PMID- 34319645
OWN - NLM
STAT- MEDLINE
DCOM- 20220331
LR  - 20230102
IS  - 1552-4965 (Electronic)
IS  - 1549-3296 (Print)
IS  - 1549-3296 (Linking)
VI  - 110
IP  - 1
DP  - 2022 Jan
TI  - Macrophage depletion increases target specificity of bone-targeted nanoparticles.
PG  - 229-238
LID - 10.1002/jbm.a.37279 [doi]
AB  - Despite efforts to achieve tissue selectivity, the majority of systemically 
      administered drug delivery systems (DDSs) are cleared by the mononuclear 
      phagocyte system (MPS) before reaching target tissues regardless of disease or 
      injury pathology. Previously, we showed that while tartrate-resistant acid 
      phosphatase (TRAP) binding peptide (TBP)-targeted polymeric nanoparticles 
      (TBP-NP) delivering a bone regenerative Wnt agonist improved NP fracture 
      accumulation and expedited healing compared with controls, there was also 
      significant MPS accumulation. Here we show that TBP-NPs are taken up by liver, 
      spleen, lung, and bone marrow macrophages (Mvarphi), with 76 +/- 4%, 49 +/- 11%, 27 +/- 9%, 
      and 92 +/- 5% of tissue-specific Mvarphi positive for NP, respectively. Clodronate 
      liposomes (CLO) significantly depleted liver and spleen Mvarphi, resulting in 1.8-fold 
      and 3-fold lower liver and spleen and 1.3-fold and 1.6-fold greater fracture and 
      naive femur accumulation of TBP-NP. Interestingly, depletion and saturation of 
      MPS using 10-fold greater TBP-NP doses also resulted in significantly higher 
      TBP-NP accumulation at lungs and kidneys, potentially through compensatory 
      clearance mechanisms. The higher NP dose resulted in greater TBP-NP accumulation 
      at naive bone tissue; however, other MPS tissues (i.e., heart and lungs) 
      exhibited greater TBP-NP accumulation, suggesting uptake by other cell types. 
      Most importantly, neither Mvarphi depletion nor saturation strategies improved 
      fracture site selectivity of TBP-NPs, possibly due to a reduction of Mvarphi-derived 
      osteoclasts, which deposit the TRAP epitope. Altogether, these data support that 
      MPS-mediated clearance is a key obstacle in robust and selective fracture 
      accumulation for systemically administered bone-targeted DDS and motivates the 
      development of more sophisticated approaches to further improve fracture 
      selectivity of DDS.
CI  - (c) 2021 Wiley Periodicals LLC.
FAU - Ackun-Farmmer, Marian A
AU  - Ackun-Farmmer MA
AUID- ORCID: 0000-0003-3081-5115
AD  - Department of Biomedical Engineering, University of Rochester, Rochester, New 
      York, USA.
AD  - Department of Orthopaedics and Center for Musculoskeletal Research, University of 
      Rochester Medical Center, Rochester, New York, USA.
FAU - Xiao, Baixue
AU  - Xiao B
AUID- ORCID: 0000-0001-8337-8401
AD  - Department of Biomedical Engineering, University of Rochester, Rochester, New 
      York, USA.
AD  - Department of Orthopaedics and Center for Musculoskeletal Research, University of 
      Rochester Medical Center, Rochester, New York, USA.
FAU - Newman, Maureen R
AU  - Newman MR
AUID- ORCID: 0000-0002-9004-3332
AD  - Department of Biomedical Engineering, University of Rochester, Rochester, New 
      York, USA.
AD  - Department of Orthopaedics and Center for Musculoskeletal Research, University of 
      Rochester Medical Center, Rochester, New York, USA.
FAU - Benoit, Danielle S W
AU  - Benoit DSW
AUID- ORCID: 0000-0001-7137-8164
AD  - Department of Biomedical Engineering, University of Rochester, Rochester, New 
      York, USA.
AD  - Department of Orthopaedics and Center for Musculoskeletal Research, University of 
      Rochester Medical Center, Rochester, New York, USA.
AD  - Department of Chemical Engineering, University of Rochester, Rochester, New York, 
      USA.
AD  - University of Rochester, Materials Science Program, Rochester, New York, USA.
LA  - eng
GR  - P30 AR069655/AR/NIAMS NIH HHS/United States
GR  - P30 AR069655/NH/NIH HHS/United States
GR  - F31 CA228391/NH/NIH HHS/United States
GR  - R01 AR056696/AR/NIAMS NIH HHS/United States
GR  - S10 RR026542/RR/NCRR NIH HHS/United States
GR  - F31 CA228391/CA/NCI NIH HHS/United States
GR  - R01 AR064200/NH/NIH HHS/United States
GR  - UL1 TR002001/TR/NCATS NIH HHS/United States
GR  - R01 AR056696/NH/NIH HHS/United States
GR  - R01 AR064200/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210728
PL  - United States
TA  - J Biomed Mater Res A
JT  - Journal of biomedical materials research. Part A
JID - 101234237
RN  - 0 (Liposomes)
SB  - IM
MH  - Bone and Bones
MH  - Drug Delivery Systems
MH  - Liposomes
MH  - Macrophages/metabolism
MH  - *Nanoparticles
PMC - PMC8595540
MID - NIHMS1726539
OTO - NOTNLM
OT  - biodistribution
OT  - bone targeting
OT  - clodronate-liposomes
OT  - macrophages
OT  - nanoparticles
COIS- Conflict of Interest The authors have no conflict of interest to declare.
EDAT- 2021/07/29 06:00
MHDA- 2022/04/01 06:00
PMCR- 2023/01/01
CRDT- 2021/07/28 13:02
PHST- 2021/07/13 00:00 [revised]
PHST- 2021/04/23 00:00 [received]
PHST- 2021/07/15 00:00 [accepted]
PHST- 2021/07/29 06:00 [pubmed]
PHST- 2022/04/01 06:00 [medline]
PHST- 2021/07/28 13:02 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.1002/jbm.a.37279 [doi]
PST - ppublish
SO  - J Biomed Mater Res A. 2022 Jan;110(1):229-238. doi: 10.1002/jbm.a.37279. Epub 
      2021 Jul 28.