Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Photoacoustic molecular imaging-escorted adipose photodynamic–browning synergy for fighting obesity with virus-like complexes

Nature Nanotechnology volume 16, pages 455–465 (2021)Cite this article

Subjects

Abstract

Photodynamic therapy and adipose browning induction are two promising approaches to reverse obesity. The former strategy acts rapidly and locally, whereas the latter has a more gradual and widespread effect. Despite their complementarity, they have rarely been combined and imaged non-invasively in vivo. Here we introduce an adipose-targeting hepatitis B core protein complex that contains a traceable photosensitizer (ZnPcS4 (zinc phthalocyanine tetrasulfonate)) and a browning agent (rosiglitazone) that allows simultaneous photodynamic and browning treatments, with photoacoustic molecular imaging. After intravenous injection in obese mice, the complex binds specifically to white adipose tissues, especially those rich in blood supply, and drives adipose reduction thanks to the synergy of ZnPcS4 photodynamics and rosiglitazone browning. Using photoacoustic molecular imaging, we could monitor the changes induced by the treatment, which included complex activity, lipid catabolism and angiogenesis. Our findings demonstrate the anti-obesity potential of our feedback-based synergic regimen orchestrated by the targeted hepatitis B core complex.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Scheme 1: Fabrication process of Pat-HBc/RSG&ZnPcS4 and its application in targeted PDB anti-obesity under the navigation of PA molecular imaging.
Fig. 1: Characterization of fabricated Pat-HBc complexes.
Fig. 2: In vitro assessments for cellular uptake and anti-obesity of Pat-HBc/RSG&ZnPcS4.
Fig. 3: Ex vivo and in vivo PAI for tracking fat accumulation of Pat-HBc/RSG&ZnPcS4.
Fig. 4: Fat reduction with the Pat-HBc/RSG&ZnPcS4-PDB regimen under PA surveillance.
Fig. 5: Alterations at the molecular level in adipose tissues after PDB treatment strategy.
Scheme 2: Anti-obesity mechanisms of Pat-HBc/RSG&ZnPcS4-mediated combination therapy.

Similar content being viewed by others

Data availability

All the datasets in the current study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

References

  1. Friedman, J. M. Causes and control of excess body fat. Nature 459, 340–342 (2009).

    Article  CAS  Google Scholar 

  2. Ng, M. et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766–781 (2014).

    Article  Google Scholar 

  3. Afshin, A. et al. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med. 377, 13–27 (2017).

    Article  Google Scholar 

  4. Van Gaal, L. F., Mertens, I. L. & De Block, C. E. Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 (2006).

    Article  Google Scholar 

  5. Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    Article  CAS  Google Scholar 

  6. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    Article  CAS  Google Scholar 

  7. Olson, O. C., Quail, D. F. & Joyce, J. A. Obesity and the tumor microenvironment. Science 358, 1130–1131 (2017).

    Article  CAS  Google Scholar 

  8. Heymsfield, S. B. & Wadden, T. A. Mechanisms, pathophysiology, and management of obesity. N. Engl. J. Med. 376, 254–266 (2017).

    Article  CAS  Google Scholar 

  9. Vetter, M. L., Faulconbridge, L. F., Webb, V. L. & Wadden, T. A. Behavioral and pharmacologic therapies for obesity. Nat. Rev. Endocrinol. 6, 578–588 (2010).

    Article  CAS  Google Scholar 

  10. Agostinis, P. et al. Photodynamic therapy of cancer: an update. Ca. Cancer J. Clin. 61, 250–281 (2011).

    Article  Google Scholar 

  11. Zhou, Z., Song, J., Nie, L. & Chen, X. Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem. Soc. Rev. 45, 6597–6626 (2016).

    Article  CAS  Google Scholar 

  12. Chilakamarthi, U. & Giribabu, L. Photodynamic therapy: past, present and future. Chem. Rec. 17, 775–802 (2017).

    Article  CAS  Google Scholar 

  13. Wanner, M. et al. Use of photodynamic therapy and sterile water to target adipose tissue. Dermatologic Surg. 41, 803–811 (2015).

