Abstract
First-in-class membrane stabilizer Poloxamer 188 (P188) has been shown to confer membrane protection in an extensive range of clinical conditions; however, elements of the systemic distribution and localization of P188 at the organ, tissue, and muscle fiber levels in vivo have not yet been elucidated. Here we used non-invasive fluorescence imaging to directly visualize and track the distribution and localization of P188 in vivo. The results demonstrated that the Alx647 probe did not alter the fundamental properties of P188 to protect biological membranes. Distribution kinetics in mdx mice demonstrated that Alx647 did not interface with muscle membranes and had fast clearance kinetics. In contrast, the distribution kinetics for P188-Alx647 was significantly slower, indicating a dramatic depot and retention effect of P188. Results further demonstrated the significant retention of P188-Alx647 in the skeletal muscle of mdx mice, showing a significant genotype effect with a higher fluorescence signal in the mdx muscles over BL10 mice. High-resolution optical imaging provided direct evidence of P188 surrounding the sarcolemma of skeletal and cardiac muscle cells. Taken together, these findings provide direct evidence of muscle-disease-dependent molecular homing and retention of synthetic copolymers in striated muscles thereby facilitating advanced studies of copolymer-membrane association in health and disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 162-176 |
| Number of pages | 15 |
| Journal | Molecular Therapy Methods and Clinical Development |
| Volume | 28 |
| DOIs | |
| State | Published - Mar 9 2023 |
Bibliographical note
Funding Information:This work was supported by grants from NIH (R01HL138490, R01HL132874, R01AR071349, and R01HL122323) and the Muscular Dystrophy Association. We are grateful to the assistance of the UMN UIC Nikon Center of Excellence Imaging group and members of the Metzger lab for helpful discussions. A.B.B.A. conceived and designed the study, conducted animal experiments, analyzed data, and wrote the manuscript. H.C. helped design the study, conducted animal experiments, analyzed data, and wrote the manuscript. M.K. helped in designing the study, performed the P188-Alx647 synthesis and molecular characterization, analyzed data, and assisted in writing the manuscript. D.H. performed the FDB experiment and confocal images. N.V.Z. performed the P188-Alx647 synthesis and molecular characterization. T.P.L. M.A.H. B.J.H. and F.S.B. were essential in supervising M.K. and N.V.Z. and in conducting and editing the study. J.M.M. conceived and designed the study, supervised research, and aided in writing and editing the manuscript. J.M.M. is on the scientific advisory board and holds shares in Phrixus Pharmaceuticals Inc. a company developing novel therapeutics for heart failure. The terms of this arrangement have been reviewed and approved by the University of Minnesota in accordance with its conflict of interest policies.
Funding Information:
This work was supported by grants from NIH ( R01HL138490 , R01HL132874 , R01AR071349 , and R01HL122323 ) and the Muscular Dystrophy Association . We are grateful to the assistance of the UMN UIC Nikon Center of Excellence Imaging group and members of the Metzger lab for helpful discussions.
Publisher Copyright:
© 2022 The Author(s)
Keywords
- Duchenne muscular dystrophy
- Poloxamer 188
- biodistribution
- copolymer-membrane association
- damaged muscle membrane
- dystrophin-deficient mdx mice
- membrane stabilizer
- synthetic block copolymers
PubMed: MeSH publication types
- Journal Article