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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Imiquimod (AldaraTM, ZyclaraTM) is a low molecular weight (240.30 g/mol) imidazoquinoline compound that acts as an immune response modifier (Figure 9.12). It is used to treat superficial basal cell carcinoma lesions usually after surgery but is also used for actinic keratosis (considered to be pre-cancerous) and warts (including genital warts). Imiquimod was discovered by researchers at 3M who were investigating inhibitors of herpes virus replication based on the structure of adenine. 3M obtained the first FDA approval in 1997 under the brand AldaraTM for the treatment of external genital and perianal warts. After the topical anticancer properties of imiquimod were established, 3M obtained a second approval in 2004 for its use as a treatment for superficial basal cell carcinoma. As of 2015, imiquimod became generic and available worldwide under a number of brand names. Structure of imiquimod (AldaraTM).
Treatment
Published in William Bonnez, Guide to Genital HPV Diseases and Prevention, 2019
Imiquimod is an imidazoquinoline that induces the local production of interferon α and other cytokines. Available as a 5% cream (Aldara) it is approved for the self-treatment of external genital warts, but it also has been used with success for the treatment of internal anogenital warts and of intraepithelial neoplasias of the anus, vulva, and vagina. Warts located in moist areas tend to respond better that those located on dry skin, and this explains the approximately two-fold greater efficacy in women than men. Local side-effects are common, but usually well-tolerated. They include itching, burning sensation, redness, erosion, and edema. Length of treatment, up to 16 weeks, and its related cost are two disadvantages of Aldara. It should not be used during pregnancy. - Imiquimod(Aldara box of 12 single use 250-mg packets): 5% cream applied at bedtime, three times a week, every other day, for at least 8 weeks and up to 16 weeks.
Special Senses
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Kenneth A. Schafer, Oliver C. Turner, Richard A. Altschuler
Toxicity involving the tapetum lucidum is occasionally observed in the dog, and since humans do not have this ocular structure, compound-related tapetal findings may not be relevant to humans (Heywood 1974; Hockwin et al. 1991). In an attempt to determine relevancy, atapetal beagles, which have tapetal cells but lack intracytoplasmic rodlets, have at times been used (Bellhorn et al. 1975; Heywood 1972). For example, administration of imidazoquinoline to normal beagles results in tapetal and retinal changes, but atapetal beagles have no retinal changes (Schiavo 1972). The principal toxicity-related finding involving the tapetum lucidum is degeneration (Haggerty et al. 2007; Heywood et al. 1976). Tapetal cells appear dull, discolored, or mottled, funduscopically. Microscopically, inflammation, edema, hemorrhage, or retinal detachment will be present (Hockwin et al. 1991; Rubin 1974).
Tilsotolimod: an investigational synthetic toll-like receptor 9 (TLR9) agonist for the treatment of refractory solid tumors and melanoma
Published in Expert Opinion on Investigational Drugs, 2022
Christian Karime, Jing Wang, Gregory Woodhead, Kabir Mody, Charles T. Hennemeyer, Mitesh J. Borad, Daruka Mahadevan, Sreenivasa R. Chandana, Hani Babiker
Research has shown that members of the TLR family have an immunostimulatory role on effector cells involved in the anti-tumor immune response [20]. As such, TLR agonists at have become a promising class of agents for the development of novel immunotherapeutic approaches. TLR-3 agonists such as polyinosinic:polycytidylic acid have been shown to reduce cancer progression through cytokine-mediated attraction of TIL and checkpoint upregulation, while TLR-4 agonists such as synthetic lipid A analog have been shown to promote chemoradiotherapy sensitization of tumor cells through proinflammatory cytokine production [36,37]. Furthermore, TLR-7 and TLR-8 agonists of the imidazoquinoline family have shown good topical anti-tumoral efficacy through inducing inflammatory cell infiltration [38,39]. Important in cancers whose immunosuppressive characteristics reduce the efficacy of checkpoint inhibitor therapy, TLR-9 activation has been implicated in modulating the TME toward a more immunopotentiating composition and enhancing the Type 1 helper (Th1) immune response [4].
The role of MPL and imiquimod adjuvants in enhancement of immune response and protection in BALB/c mice immunized with soluble Leishmania antigen (SLA) encapsulated in nanoliposome
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Tara Emami, Seyed Mahdi Rezayat, Ali Khamesipour, Rasool Madani, Gholamreza Habibi, Mansure Hojatizade, Mahmoud Reza Jaafari
In this study, two adjuvants were used in liposome formulation, imiquimod (IMQ) (TLR7 ligand) and MPL (TLR4 ligand), which trigger Toll-like receptors to activate immune system [26,27]. MPL is a portion of Salmonella minnesota lipopolysaccharide in which the (R)-3-hydroxytetradecanoyl group and 1-phosphate have been omitted by hydrolysis. MPL stimulate immune system through innate immune response by TLR4 receptor [28,29]. IMQ is a synthetic small-molecule compound in the imidazoquinoline family, which is FDA approved, it is used in dermatology lesion as an immunopotentiator agent. It could stimulate innate immune system through cytokine induction [30]. IMQ is the agonist of TLR7 and has immunomodulatory activity. Innate immune cells could be activated through Toll-like receptor agonists [31,32]. Pathogen-associated molecular patterns are recognized through receptors of innate immune system. TLRs include the main class of cell surface PRP’s, which are presented on dendritic cells and macrophages. TLR7 commonly recognize single strand RNA (of viruses) and lead Th1-type cytokine secretion [31]. These TLRs agonists activate innate immune cells by TLR/MyD88/NF-kB and IFN regulatory factor 3/7 pathways [32]. Antigen, which was used, is SLA. Eight liposomal formulations were designed to investigate the effect of antigen and adjuvant in liposome formulation, and thirteen groups containing 10 mice designed to study the experimental vaccine.
Resistance of hepatocellular carcinoma to sorafenib can be overcome with co-delivery of PI3K/mTOR inhibitor BEZ235 and sorafenib in nanoparticles
Published in Expert Opinion on Drug Delivery, 2020
Binquan Wu, Amin Li, Yinci Zhang, Xueke Liu, Shuping Zhou, Huaiyong Gan, Shiyu Cai, Yong Liang, Xiaolong Tang
We have confirmed that BEZ235, an imidazoquinoline derivative, inhibits the kinase activities of PI3K, mTORC1 and mTORC2, and its anti-tumor efficacy has been demonstrated in preclinical models [26,27], plays a key role in enhancing the antitumor activity of SFB in HCC cells. In this study, based on the synthesis of PCL-TPGS (through structural optimization and chemical modification), we prepared a dual drug-delivery system by combined loading of SFB and BEZ235 into naoparticles (SFB/BEZ235-NPs). With the system, we aim to co-deliver drugs and target tissue enrichment to exert the synergistic effect of BEZ235 and SFB, increase SFB therapeutic effectiveness against HCC, and, especially, improve the effectiveness of treatment of SFB-resistant HCC and reduce the side effects of drugs.