    Article  CAS  Google Scholar 

  14. Peirce, V., Carobbio, S. & Vidal-Puig, A. The different shades of fat. Nature 510, 76–83 (2014).

    Article  CAS  Google Scholar 

  15. Liu, Y., Nie, L. & Chen, X. Photoacoustic molecular imaging: from multiscale biomedical applications towards early-stage theranostics. Trends Biotechnol. 34, 420–433 (2016).

    Article  CAS  Google Scholar 

  16. Wang, L. V. & Hu, S. Photoacoustic tomography: in vivo imaging from organelles to organs. Science 335, 1458–1462 (2012).

    Article  CAS  Google Scholar 

  17. Wang, L. V. & Yao, J. A practical guide to photoacoustic tomography in the life sciences. Nat. Methods 13, 627–638 (2016).

    Article  CAS  Google Scholar 

  18. Valluru, K. S., Wilson, K. E. & Willmann, J. K. Photoacoustic imaging in oncology: translational preclinical and early clinical experience. Radiology 280, 332–349 (2016).

    Article  Google Scholar 

  19. Reber, J. et al. Non-invasive measurement of brown fat metabolism based on optoacoustic imaging of hemoglobin gradients. Cell Metab. 27, 689–701 (2018).

    Article  CAS  Google Scholar 

  20. Lovell, J. F., Liu, T. W. B., Chen, J. & Zheng, G. Activatable photosensitizers for imaging and therapy. Chem. Rev. 110, 2839–2857 (2010).

    Article  CAS  Google Scholar 

  21. Calixto, G. M. F. et al. Nanotechnology-based drug delivery systems for photodynamic therapy of cancer: a review. Molecules 21, 342 (2016).

    Article  Google Scholar 

  22. Ho, C. J. H. et al. Multifunctional photosensitizer-based contrast agents for photoacoustic imaging. Sci. Rep. 4, 5342 (2014).

    Article  CAS  Google Scholar 

  23. Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 (2014).

    Article  CAS  Google Scholar 

  24. Mannerås-Holm, L. & Krook, A. Targeting adipose tissue angiogenesis to enhance insulin sensitivity. Diabetologia 55, 2562–2564 (2012).

    Article  Google Scholar 

  25. Festuccia, W. T., Laplante, M., Berthiaume, M., Gélinas, Y. & Deshaies, Y. PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control. Diabetologia 49, 2427–2436 (2006).

    Article  CAS  Google Scholar 

  26. Clarke, B. E. et al. Improved immunogenicity of a peptide epitope after fusion to hepatitis B core protein. Nature 330, 381–384 (1987).

    Article  CAS  Google Scholar 

  27. Ji, M. et al. Hepatitis B core VLP-based mis-disordered tau vaccine elicits strong immune response and alleviates cognitive deficits and neuropathology progression in Tau.P301S mouse model of Alzheimer’s disease and frontotemporal dementia. Alzheimers Res. Ther. 10, 55 (2018).

    Article  Google Scholar 

  28. Lu, Y. et al. Assessing sequence plasticity of a virus-like nanoparticle by evolution toward a versatile scaffold for vaccines and drug delivery. Proc. Natl Acad. Sci. USA 112, 12360–12365 (2015).

    Article  CAS  Google Scholar 

  29. Kolonin, M. G., Saha, P. K., Chan, L., Pasqualini, R. & Arap, W. Reversal of obesity by targeted ablation of adipose tissue. Nat. Med. 10, 625–632 (2004).

    Article  CAS  Google Scholar 

  30. Won, Y. W. et al. Oligopeptide complex for targeted non-viral gene delivery to adipocytes. Nat. Mater. 13, 1157–1164 (2014).

    Article  CAS  Google Scholar 

  31. Shan, W. et al. Improved stable indocyanine green (ICG)-mediated cancer optotheranostics with naturalized hepatitis B core particles. Adv. Mater. 30, 1707567 (2018).

    Article  Google Scholar 

  32. Kershaw, E. E. et al. PPARγ regulates adipose triglyceride lipase in adipocytes in vitro and in vivo. Am. J. Physiol. Endocrinol. Metab. 293, 1736–1745 (2007).

