Using photodynamic therapy (PDT) to treat deep-seated cancers is limited due to inefficient delivery of photosensitizers and low tissue penetration of light. Polymeric nanocarriers are widely used for photosensitizer delivery, while the self-quenching of the encapsulated photosensitizers would impair the PDT efficacy. Furthermore, the generated short-lived reactive oxygen spieces (ROS) can hardly diffuse out of nanocarriers, resulting in low PDT efficacy. Therefore, a smart nanocarrier system which can be degraded by light, followed by photosensitizer activation can potentially overcome these limitations and enhance the PDT efficacy. A light-sensitive polymer nanocarrier encapsulating photosensitizer (RB-M) was synthesized. An implantable wireless dual wavelength microLED device which delivers the two light wavelengths sequentially was developed to programmatically control the release and activation of the loaded photosensitizer. Two transmitter coils with matching resonant frequencies allow activation of the connected LEDs to emit different wavelengths independently. Optimal irradiation time, dose, and RB-M concentration were determined using an agent-based digital simulation method. In vitro and in vivo validation experiments in an orthotopic rat liver hepatocellular carcinoma disease model confirmed that the nanocarrier rupture and sequential low dose light irradiation strategy resulted in successful PDT at reduced photosensitizer and irradiation dose, which is a clinically significant event that enhances treatment safety.

ConspectusPhototherapy including optogenetics, photodynamic therapy (PDT), photothermal therapy (PTT), and photoimmunotherapy (PIT) has been proven to be effective against different diseases. However, as the name suggests, phototherapy requires light irradiation, thus its therapeutic efficiency is often restricted by limited depth of light penetration within biological tissue. This light penetration limitation is significantly adverse to PDT and optogenetics because both therapies are usually activated with UV and visible light of very poor tissue penetration efficiency. Current light delivery methods usually involve cumbersome setups and require optical fiber or catheter insertion, which not only restrict the movement of patients but also impose incompatibility issues with chronic implantation. To address the existing challenges, wireless phototherapy was developed through various approaches over recent years, which usually relies on implantable wireless electronic devices. However, the application of wireless electronic devices is limited by invasion during implantation, unwanted heat generation, and adverse immunogenicity of these devices.Over the recent years, applying light conversion nanomaterials as light transducers for wireless phototherapy has garnered much interest. Compared with implantable electronic devices and optical fiber, nanomaterials can be easily injected into the body with minimal invasiveness and can also be surface functionalized to increase their biocompatibility and cell accumulation efficiency. Commonly applied light conversion nanomaterials include upconversion nanoparticles (UCNPs), X-ray nanoscintillators, and persistent luminescence nanoparticles (PLNPs). UCNPs and X-ray nanoscintillators can respectively convert near-infrared (NIR) light and X-ray, which have good tissue penetration efficiency, to UV or visible light, which is suitable for activating phototherapy. PLNPs can be excited by external light such as X-rays and NIR light and retain long afterglow luminescence after the removal of the excitation light source. As a result, applying PLNPs in phototherapy can potentially reduce irradiation time from external light sources, thus minimizing tissue photodamage. This Account aims to briefly discuss (i) the mechanisms of different phototherapies, (ii) the development and mechanisms of light conversion nanomaterials, (iii) the application of light conversion nanomaterials in wireless phototherapy, highlighting how they relieve current challenges in phototherapy, and (iv) perspectives for future development of light conversion nanomaterials for wireless phototherapy.

Photodynamic therapy (PDT) is an effective non-invasive or minimally invasive treatment method against different tumors. Loading photosensitizers in nanocarriers can potentially increase their accumulation in tumor sites. However, the PDT efficacy may be hindered because of self-quenching of the encapsulated photosensitizer and the small diffusion radii of the generated reactive oxygen species (ROS). Herein, light responsive nano assemblies composed of (Polyethylene glycol)-block-poly(4,5-dimethoxy-2-nitrobenzylmethacrylate) (PEG-b-PNBMA) were designed and loaded with the photosensitizer, Rose Bengal lactone (RB), to act as a smart nanocarrier (RB-M) for the delivery of the photosensitizer. A wirelessly activated light-emitting diode (LED) implant was designed to programmatically induce the release of the loaded RB first, followed by activating PDT after diffusion of RB into the cytoplasm. The results showed that sequential '405-580 nm' irradiation of the RB-M treated 22RV1 cells resulted in the highest PDT outcome among different irradiation protocols. The combination of this smart nanocarrier and sequential '405-580 nm' irradiation strategy exhibited good PDT efficacy against 2D 22RV1 prostate cancer cells as well as 3D cancer cell spheroids. This platform overcomes the light penetration limitations in PDT, and can potentially be applied in cancer bearing patients who are unfit for chemotherapy. STATEMENT OF SIGNIFICANCE: Nanocarriers for the delivery of photosensitizer in photodynamic therapy may result in relatively low therapeutic efficacy because of self-quenching of the encapsulated photosensitizer and the small diffusion radii of the generated reactive oxygen species (ROS). Light responsive smart nanocarriers can potentially overcome this challenge. In this study, a light responsive polymer (Polyethylene glycol)-block-poly(4,5-dimethoxy-2-nitrobenzylmethacrylate) (PEG-b-PNBMA) was synthesized and utilized to fabricate the smart nanocarrier. A wirelessly activated light-emitting diode (LED) implant was designed for light delivery in deep tissue. This new approach permits wirelessly and programmatically control of photosensitizer release and PDT activation under deep tissue, thus significantly enhancing PDT efficacy against prostate cancer cells as well as 3D cancer cell spheroids. This design should have a significant impact on controllable PDT under deep tissue.

