Thermosensitive Gel–Based Formulation for Intratumoral Delivery of Toll-Like Receptor 7/8 Dual Agonist, MEDI9197
| Autor: | James Elvecrog, Amir Fakhari, Sean Nugent, John P. Vasilakos, Alexander Schwarz, Ashenafi Y. Tilahun, Marta Corcoran, J. Anand Subramony, Kristen Siebenaler, Jenny Sun |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class medicine.medical_treatment Melanoma Experimental Pharmaceutical Science Antineoplastic Agents Poloxamer Pharmacology Mice 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems 0302 clinical medicine Pharmacokinetics medicine Animals Receptor Temperature Mice Inbred C57BL Imidazoquinoline 030104 developmental biology Cytokine Toll-Like Receptor 7 chemistry Toll-Like Receptor 8 Delayed-Action Preparations 030220 oncology & carcinogenesis Poloxamer 407 Drug delivery Systemic administration Cytokines Female Gels Heterocyclic Compounds 3-Ring Stearic Acids medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 106:2037-2045 |
| ISSN: | 0022-3549 |
| DOI: | 10.1016/j.xphs.2017.04.041 |
| Popis: | Toll-like receptor (TLR) agonists TLR 7/8, MEDI9197, is a imidazoquinoline analogue that can be used for cancer immunotherapy based on its efficacy toward a variety of tumors. Systemic administration of TLR agonists results in stimulation of the immune system throughout the entire body causing undesirable side effects. To minimize these adverse events, local administration of TLR agonists including intratumoral (IT) delivery has been introduced. Here, a poloxamer 407 thermogel formulation for IT delivery of a TLR 7/8 dual agonist, MEDI9197, is described in which the combination of the aqueous thermogel and the ethanolic TLR 7/8 dual agonist, MEDI9197, solution leads to precipitated drug particles within the gel. The in vitro release profile showed an initial burst followed by sustained release. A B16-OVA mouse tumor model was used to assess the in vivo pharmacokinetics, efficacy, and systemic cytokine and chemokine (cytokine) production of the poloxamer 407–based thermogel formulation. The pharmacokinetic evaluation showed that the agonist level within the tumor was reduced by ∼70% over 14 days while serum agonist levels indicated an initial burst at the 6-h time point followed by a drop in serum drug levels over the 14 days of the experiment. The tumor growth inhibition, survival, and serum cytokines for post-IT injection of the poloxamer 407 formulation showed that it slowly released TLR 7/8 agonist, MEDI9197, resulting in more efficacious tumor growth inhibition compared with control groups. In addition, the cytokine levels in circulation indicated that a dose increase led to a decrease in the serum inflammatory and interferon-inducible cytokines levels. This observation could be due to a reduction of drug diffusion and escape from the tumor site due to the precipitation of the drug inside the tumor leading to sustained release. IT delivery of TLR 7/8 dual agonist, MEDI9197, via a thermosensitive gel–based formulation was efficacious and could offer an alternate method of local drug delivery. |
| Databáze: | OpenAIRE |
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