Jason Olejniczak

Light-responsive nanoparticle depot to control release of a small molecule angiogenesis inhibitor in the posterior segment of the eye

Therapies for macular degeneration and diabetic retinopathy require intravitreal injections every 4-8 weeks. Injections are uncomfortable, time-consuming, and carry risks of infection and retinal damage. However, drug delivery via noninvasive methods to the posterior segment of the eye has been a major challenge due to the eyes unique anatomy and physiology. Here we present a novel nanoparticle depot platform for on-demand drug delivery using a far ultraviolet (UV) light-degradable polymer, which allows noninvasively triggered drug release using brief, low-power light exposure. Nanoparticles stably retain encapsulated molecules in the vitreous, and can release cargo in response to UV exposure up to 30 weeks post-injection. Light-triggered release of nintedanib (BIBF 1120), a small molecule angiogenesis inhibitor, 10 weeks post-injection suppresses choroidal neovascularization (CNV) in rats. Light-sensitive nanoparticles are biocompatible and cause no adverse effects on the eye as assessed by electroretinograms (ERG), corneal and retinal tomography, and histology.

Photocontrolled release using one-photon absorption of visible or NIR light.

Light is an excellent means to externally control the properties of materials and small molecules for many applications. Lights ability to initiate chemistries largely independent of a materials local environment makes it particularly useful as a bio-orthogonal and on-demand trigger in living systems. Materials responsive to UV light are widely reported in the literature; however, UV light has substantial limitations for in vitro and in vivo applications. Many biological molecules absorb these energetic wavelengths directly, not only preventing substantial tissue penetration but also causing detrimental photochemical reactions. The more innocuous nature of long-wavelength light (>400nm) and its ability at longer wavelengths (600-950nm) to effectively penetrate tissues is ideal for biological applications. Multi-photon processes (e.g. two-photon excitation and upconversion) using longer wavelength light, often in the near-infrared (NIR) range, have been proposed as a means of avoiding the negative characteristics of UV light. However, high-power focused laser light and long irradiation times are often required to initiate photorelease using these inefficient non-linear optical methods, limiting their in vivo use in mammalian tissues where NIR light is readily scattered. The development of materials that efficiently convert a single photon of long-wavelength light to chemical change is a viable solution to achieve in vivo photorelease. However, to date only a few such materials have been reported. Here we review current technologies for photo-regulated release using photoactive organic materials that directly absorb visible and NIR light.

Short Soluble Coumarin Crosslinkers for Light-Controlled Release of Cells and Proteins from Hydrogels

Materials that degrade or dissociate in response to low power light promise to enable on-demand, precisely localized delivery of drugs or bioactive molecules in living systems. Such applications remain elusive because few materials respond to wavelengths that appreciably penetrate tissues. The photocage bromohydroxycoumarin (Bhc) is efficiently cleaved upon low-power ultraviolet (UV) and near-infrared (NIR) irradiation through one- or two-photon excitation, respectively. We have designed and synthesized a short Bhc-bearing crosslinker to create light-degradable hydrogels and nanogels. Our crosslinker breaks by intramolecular cyclization in a manner inspired by the naturally occurring ornithine lactamization, in response to UV and NIR light, enabling rapid degradation of polyacrylamide gels and release of small hydrophilic payloads such as an ∼10 nm model protein and murine mesenchymal stem cells, with no background leakage.

Efficient red light photo-uncaging of active molecules in water upon assembly into nanoparticles

One-photon red visible light-responsive photocage–drug conjugate nanoparticles dissolve and release free drug upon irradiation.

Disease‐Triggered Drug Release Effectively Prevents Acute Inflammatory Flare‐Ups, Achieving Reduced Dosing

For conditions with inflammatory flare-ups, fast drug-release from a depot is crucial to reduce cell infiltration and prevent long-term tissue destruction. While this concept has been explored for chronic diseases, preventing acute inflammatory flares has not been explored. To address this issue, a preventative inflammation-sensitive system is developed and applied to acute gout, a condition where millions of inflammatory cells are recruited rapidly, causing excruciating and debilitating pain. Rapid drug release is first demonstrated from a pH-responsive acetalated dextran particle loaded with dexamethasone (AcDex-DXM), reducing proinflammatory cytokines in vitro as efficiently as free drug. Then, using the air pouch model of gout, mice are pretreated 24 h before inducing inflammation. AcDex-DXM reduces overall cell infiltration with decreased neutrophils, increases monocytes, and diminishes cytokines and chemokines. In a more extended prophylaxis model, murine joints are pretreated eight days before initiating inflammation. After quantifying cell infiltration, only AcDex-DXM reduces the overall joint inflammation, where neither free drug nor a conventional drug-depot achieves adequate anti-inflammatory effects. Here, the superior efficacy of disease-triggered drug-delivery to prevent acute inflammation is demonstrated over free drug and slow-release depots. This approach and results promise exciting treatment opportunities for multiple inflammatory conditions suffering from acute flares.