Combination of Photodynamic Therapy (PDT) and Upconverting Nanoparticles
PDT kills cancer cells by generating reactive oxygen species (ROS) under specific wavelength light by photosensitizers, but its clinical application is limited by the insufficient penetration depth of visible light (usually only 2-3 mm) and the problem of photosensitizers being prone to photobleaching. The introduction of Upconverting nanoparticles (UCNPs) provides a new idea to break through these bottlenecks. UCNPs can convert near-infrared light (NIR, such as 980 nm) into visible light or ultraviolet light through two-photon or multi-photon processes of lanthanide elements (such as Yb³⁺, Er³⁺, Tm³⁺), thereby activating surface-loaded photosensitizers (such as phthalocyanine, C60) to produce ROS. Compared with traditional PDT, NIR excitation not only has a penetration depth of several centimeters, but also reduces tissue damage and autofluorescence interference. In addition, the high photostability of UCNPs enables them to withstand long-term irradiation, avoid photobleaching problems, and are suitable for multiple treatments. As a multifunctional platform, UCNPs can carry photosensitizers, targeting molecules (such as chlorotoxins) and chemotherapy drugs at the same time to achieve integrated diagnosis and treatment.
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Unique Optical Properties and PDT Mechanism of UCNPs
The optical properties of Upconverting nanoparticles (UCNPs) work in tandem with photodynamic therapy (PDT) mechanisms creating unique effects. The luminescence mechanism functions based on step-like energy level transitions within lanthanide elements. For example, under the excitation of 980 nm near-infrared (NIR) light, NaYF₄: The Yb³⁺/Er³⁺ structure absorbs photons to energize Er³⁺ which transitions to a high-energy state before emitting visible light at wavelengths like 540 nm green or 650 nm red through non-radiative processes which activate adjacent photosensitizers including zinc phthalocyanine and rose bengal. The process generates reactive oxygen species (ROS which contain ¹O₂ and ·OH among others). The emission wavelength of UCNPs can be adjusted through the doping of specific lanthanide ions including Tm³⁺ and Ho³⁺. The red emission at approximately 650 nm wavelength matches the absorption spectrum of commercial photosensitizers leading to better fluorescence resonance energy transfer (FRET) efficiency. UCNPs possess photocatalytic properties that make them usable as photocatalysts. Surface defects or metal doping agents like TiO₂ and g-C3N4 improve photocatalytic activity which enables direct decomposition of water or H₂O₂ to create ROS through light excitation in the ultraviolet or visible spectrum while boosting PDT performance. The UCNP@TiO₂ core-shell structure utilizes ultraviolet emissions from UCNPs to stimulate TiO₂ when exposed to NIR light, producing both photocatalytic reactions and PDT which results in higher cancer cell apoptosis rates.
In order to overcome the problem of insufficient tissue penetration depth in traditional PDT, the NIR excitation characteristics of UCNPs (980 nm or 808 nm) have become a key advantage. Compared with visible light, NIR light can penetrate as deep as centimeters. For example, it can still effectively excite UCNPs and activate photosensitizers to generate ROS in 1 cm thick tissue. In addition, some UCNPs (such as NaErF4@NaLuF4) balance luminescence efficiency and energy transfer by optimizing the shell thickness (~5 nm), reducing the overheating effect caused by water molecule absorption under 808 nm excitation, and achieving safer deep treatment.
The integration of synergistic treatment strategies further expands the application potential of UCNPs. For example, after UCNPs are combined with gold nanorods or carbon nitrides, photothermal effect (PTT) and PDT can be simultaneously generated which can enhance the permeability of tumor cell membranes through local heating (40–45 ° C), promote ROS diffusion and induce mitochondrial pathway apoptosis. In addition, the multifunctional nanoplatform can also be combined with gene therapy (such as siRNA silencing Plk1 gene) or chemotherapy drugs (such as doxorubicin) to achieve multimodal synergistic enhancement.
Intelligent response design for tumor microenvironment (such as hypoxia, weak acidity) has also been widely explored. For example, MnO₂-modified UCNPs can catalyze the decomposition of H₂O₂ into O₂ in tumors, alleviating the oxygen-dependent limitation of PDT; pH-sensitive charge reversal coatings (such as DMMA-PEG) expose positive charges in the weakly acidic environment of tumors, enhancing the tumor targeting and cellular internalization of nanoparticles. The stem cell membrane camouflage strategy gives UCNPs a long circulation time and active targeting ability, achieving efficient tumor enrichment through intravenous injection.
Image-guided precision therapy is another important direction. The intrinsic Upconverting luminescence (UCL) of UCNPs can be used for real-time imaging, while Gd³⁺ or Mn²⁺ doping is compatible with magnetic resonance imaging (MRI) and X-ray computed tomography (CT), realizing multimodal monitoring of the treatment process. For example, orthogonal emission UCNPs (808 nm green excitation, 980 nm red excitation) can simultaneously trigger PDT and monitor efficacy, reducing the risk of "off-target" damage.
Laboratory Research Progress of Optical Properties and PDT
Material design: Through combinatorial chemistry and high-throughput screening, the components (such as NaYF₄:Yb, Er/Tm) and morphology (core-shell structure) of UCNPs are optimized to improve luminescence efficiency. Surface modification with polyethylene glycol (PEG) or mesoporous silica can enhance biocompatibility and increase drug loading (such as photosensitizer porphyrin IX or chemotherapy drug doxorubicin).
Targeted delivery: Chlorotoxin-modified UCNPs can specifically bind to CD44 receptors on the surface of glioma cells to improve tumor selectivity. Other strategies include pH-responsive release (such as charge-reversible UCNPs releasing drugs in the slightly acidic environment of tumors) and antibody-antigen targeting.
In vitro validation: Using wide-field two-photon microscopy technology, the distribution of UCNPs in cells is tracked at the single-particle level. Experiments show that UCNPs loaded with photosensitizers can significantly induce cancer cell apoptosis in vitro, and the ROS generation efficiency is 3-5 times higher than that of traditional PDT.
Towards Clinical Application: in Vivo Application
In vivo treatment: The multimodal imaging capabilities of UCNPs (such as MRI, CT, and fluorescence imaging) support precise tumor localization. In animal models, NIR-excited UCNPs showed significant inhibitory effects on in situ tumors and metastases, especially for deep tumors (such as pancreatic cancer).
Safety: PEG-coated UCNPs have no hemolytic activity at a concentration of 25 µg/mL and low short-term toxicity. However, long-term toxicity remains controversial, and attention should be paid to its accumulation in organs such as the liver and spleen and the potential immune response of surface ligands.
Future Direction: Multifunctional Platform beyond PDT
PDT+immunotherapy: UCNPs-mediated PDT can release tumor antigens and be combined with PD-1/PD-L1 inhibitors to enhance anti-tumor immune response.
PDT+chemotherapy: UCNPs loaded with doxorubicin achieve synergistic chemotherapy and photodynamic therapy to overcome multidrug resistance.
Stimulus-responsive system: light-controlled drug release (such as near-infrared triggered doxorubicin release) or ROS-sensitive nanoplatform.
Gene editing: UCNPs combined with CRISPR technology can achieve light-controlled gene editing (such as knocking out cancer-promoting genes).
Preclinical exploration: Focus on solid tumors such as melanoma and breast cancer, and develop a standardized toxicity assessment system.
UCNPs provide a comprehensive innovation for PDT from light source penetration to therapeutic efficacy, but its clinical transformation still needs to solve challenges such as toxicity and standardized production. With the advancement of multifunctional combined strategies and intelligent design, UCNPs are expected to become a milestone technology for precision tumor treatment.
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