well as for their cytotoxicity to non-cancer cells, using a variety of enzymatic and cellular assays. All compounds except one were able to significantly inhibit lipoxygenase (LOX) enzyme at a similar level to naproxen. One of the compounds was able to inhibit the cyclooxygenase-2 (COX-2) to a greater extent than naproxen, without inhibiting cyclooxygenase-1 (COX-1), and therefore is a potential lead in the search for selective COX-2 inhibitors. This hydrogelator is a potential candidate for dual COX/LOX inhibition as an optimised strategy for treating inflammatory conditions.
肽-药物缀合物的应用正成为一种强大的靶向给药策略。此前，我们发现与非甾体抗炎药（NSAID）缀合的肽，更具体地说是萘普生-脱氢二肽缀合物，很容易形成纳米结构的纤维状超分子水凝胶。这些水凝胶被证明是用于药物递送应用的有效纳米载体。此外，超顺磁性氧化铁纳米颗粒（SPIONs）的加入使水凝胶对外部磁场产生响应，在远程磁激发下发生凝胶-溶液相变。因此，基于磁性脱氢二肽的水凝胶可能作为响应性磁共振成像（MRI）造影剂以及用于磁热疗触发的药物释放应用而具有有趣的应用前景。水凝胶剂分子具有内在药理特性的超分子水凝胶在药物递送系统中可能具有双重功能，既作为所包封药物的（被动）纳米载体，又作为活性药物本身。在本研究中，我们研究了一组萘普生-脱氢二肽缀合物的药理活性，这些缀合物之前已因其凝胶化能力以及作为药物递送应用的纳米载体而被研究。使用各种酶促和细胞测定法，评估了一个聚焦的脱氢二肽文库，该文库包含用萘普生封端并与一个末端脱氢氨基酸（ΔPhe、ΔAbu）相连的 -末端标准氨基酸（Phe、Tyr、Trp、Ala、Asp、Lys、Met），评估其抗炎和抗癌活性以及对非癌细胞的细胞毒性。除一种化合物外，所有化合物都能在与萘普生相似的水平上显著抑制脂氧合酶（LOX）酶。其中一种化合物 能够比萘普生更有效地抑制环氧合酶-2（COX-2），而不抑制环氧合酶-1（COX-1），因此是寻找选择性COX-2抑制剂的潜在先导化合物。这种水凝胶剂作为治疗炎症性疾病的优化策略，是双重COX/LOX抑制的潜在候选物。
