Abstract
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Objectives: To develop a multicomponent nanosystem, integrating photothermal (PT) and photodynamic therapy (PDT) for tumor eradication under the guidance of fluorescence imaging (FL) and positron emission tomography (PET).
Methods: Hollow mesoporous silica nanoparticles (HMSNs) were synthesized and modified with -NH2 groups for further surface functionalization. The hollow cavity was loaded with porphyrin (TCPP). Electrostatic adsorption was used to assemble positively charged TCPP loaded HMSN ([TCPP]HMSN-NH2) and negatively charged citrate-stabilized CuS to form the final [TCPP]HMSN_nCuS core-satellite nanoconjugates (CSNCs). CSNCs were grafted with polyethylene glycol (PEG) for improved stability and biocompatibility. After physicochemical characterization, photothermal (due to CuS) and photodynamic (due to TCPP) property of CSNCs was studied by irradiation with near infrared (NIR; 980 nm) and ultrared (660 nm) lasers, respectively. The nanoconstructs were intrinsically radiolabeled with 89Zr (t1/2 = 78.4 h) and serial PET and FL (based on intrinsic FL of TCPP; ex/em: 640/ 720 nm) were performed in subcutaneous 4T1 tumor-bearing mice to evaluate the tumor-seeking ability of CSNCs. Combined PT/PD therapy was performed in 4T1 tumors (n = 5 per group) after a single intratumor injection of CSNCs, followed by laser irradiation (L980 for 10 min and L660 for 20 min) and tumor growth monitoring upto 15 days.
Results: Transmission electron microscopy (TEM) indicated uniform morphology and excellent dispersibility of HMSN and CuS nanoparticles, as well as assembled CSNCs (~ 163 nm). High loading efficiency of TCPP into HMSN (~ 48 %) was observed. Mass spectrometric measurements indicated ~ 7800 CuS nanosatellites attached per core. CSNCs demonstrated high absorption in the ultrared and NIR windows and excellent PD and PT conversion efficiency upon laser irradiation in vitro. The oxophillic nature of 89Zr and abundant deprotonated -SiO2- groups in HMSN were harnessed for chelator-free radiolabeling of CSNCs demonstrating excellent labeling yield (~ 80 %) and serum radiostability. Radolabeled CSNCs also demonstrated Cerenkov Luminescence (CL) and Cerenkov Radiation Energy Transfer (CRET) in vitro. In vivo FL and PET imaging showed rapid and persistent accumulation of CSNC-PEG in 4T1 tumors via enhanced permeability and retention (EPR) effect (2.2 ± 0.8, 5.5 ± 1.2, 5.2 ± 1.4 and 5.0 ± 1.0 %ID/g at 1, 4, 24 and 48 h post-injection (pi)). Single dose (5 mg/mL; 50 uL) of intratumorally injected CSNCs and dual laser treatment demonstrated synergistic phototherapeutic effect, resulting in complete tumor remission within day 1 pi with no relapse during 15 days of observation. Tumors receiving same dose of CSNC but single laser treatment (either 980 or 660 nm), showed initial growth retardation up to day 7 pi followed by a relapse, reaching a relative tumor volume (V/Vo) of 1.7±0.9 and 2.6±0.4, respectively. Control cohorts receiving CSNC dose only without laser irradiation or PBS (with and without laser) reached final relative tumor volumes of 8.1±1.6, 6.3±1.7 and 10.5±0.5, respectively indicating negligible therapeutic effect.
Conclusion: A multifunctional core-satellite nanotheranostic construct is reported, integrating PET, FL, PDT and PTT into a single platform for image-guided synergistic therapy. Detailed in vitro and in vivo studies indicate that, (1) CSNCs retain the photosensitizing and thermal ablative properties of their building blocks, (2) intrinsically radiolabeled PEGylated-CSNCs possess multimodal imaging capability, namely PET, FL, CL and CRET to efficiently reveal tumor location, and (3) one time administration of CSNCs demonstrates complete tumor eradication upon laser irradiation, due to a strong, synergistic phototherapeutic effect which is more potent than monotherapies from its individual components. Research Support: NIH, American Cancer Society, and University of Wisconsin - Madison (6AC630B0-93A9-4C19-9FBD-D72BFD473037}
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