ABSTRACT
Recent cancer immunotherapy has attracted much attention due to high specificity and recurrence prevention of tumor. Nevertheless, its therapeutic effects are still challenging in solid cancer. To establish superior antitumor immunity, chlorin e6 (Ce6)-loaded pH sensitive carbon dots were investigated (Ce6@IDCDs). At tumoral pH 6.5, Ce6 was released four times compared with the release at physiological pH 7.4 due to an imbalance between hydrophilic and hydrophobic forces via protonation of imidazole groups in Ce6@IDCDs. This result led to the superior singlet oxygen generating activity of Ce6@IDCDs without Ce6 quenching. The maturation effects of dendritic cells after co-incubation with supernatant media obtained from Ce6@IDCDs with laser-treated cells at pH 6.5 were much higher than at physiological pH. Furthermore, Ce6@IDCDs following a laser at pH 6.5 significantly promoted calreticulin exposure and high-mobility group box 1 release, as major immunogenic cell death markers. In bilateral CT-26-bearing mice model, the Ce6@IDCDs elicited significant antitumoral effects at laser treated-primary tumor regions via therapeutic reactive oxygen species. Furthermore, Ce6@IDCDs upon laser irradiation induced a large amount of activated CD8+ T cells, natural killer cells, and mature dendritic cells recruitment into tumoral tissue and hampered tumor growth even at untreated sites approximately four-fold compared with those of others. Overall, this pH-sensitive immunoinducer can accomplish primary and distant tumor ablation via photomediated cancer immunotherapy.
Subject(s)
Carbon/chemistry , Dendritic Cells/drug effects , Immunotherapy/methods , Nanoparticles/chemistry , Neoplasms/drug therapy , Photochemotherapy/methods , Porphyrins/administration & dosage , Radiation-Sensitizing Agents/administration & dosage , Animals , Calreticulin/metabolism , Cell Death/drug effects , Cell Death/immunology , Cell Death/radiation effects , Cell Line, Tumor , Chlorophyllides , Dendritic Cells/immunology , Dendritic Cells/radiation effects , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Imidazoles/chemistry , Lasers , Mice , Mice, Inbred BALB C , Mice, Nude , Microscopy, Electron, Transmission , Nanoparticles/radiation effects , Nanoparticles/ultrastructure , Neoplasms/immunology , Neoplasms/radiotherapy , Particle Size , Porphyrins/chemistry , Porphyrins/pharmacokinetics , Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/radiation effects , Reactive Oxygen Species/metabolism , Reactive Oxygen Species/therapeutic use , Spectroscopy, Fourier Transform Infrared , Tumor Microenvironment , Xenograft Model Antitumor AssaysABSTRACT
Nonpolymer, pH-sensitive carbon dots (pSCDs) were developed to overcome the disadvantages of pH-sensitive polymers such as inevitable synthesis, wide distribution of molecular weight, uncontrolled loading and release rate of drugs, and toxicity by biodegradation. The pSCDs were synthesized via one spot synthesis for 3 min using citric acid (CA) and 1-(3-aminopropyl) imidazole (API). Imidazole groups were present on pSCD surfaces and facilitated DOX loading via hydrophobic interactions (loading efficiency: 78.55%). The DOX-loaded pSCDs collapsed at tumoral pH (pH â¼ 6.5) due to protonation of the imidazole groups, and DOX was released about 7 times higher than the control group. The therapeutic effect was confirmed in vitro using HCT-116 (human colon cancer), PANC-1 (human pancreatic cancer), and SKBR-3 (human breast cancer) cells. Additionally, the DOX-loaded pSCDs successfully inhibited tumor growth in an HCT-116-bearing mouse model and did not show toxicity. These results indicate that a nonpolymeric pSCDs platform has the potential to be used as a cancer targeting therapeutic material.
