PMID- 32042330 OWN - NLM STAT- MEDLINE DCOM- 20210413 LR - 20210413 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 10 IP - 4 DP - 2020 TI - Sex Differences Revealed in a Mouse CFA Inflammation Model with Macrophage Targeted Nanotheranostics. PG - 1694-1707 LID - 10.7150/thno.41309 [doi] AB - Monocyte derived macrophages (MDMs) infiltrate sites of infection or injury and upregulate cyclooxygenase-2 (COX-2), an enzyme that stimulates prostaglandin-E2 (PgE2). Nanotheranostics combine therapeutic and diagnostic agents into a single nanosystem. In previous studies, we demonstrated that a nanotheranostic strategy, based on theranostic nanoemulsions (NE) loaded with a COX-2 inhibitor (celecoxib, CXB) and equipped with near-infrared fluorescent (NIRF) reporters, can specifically target circulating monocytes and MDMs. The anti-inflammatory and anti-nociceptive effects of such cell-specific COX-2 inhibition lasted several days following Complete Freund's Adjuvant (CFA) or nerve injury in male mice. The overall goal of this study was to investigate the extended (up to 40 days) impact of MDM-targeted COX-2 inhibition and any sex-based differences in treatment response; both of which remain unknown. Our study also evaluates the feasibility and efficacy of a preclinical nanotheranostic strategy for mechanistic investigation of the impact of such sex differences on clinical outcomes. Methods: CFA was administered into the right hind paws of male and female mice. All mice received a single intravenous dose of NIRF labeled CXB loaded NE twelve hours prior to CFA injection. In vivo whole body NIRF imaging and mechanical hypersensitivity assays were performed sequentially and ex vivo NIRF imaging and immunohistopathology of foot pad tissues were performed at the end point of 40 days. Results: Targeted COX-2 inhibition of MDMs in male and female mice successfully improved mechanical hypersensitivity after CFA injury. However, we observed distinct sex-specific differences in the intensity or longevity of the nociceptive responses. In males, a single dose of CXB-NE administered via tail vein injection produced significant improved mechanical hypersensitivity for 32 days as compared to the drug free NE (DF-NE) (untreated) control group. In females, CXB-NE produced similar, though less prominent and shorter-lived effects, lasting up to 11 days. NIRF imaging confirmed that CXB-NE can be detected up to day 40 in the CFA injected foot pad tissues of both sexes. There were distinct signal distribution trends between males and females, suggesting differences in macrophage infiltration dynamics between the sexes. This may also relate to differences in macrophage turnover rate between the sexes, a possibility that requires further investigation in this model. Conclusions: For the first time, this study provides unique insight into MDM dynamics and the early as well as longer-term targeted effects and efficacy of a clinically translatable nanotheranostic agent on MDM mediated inflammation. Our data supports the potential of nanotheranostics as presented in elucidating the kinetics, dynamics and sex-based differences in the adaptive or innate immune responses to inflammatory triggers. Taken together, our study findings lead us closer to true personalized, sex-specific pain nanomedicine for a wide range of inflammatory diseases. CI - (c) The author(s). FAU - Liu, Lu AU - Liu L AD - Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, USA. AD - Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA, US. FAU - Karagoz, Huseyin AU - Karagoz H AD - Department of Surgery, Institute of Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States. FAU - Herneisey, Michele AU - Herneisey M AD - Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, USA. AD - Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA, US. FAU - Zor, Fatih AU - Zor F AD - Department of Surgery, Institute of Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States. FAU - Komatsu, Takaaki AU - Komatsu T AD - Department of Pharmacology, Daiichi University of Pharmacy, Fukuoka, Japan. FAU - Loftus, Shannon AU - Loftus S AD - Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, USA. AD - Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA, US. FAU - Janjic, Bratislav M AU - Janjic BM AD - NRG Oncology Foundation Inc., University of Pittsburgh, Pittsburgh PA, United States. FAU - Gorantla, Vijay S AU - Gorantla VS AD - Department of Surgery, Institute of Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States. FAU - Janjic, Jelena M AU - Janjic JM AD - Graduate School of Pharmaceutical Sciences, School of Pharmacy, Duquesne University, Pittsburgh, PA, USA. AD - Chronic Pain Research Consortium, Duquesne University, Pittsburgh, PA, US. LA - eng GR - R21 DA039621/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200101 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (Adjuvants, Immunologic) RN - 0 (Cyclooxygenase 2 Inhibitors) RN - 9007-81-2 (Freund's Adjuvant) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - JCX84Q7J1L (Celecoxib) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Adjuvants, Immunologic/administration & dosage/pharmacology MH - Administration, Intravenous MH - Animals MH - Celecoxib/administration & dosage/pharmacology/therapeutic use MH - Cyclooxygenase 2/metabolism MH - Cyclooxygenase 2 Inhibitors/administration & dosage/pharmacology/therapeutic use MH - Dinoprostone/metabolism MH - Disease Models, Animal MH - Drug Delivery Systems MH - Feasibility Studies MH - Female MH - Freund's Adjuvant/administration & dosage/pharmacology MH - Inflammation/chemically induced/*drug therapy MH - Macrophages/*drug effects MH - Male MH - Mice MH - Nanomedicine/*methods MH - Pain/chemically induced/*drug therapy MH - Sex Characteristics MH - Up-Regulation PMC - PMC6993234 OTO - NOTNLM OT - Pain nanomedicine OT - inflammatory pain OT - macrophages OT - nanotheranostic. OT - sex differences COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2020/02/12 06:00 MHDA- 2021/04/14 06:00 PMCR- 2020/01/01 CRDT- 2020/02/12 06:00 PHST- 2019/10/18 00:00 [received] PHST- 2019/11/12 00:00 [accepted] PHST- 2020/02/12 06:00 [entrez] PHST- 2020/02/12 06:00 [pubmed] PHST- 2021/04/14 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - thnov10p1694 [pii] AID - 10.7150/thno.41309 [doi] PST - epublish SO - Theranostics. 2020 Jan 1;10(4):1694-1707. doi: 10.7150/thno.41309. eCollection 2020.