Development of multifunctional nanoplatforms for tumor multimode imaging and therapy is of great necessity. Herein, we report a new type of Au nanostar (NS)-coated, perfluorohexane (PFH)-encapsulated hollow mesoporous silica nanocapsule (HMS) modified with poly(ethylene glycol) (PEG) for tumor multimode ultrasonic (US)/computed tomography (CT)/photoacoustic (PA)/thermal imaging, and photothermal therapy (PTT). HMSs were first synthesized, silanized to have thiol surface groups, and coated with gold nanoparticles via a Au-S bond. Followed by growth of Au NSs on the surface of the HMSs, encapsulation of PFH in the interior of the HMSs, and surface conjugation of thiolated PEG, multifunctional HMSs@Au-PFH-mPEG NSs (for short, HAPP) were formed and well-characterized. We show that the HAPP are stable in a colloidal manner and noncytotoxic in the studied range of concentrations, possess multimode US/CT/PA/thermal imaging ability, and can be applied for multimode US/CT/PA/thermal imaging of tumors in vivo after intravenous or intratumoral injection. Additionally, the near-infrared absorption property of the HAPP enables the use of the HAPP for photothermal ablation of cancer cells in vitro and a tumor model in vivo after intratumoral injection. The developed multifunctional HAPP may be used as a novel multifunctional theranostic nanoplatform for tumor multimode imaging and PTT.

Pancreatic cancer, one of the most lethal human malignancies with dismal prognosis, is refractory to existing radio-chemotherapeutic treatment modalities. There is a critical unmet need to develop effective approaches, especially for targeted pancreatic cancer drug delivery. Targeted and drug-loaded nanoparticles (NPs) combined with ultrasound-mediated microbubble destruction (UMMD) have been shown to significantly increase the cellular uptake in vitro and drug retention in vivo, suggesting a promising strategy for cancer therapy. In this study, we synthesized pancreatic cancer-targeting organic NPs that were modified with anti CA19-9 antibody and encapsulated paclitaxol (PTX). The three-block copolymer methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) constituted the skeleton of the NPs. We speculated that the PTX-NPs-anti CA19-9 would circulate long-term in vivo, "actively target" pancreatic cancer cells, and sustainably release the loaded PTX while UMMD would "passively target" the irradiated tumor and effectively increase the permeability of cell membrane and capillary gaps. Our results demonstrated that the combination of PTX-NPs-anti CA19-9 with UMMD achieved a low IC50, significant cell cycle arrest, and cell apoptosis in vitro. In mouse pancreatic tumor xenografts, the combined application of PTX-NP-anti CA19-9 NPs with UMMD attained the highest tumor inhibition rate, promoted the pharmacokinetic profile by increasing AUC, t1/2, and mean residence time (MRT), and decreased clearance. Consequently, the survival of the tumor-bearing nude mice was prolonged without obvious toxicity. The dynamic change in cellular uptake, targeted real-time imaging, and the concentration of PTX in the plasma and tumor were all closely associated with the treatment efficacy both in vitro and in vivo. Our study suggests that PTX-NP-anti CA19-9 NPs combined with UMMD is a promising strategy for the treatment of pancreatic cancer.