Light-responsive polymeric nanoparticles for retinal drug delivery: design cues, challenges and future perspectives

Abstract

A multitude of sight-threatening retinal diseases, affecting hundreds of millions around the globe, lack effective pharmacological treatments due to ocular barriers and common drug delivery limitations. Polymeric nanoparticles (PNPs) are versatile drug carriers with sustained drug release profiles and tunable physicochemical properties which have been explored for ocular drug delivery to both anterior and posterior ocular tissues. PNPs can incorporate a wide range of drugs and overcome the challenges of conventional retinal drug delivery. Moreover, PNPs can be engineered to respond to specific stimuli such as ultraviolet, visible, or near-infrared light, and allow precise spatiotemporal control of the drug release, enabling tailored treatment regimens and reducing the number of required administrations. The objective of this study is to emphasize the therapeutic potential of light-triggered drug-loaded polymeric nanoparticles to treat retinal diseases through an exploration of ocular pathologies, challenges in drug delivery, current production methodologies and recent applications. Despite challenges, light-responsive PNPs hold the promise of substantially enhancing the treatment landscape for ocular diseases, aiming for an improved quality of life for patients.

Keywords: Light-triggered release; Ocular nanomedicine; Polymeric nanoparticles; Retinal diseases.

Graphical abstract

Fig. 1

A schematic depiction of ocular anatomy and its main delivery barriers, as detailed in the previous paragraphs.

Fig. 2

A detailed scheme of the layers constituting the retina and its neighbouring structures (the nerve fibre layer and the sclera-choroid complex).

Fig. 3

A schematic representation of the main drug delivery routes discussed in paragraph 3.3.

Fig. 4

Schematic of the different penetration depths for light sources into the eye spanning various wavelengths.

Fig. 5

A novel photocleavable PNP formulation for the treatment of CNV devised by Wang et al. [96]. A) A scheme of the phototargeting strategy adopted by the researchers. The NP-[CPP], composed of maleimide-modified PEG-PLA, the CPP and the photocleavable group DEACM-OH are injected intravenously and activated by a blue-light radiation directed at the eye. B) Transmission electron microscopy (TEM) image of the NP-[CPP] complex obtained by thin film hydration. C) In vivo phototargeting of a CNV model. Shown here is one representative image (out of 8) of fluorescently labelled flat-mounted choroid tissues captured 24 h post-injection with nanoparticles (NPs). The scale bar corresponds to 100 μm. D) Exemplary images of choroidal neovascularization (CNV) stained with isolectin GS IB4 (scale bar: 100 μm) and a histogram of the average CNV lesion size. These images depict CNV in laser-induced mice treated with different modalities: PBS, NP-[CPP], doxorubicin (doxo), NP-[CPP]-doxorubicin, and NP-[CPP]-doxorubicin with irradiation. The error bars represent the standard error of the mean, and the dataset comprises a total of 28 CNV lesions. Statistical significance is denoted as follows: *P < 0.05, **P < 0.005, determined using an unpaired t-test. Adapted under the terms of the Creative Commons CC BY license from Wang et al., 2019, Ref. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 6

The multifunctional PNP DDS designed by Mudigunda et al. [252]. A) A scheme depicting the design principle of the DDS, composed of PCL, PLGA, the NIR-photoresponsive dye IR820 and the drug PCB. B) A TEM image of the produced PNPs, sizing between 170 and 200 nm. C) Fluorescence microscopy images of the PCB/IR PNP-treated Y79 retinoblastoma cell line, illustrating the internalization capabilities of the DDS. D) Functional behaviour of the DDS i) Photoresponsive behaviour of the PNPs in three different formulations, incorporating either only the IR820 dye, only the PCB drug, neither of them or both, plotted against milli-Q water as control. ii) The time-dependent PCB release under NIR irradiation as opposed to the non-irradiated sample. iii) A graphic visualization of the biocompatibility, in terms of % of survived cells, of various concentrations of the PNPs, as tested on an L929 cell line using the four different formulations described in bullet point D-i. iv) The cytotoxic effect on a retinoblastoma cell line of the four different PNP formulations either under NIR-irradiation or not. The data are plotted as mean ± standard deviation. The variations among groups were considered significant for *P < 0.05, **P < 0.01, and ***P < 0.001. Adapted with permission from Mudigunda et al., 2022. Copyright 2023 American Chemical Society, Ref. [252].

Fig. 7

A schematic of the functioning principles of the cited nonlinear photo conversion processes, as detailed in paragraph 5.3.