Photodynamic therapy (PDT) has emerged as a promising strategy in cancer treatment due to its minimal invasiveness, spatially focused action, and lack of drug resistance. Central to PDT is the photosensitizer (PS), which generates reactive oxygen species (ROS) upon light irradiation, leading to irreversible damage in cancer cells. However, conventional PSs often suffer from “always-on” phototoxicity and poor tumor specificity, causing skin photosensitivity and harm to healthy tissues. To address this, activatable PSs have been developed, designed to remain inert during circulation but become active only under specific tumor microenvironment conditions such as low pH or high glutathione levels. This selective activation enables precise control over ROS generation, minimizing off-target effects.
In this study, boron dipyrromethene (BDP)-based nanoparticles were engineered through self-assembly of a multifunctional “one-for-all” building block—PEG-RGD-BDP-NEt—aimed at enhancing tumor penetration and enabling activatable PDT.MKL1 Antibody Description The design leverages the acidity-responsive nature of the system: in the slightly acidic tumor extracellular environment (pH ~6.5), Schiff base bonds between polyethylene glycol (PEG) and the cyclic Arg-Gly-Asp (cRGD) peptide hydrolyze, triggering the first-stage size reduction. This exposes the cRGD ligands, facilitating specific recognition by integrin αvβ3 receptors overexpressed on cancer cells. Upon endocytosis, further acidification in lysosomes (pH ~4.5) induces complete disassembly of the nanoparticles into single BDP molecules. Protonation of the diethylamino (NEt) groups blocks photoinduced electron transfer from the amine donor to the excited PS, restoring both fluorescence and photodynamic activity.
The resulting hierarchical disassembly—from nano-scale particles down to molecular monomers—provides dual advantages: enhanced tumor penetration due to reduced particle size and full reactivation of PS function inside subcellular compartments. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirmed progressive size reduction from ~78 nm at pH 7.4 to ~5.5 nm at pH 4.5. Zeta potential measurements showed surface charge reversal from near-neutral to positive after PEG shedding, confirming detachment of the shielding layer. Fluorescence imaging revealed strong NIR emission only under acidic conditions, validating the pH-dependent activation mechanism. In vitro studies demonstrated superior cellular uptake in MDA-MB-231 cells (integrin-positive) compared to MCF-10A cells (integrin-negative), with inhibition observed when free cRGD was pre-incubated, confirming receptor-mediated internalization.
Moreover, confocal microscopy of multicellular spheroids showed significantly improved penetration of PEG-R-BDP-NEt NPs at pH 6.5 versus pH 7.4, with deep diffusion confirmed via line-scan profiles and Z-stacking analysis.Histone H2A Antibody Epigenetic Reader Domain Intracellular ROS generation, measured using DCFH-DA, was markedly higher in acidic conditions, correlating with enhanced PDT efficacy.PMID:35087210 In vivo experiments in tumor-bearing mice demonstrated prolonged blood circulation, high tumor accumulation, and effective tumor growth suppression upon laser irradiation. Histological analysis revealed extensive necrosis in treated tumors with no significant toxicity in major organs, underscoring excellent biocompatibility.
This work presents a smart delivery platform based on acidity-triggered hierarchical disassembly, combining efficient tumor targeting, deep penetration, and precise activation of photodynamic activity. The one-pot self-assembly synthesis allows scalability and reproducibility, offering strong potential for clinical translation in image-guided cancer therapy.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com