Present day strategies for delivery of wireless photodynamic therapy (PDT) to deep-seated targets are limited by the inadequacy of irradiance and insufficient therapeutic depth. Here we report the design and preclinical validation of a flexible wireless upconversion nanoparticle (UCNP) implant (SIRIUS) that is capable of large field, high intensity illumination for PDT of deep-seated tumors. The implant achieves this by incorporating submicrometer core-shell-shell NaYF4 UCNPs into its design, which significantly enhances upconversion efficiency and mitigates light loss from surface quenching. We demonstrate the efficacy of SIRIUS UCNP implant mediated PDT in preclinical breast cancer disease models. In our in vitro experiments, SIRIUS directed 5-Aminolevulinic Acid (5-ALA) based wireless PDT leads to significant reactive oxygen species (ROS) generation and tumor apoptosis in hormonal receptor+/HER2+ (MCF7) and triple-negative (MDA-MB-231) breast cancer cell lines. In our in vivo rodent model, SIRIUS-driven PDT is shown to be significant in regressing tumors when applied to orthotopically inoculated breast tumors. Following successful preclinical validation, we also describe a clinical prototype of UCNP breast implant with potential dual cosmetic and onco-therapeutic functions. SIRIUS is an upconversion breast implant for wireless PDT that fulfils all the design prerequisites necessary for seamless clinical translation.

Abstract Photochemical internalization (PCI) is a promising intervention using photodynamic therapy (PDT) to enhance the activity of chemotherapeutic drugs. However, current bladder cancer treatments involve high‐dose chemotherapy and high‐irradiance PDT which cause debilitating side effects. Moreover, low penetration of light and drugs in target tissues and cumbersome light delivery procedures hinder the clinical utility of PDT and chemotherapy combination for PCI. To circumvent these challenges, a photodynamic‐chemotherapy approach is developed comprising tumor‐targeting glycosylated nanocarriers, coloaded with chlorin e6 (Ce6) and gemcitabine elaidate (GemE), and a miniaturized implantable wirelessly powered light‐emitting diode (LED) as a light source. The device successfully delivers four weekly light doses to the bladder while the nanocarrier promoted the specific accumulation of drugs in tumors. This approach facilitates the combination of low‐irradiance PDT (1 mW cm−2) and low‐dose chemotherapy (≈1500× lower than clinical dose) which significantly cures and controls orthotopic disease burden (90% treated vs control, 35%) in mice, demonstrating a potential new bladder cancer treatment option.

Photodynamic therapy (PDT) is a promising localized cancer treatment modality. It has been used successfully to treat a range of dermatological conditions with comparable efficacy to conventional treatments. However, some drawbacks limit the clinical utility of PDT in treating deep-seated tumors. Notably, the penetration limitation of UV and visible light, commonly applied to activate photosensitizers, makes PDT incompetent in treating deep-seated tumors. Development in light delivery technologies, especially fiber optics, led to improved clinical strategies for accessing deep tissues for irradiation. However, PDT efficacy issues remained partly due to light penetration limitations. In this review, we first summarized the current PDT applications for deep-seated tumor treatment. Then, the most recent progress in advanced techniques to overcome the light penetration limitation in PDT, including using functional nanomaterials that can either self-illuminate or be activated by near-infrared (NIR) light and X-rays as transducers, and implantable light delivery devices were discussed. Finally, current challenges and future opportunities of these technologies were discussed, which we hope may inspire the development of more effective techniques to enhance PDT efficacy against deep-seated tumors.

Detection of non-muscle invasive bladder cancer (NMIBC) is crucial to facilitate complete tumor resection, thus improving the survival rate as well as reducing the recurrence frequency and treatment expense. Fluorescence imaging cystoscopy is an effective method for the detection of NMIBC. However, its application is limited as the commonly applied fluorescent agents such as dyes and photosensitizers usually lack specific tumor accumulation and are vulnerable to photobleaching. Furthermore, the broad emission band of conventional fluorescent agents limits their imaging and detection efficacy. To overcome these limitations, upconversion nanoparticles (UCNPs) have been selected as the fluorescent agent, due to their resistance to photobleaching, less background auto-fluorescence, and narrow emission bands. In order to achieve active tumor targeting, the UCNPs are coated with a glycosylated phospholipid layer. The glycosylated phospholipid-coated UCNPs exhibited high selective accumulation in cancer cells over normal cells and enhanced the upconversion luminescence (UCL) (at 540 nm and 660 nm) from bladder cancer cells under 980 nm laser irradiation. Glycosylated phospholipid coating that promotes uptake of UCNPs by cancer cells, and UCL emitted from UCNPs under NIR (980 nm) laser irradiation for cancer cell imaging.