    Article  Google Scholar 

  33. Tang, J. et al. Obesity-associated family with sequence similarity 13, member A (FAM13A) is dispensable for adipose development and insulin sensitivity. Int. J. Obes. 43, 1269–1280 (2019).

    Article  CAS  Google Scholar 

  34. Thiam, A. R., Farese, R. V. J. & Walther, T. C. The biophysics and cell biology of lipid droplets. Nat. Rev. Mol. Cell Biol. 14, 775–786 (2013).

    Article  CAS  Google Scholar 

  35. Zhang, C. et al. A cystine knot peptide targeting integrin αvβ6 for photoacoustic and fluorescence imaging of tumors in living subjects. J. Nucl. Med. 57, 1629–1634 (2016).

    Article  CAS  Google Scholar 

  36. Crandall, D. L., Goldstein, B. M., Huggins, F. & Cervoni, P. Adipocyte blood flow: influence of age, anatomic location, and dietary manipulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 247, R46–R51 (1984).

    Article  CAS  Google Scholar 

  37. Wang, P. et al. Absence of an adipogenic effect of rosiglitazone on mature 3T3-L1 adipocytes: increase of lipid catabolism and reduction of adipokine expression. Diabetologia 50, 654–665 (2007).

    Article  Google Scholar 

  38. Li, G., Gong, J., Lei, H., Liu, J. & Xu, X. Z. S. Promotion of behavior and neuronal function by reactive oxygen species in C. elegans. Nat. Commun. 7, 13234 (2016).

    Article  CAS  Google Scholar 

  39. Zou, Z., Chang, H., Li, H. & Wang, S. Induction of reactive oxygen species: an emerging approach for cancer therapy. Apoptosis 22, 1321–1335 (2017).

    Article  CAS  Google Scholar 

  40. Yaribeygi, H., Farrokhi, F. R., Butler, A. E. & Sahebkar, A. Insulin resistance: review of the underlying molecular mechanisms. J. Cell Physiol. 234, 8152–8161 (2019).

    Article  CAS  Google Scholar 

  41. Krawczyk, S. A., Haller, J. F., Ferrante, T., Zoeller, R. A. & Corkey, B. E. Reactive oxygen species facilitate translocation of hormone sensitive lipase to the lipid droplet during lipolysis in human differentiated adipocytes. PLoS ONE 7, e34904 (2012).

    Article  CAS  Google Scholar 

  42. Straus, D. S. & Glass, C. K. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 28, 551–558 (2007).

    Article  CAS  Google Scholar 

  43. Bensinger, S. J. & Tontonoz, P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454, 470–477 (2008).

    Article  CAS  Google Scholar 

  44. Polvani, S., Tarocchi, M. & Galli, A. PPAR and oxidative stress: Con(β) catenating NRF2 and FOXO. PPAR Res 2012, 641087 (2012).

    Article  Google Scholar 

  45. Xue, Y. et al. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab. 9, 99–109 (2009).

    Article  CAS  Google Scholar 

  46. Reuter, S., Gupta, S. C., Chaturvedi, M. M. & Aggarwal, B. B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med. 49, 1603–1616 (2010).

    Article  CAS  Google Scholar 

  47. Sackmann-Sala, L., Berryman, D. E., Munn, R. D., Lubbers, E. R. & Kopchick, J. J. Heterogeneity among white adipose tissue depots in male C57BL/6J mice. Obesity 20, 101–111 (2012).

    Article  CAS  Google Scholar 

  48. Nathan, D. M. Rosiglitazone and cardiotoxicity—weighing the evidence. N. Engl. J. Med. 357, 64–66 (2007).

    Article  CAS  Google Scholar 

  49. Ratziu, V. et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51, 445–453 (2010).

    Article  CAS  Google Scholar 

  50. Moreno, A. M. et al. Immune-orthogonal orthologues of AAV capsids and of Cas9 circumvent the immune response to the administration of gene therapy. Nat. Biomed. Eng. 3, 806–816 (2019).

    Article  CAS  Google Scholar 

  51. Wu, Z. et al. In vivo dual-scale photoacoustic surveillance and assessment of burn healing. Biomed. Opt. Express 10, 3425–3433 (2019).

