| Autor: |
Lacinski, Ryan A., Markel, Justin E., Pratt, Hillary G., Reinbeau, Ryan M., Stewart, Amanda, Santiago, Stell P., Lindsey, Brock A. |
| Předmět: |
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| Zdroj: |
Journal of Orthopaedic Research; Jul2023, Vol. 41 Issue 7, p1565-1581, 17p |
| Abstrakt: |
Clinical trials exploring bolus intravenous delivery of interleukin‐12 (IL‐12) for treatment of solid tumors ultimately failed due to lack of clinical response and severe dose‐limiting toxicities. The present study was conducted to evaluate whether recombinant murine IL‐12 (rmIL‐12) could be successfully encapsulated within Poly (D, l‐lactide‐co‐glycolide) (PLGA) nanospheres (rmIL‐12ns) for safe and effective systemic delivery at pharmacologic scale. Optimal fabrication of rmIL‐12ns occurs with dichloromethane as the organic solvent and emulsion formation via ultrasonication at 50% power (250 W sonicator) for 10 s (50W10s). We then determined whether utilization of synthesis modifiers including fetal bovine serum (FBS), magnesium hydroxide [Mg(OH)2], trehalose, or the surfactants polysorbate 80 and Span 60 alone or in combination could increase the encapsulation efficiency (EE) and/or modify the burst elution profile characteristic of the 50W10s rmIL‐12ns formulation. The greatest EEs compared to the unmodified formulation were measured with modifications containing the surfactants polysorbate 80 and Span 60 (surfactant: 28.3 ± 6.10%, p = 0.29 and Surf/FBS: 85.4 ± 2.19%, p = 0.039). The Surf/FBS formulation was further modified for in vivo murine injection by substituting FBS with mouse serum albumin (MSA). The resulting Surf/MSA rmIL‐12ns were then characterized before delivery at three doses (0.1, 1, and 10 mg rmIL‐12ns) in our established murine model of metastatic osteosarcoma to assess efficacy. Preliminary results suggested no evidence of disease with delivery of the 0.1 mg dose in 75% of mice (3 of 4) versus a nontreated historical control (2 of 34). [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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