A novel sustained release therapy of combined VEGF and TNF-α inhibitors leads to pan-ocular protection for months after severe ocular trauma

  1. Chengxin Zhou
  2. Fengyang Lei
  3. Pui-Chuen Hui
  4. Natalie Wolkow
  5. Claes H. Dohlman
  6. Demetrios G. Vavvas
  7. James Chodosh
  8. Eleftherios I. Paschalis

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Abstract

Purpose

To develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye.

Methods

A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally in Dutch-belted pigmented rabbits after corneal alkali injury. The polymer was tuned to transition from liquid to gel upon contact with body temperature without need of a catalyst. Control rabbits received 2mg of IgG loaded DDS or 1.4mg aflibercept loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug release kinetics was assessed in vivo using aqueous humor protein analysis.

Results

A single subconjunctival administration of dual anti-TNFα/anti-VEGF DDS achieved sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45 + immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect, increased infiltration of CD45 + immune cells into the cornea, and significant loss of RGCs and optic nerve axons at 3 months. Aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site.

Conclusion

Sustained concomitant inhibition of TNF-α and VEGF using a biodegradable, slow-release thermosensitive DDS provides significant ocular protection and prevents corneal neovascularization and irreversible damage to retina and optic nerve after corneal alkali injury. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/10138538.

    Does the introduction explain the objective of the research presented in the preprint? Yes
    Are the methods well-suited for this research? Highly appropriate
    Are the conclusions supported by the data? Highly supported
    Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly
    Is the preprint likely to advance academic knowledge? Highly likely
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, it's of high quality
    Is it ready for attention from an editor, publisher or broader audience? Yes, as it is

    Competing interests

    The author declares that they have no competing interests.

  2. Version published to 10.1101/2023.03.14.531626v2 on bioRxiv
  3. Version published to 10.1101/2023.03.14.531626v1 on bioRxiv