    Article  CAS  Google Scholar 

  52. Matthews, D. R. et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (U190420008 and 81922034&91859113) and the Science Fund for Distinguished Young Scholars of Fujian Province (2018J06024). We thank X. Wang for her technical support in immunological experiments, Z. Wu for his guidance in PA data processing and S. Li for his help in PA data collection.

Author information

Authors and Affiliations

  1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnosis & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China

    Ronghe Chen, Shanshan Huang, Haosong Ma, Fei Duan, Jing Lv, Jinde Zhang & Liming Nie

  2. Department of Biomaterials, Key Laboratory of Biomedical Engineering of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surface, College of Materials, Xiamen University, Xiamen, China

    Tongtong Lin & Lei Ren

  3. Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, China

    Wenjun Shan

Authors
  1. Ronghe Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shanshan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tongtong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haosong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenjun Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fei Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jinde Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lei Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Liming Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.C. and L.N. conceived and designed the study. R.C., S.H., T.L., H.M., W.S. and J.L. carried out the experiments. R.C., S.H., F.D. and J.Z. analysed the data. R.C. wrote the first draft of the manuscript. L.R. and L.N. edited the manuscript. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Liming Nie.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Nanotechnology thanks Frank Sainsbury and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Competition assays.

a,b, Representative confocal microscope images of adipose MECs (a) and mature adipocytes (b) pretreated with/without Pat-HBc for 2 h and further incubated with HBc/RSG&ZnPcS4 or Pat-HBc/RSG&ZnPcS4 for 12 h. Prohibitin was stained with phycoerythrin-conjugated anti-prohibitin antibody (magenta channel). Nuclei were counterstained with DAPI (blue channel). The experiments were repeated three times with similar results. Scale bars, 20 μm.

Extended Data Fig. 2 Safety assessments.

a, Representative H&E stained images of major organs including liver, kidney, heart, lung and spleen in different groups after two treatment cycles. The experiment was repeated three times with similar results. Scale bars, 50 μm. b-j, Serum biochemistry in obese mice after different treatments (n = 7 mice). Serum TP (b), ALT (c) and AST (d) reflect hepatic function. Serum uric acid (e), urea (f) and creatinine (g) reflect renal function. Serum CK (h), CK-MB (i) and LDH (j) reflect cardiac function. Asterisks in c and d denote significant differences compared with the control, RSG, ZnPcS4, RSG&ZnPcS4 and Pat-HBc/ZnPcS4 groups, p < 0.05. k-m, Serum IgG (k), IL-4 (l) and IFN-γ (m) levels indicative of cellular and humoral immune responses in obese mice at designated intervals after tail-vein injection with PBS, OVA, HBc or Pat-HBc (n = 6 mice). Time points for the first injection and the second injection were set on day 0 and day 7, respectively. Asterisks denote a significant difference from the PBS group, p < 0.05. Hash signs denote significant differences compared with the OVA and HBc groups, p < 0.05. All statistical data are expressed as mean ± s.d. Statistical significance was assessed via a one-way ANOVA with Duncan post-hoc test.

Supplementary information

Supplementary Information

Supplementary Figs. 1–27 and Tables 1–4.

Reporting Summary

Supplementary Video 1

3D laser-scanning confocal microscopy for analyzing penetration properties of different ZnPcS4 formulations in MEC spheroids (scan depth: ~240 μm).

Supplementary Video 2

3D PA display of abdominal adipose vessels in the obese mouse of Pat-HBc/RSG&ZnPcS4 group before and after treatment.

Source data

Source Data Fig. 1

Statistical Source Data

Source Data Fig. 2

Statistical Source Data

Source Data Fig. 3

Statistical Source Data

Source Data Fig. 4

Statistical Source Data

Source Data Fig. 5

Statistical Source Data and Unprocessed Blots

Source Data Extended Data Figures

Statistical Source Data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, R., Huang, S., Lin, T. et al. Photoacoustic molecular imaging-escorted adipose photodynamic–browning synergy for fighting obesity with virus-like complexes. Nat. Nanotechnol. 16, 455–465 (2021). https://doi.org/10.1038/s41565-020-00844-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41565-020-00844-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research