pyrimidinones and phthalocyanine

Topical treatment using photodynamic therapy (PDT) for many types of skin cancers has largely been limited by the inability of existing photosensitizers to penetrate into the deep skin tissue. To overcome these problems, we developed a mesoporous nanovehicle with dual loading of photosensitizers and clinically relevant drugs for combination therapy, while utilizing microneedle technology to facilitate their penetration into deep skin tissue. Sub-50 nm photodynamically active mesoporous organosilica nanoparticles were synthesized with photosensitizers covalently bonded to the silica matrix, which dramatically increased the quantum yield and photostability of these photosensitizers. The mesopores of the nanoparticles were further loaded with small-molecule inhibitors, i. e., dabrafenib and trametinib, that target the hyperactive mitogen-activated protein kinase (MAPK) pathway for melanoma treatment. As-prepared empty nanovehicle was cytocompatible with normal skin cells in the dark, while NIR-irradiated drug-loaded nanovehicle showed a synergistic killing effect on skin cancer cells mainly through reactive oxygen species and caspase-activated apoptosis. The nanovehicle could significantly inhibit the proliferation of tumor cells in a 3D spheroid model in vitro. Porcine skin fluorescence imaging demonstrated that microneedles could facilitate the penetration of nanovehicle across the epidermis layer of skin to reach deep-seated melanoma sites. Tumor regression studies in a xenografted melanoma mouse model confirmed superior therapeutic efficacy of the nanovehicle through combinational PDT and targeted therapy.

Topics: Administration, Topical; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Combined Modality Therapy; Drug Delivery Systems; Female; Heterografts; Humans; Imidazoles; Indoles; Isoindoles; Melanoma; Mice, Nude; Nanostructures; Needles; Oxidative Stress; Oximes; Photochemotherapy; Photosensitizing Agents; Pyridones; Pyrimidinones; Silicon Dioxide; Skin Neoplasms

The photodynamic inactivation of herpes simplex virus type 1 (HSV-1) by two phthalocyanines (Pcs), the cationic dye HOSi-PcOSi(CH3)2(CH2)3N+(CH3)3I-(Pc5) and the amphiphilic dye aluminum dibenzodisulfophthalocyanine hydroxide (AlN2SB2POH), has been compared with that by the anionic dye, Merocyanine 540 (Mc540). Both Pc derivatives demonstrate a remarkable virucidal activity upon light activation even 3 h after the onset of HSV-1 adsorption, while Mc540 is effective for only 30 min after adsorption. Since fusion and virus penetration are promoted by membrane glycoproteins, we have studied the damage to viral proteins following photodynamic treatment (PDT) of HSV-1 and its relation to inactivation. The effect of AlN2SB2POH PDT is assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Major changes are found in the protein profile of PDT-treated HSV-1. A reduced ability of specific antibodies to react with HSV-1 major envelope proteins is detected by employing the Western blot assay. In particular, we demonstrate the related changes of glycoprotein D (gD), a structural protein of the HSV envelope. Since the envelope proteins participate in viral entry into the host cell, these alterations to viral envelope proteins may impair their ability to participate in early events of viral entry, leading to reduced infectivity of HSV-1. In contrast, no significant changes in the proteins' electrophoretic mobility could be seen after PDT with Mc540 or with Pc5. When HSV-1 purified proteins are subjected to combined electrophoretic and electro osmotic forces on cellulose acetate, there is a shift in their cathode mobility, which may indicate changes in the protein mass and protein net charges following AlN2SB2POH photosensitization. There are only minor changes in the virus proteins, assayed as above, when HSV-1 is treated with Pc5.

Topics: Animals; Chlorocebus aethiops; Gene Products, env; Indoles; Isoindoles; Kinetics; Light; Photosensitizing Agents; Pyrimidinones; Simplexvirus; Vero Cells; Viral Proteins

Topics: Animals; Female; Hematoporphyrins; Indoles; Isoindoles; Mice; Mice, Inbred DBA; Neoplasms, Experimental; Photochemotherapy; Photolysis; Pyrimidinones; Radiation-Sensitizing Agents; Spectrometry, Fluorescence