Research On Multifunctional Microcapsules For Combined Imaging And Photothermal Therapy Of Cancer

Cancer is the leading cause of death worldwide, making the early diagnosis and accurate therapy of cancer crucial. Medical imaging plays an important role in the early detection of cancer with the help of contrast agents. Among all the diagnostic imaging techniques, ultrasound imaging (US) has its unique advantage due to its features of real-time, low cost, high safety and readily availability for portable devices. Photothermal therapy (PTT) utilizes near-infrared (NIR) lasers and photoabsorbers for tumor ablation, which has gained popularity recently as a non-invasive and remote-control alternative to conventional surgery and chemotherapy.Diagnosis and therapy of cancer are usually carried out separately in the traditional medical practice, which causes the treatment inefficiency. Nowadays, a new concept called theranostics, integrating diagnostic imaging and imaging-guided therapeutic interventions in combination, receives a great deal of research interest. Theranostic agents used for the delivery of both diagnostic and therapeutic functions can especially address the challenges of cancer heterogeneity and adaptation. Therefore, ultrasound imaging integrated with photothermal therapy as a new theranostic strategy was developed to address the inefficiency of treatment. Herein, microcapsule ultrasound contrast agents were composited with gold nanostructures and other functional nanomaterials to achieve a series of multifunctional microcapsules with both imaging and therapeutic capabilities for cancer treatment. Thus, by using multifunctional theranostic agents, personalized therapeutic plan could be made based on the multimodal imaging diagnostic results immediately; and localized therapy could be carried out under the guidance of medical imaging.Firstly, the polymeric microcapsules (MCs) were generated by the water-in-oil-in-water (W/O/W) double emulsion method using biocompatible and biodegradable poly(lactic acid)(PLA). The gold nanorods were deposited on the surface of MCs via electrostatic adsorption to form gold nanorod-loaded microcapsules (GNR-MCs). The GNR-MCs were proved to have great capabilities of ultrasound contrast enhancement as well as NIR photothermal therapy. That demonstrated the feasibility of the combination of ultrasound contrast imaging and NIR photothermal therapy as novel theranostics.Based on PLA microcapsules, gold nanoshell was constructed on the surface by seeding method to achieve gold nanoshelled microcapsules (GNS-MCs) to increase the relative amount of the Au element by about5times compared to the GNR-MCs. The inner microcapsules could contribute to ultrasound-responded ability, and the gold shells on the outer surface can be heated by NIR lasers as photoabsorbers for photothermal ablation therapy, making the GNS-MCs a novel theranostic agent. Using human breast cancer xenografted animal model, ultrasound contrast imaging-guided photothermal ablation of xenografted tumors were successfully carried out with GNS-MCs.The dual modal ultrasound/CT contrast imaging and PTT capabilities of PEGylated GNS-MCs were verified in vitro due to the high X-ray attenuation coefficient of Au element. That’s the first report of gold nanoshell to carry out CT contrast imaging and PTT at the same time. To overcome the aggregation cause by large size of GNS-MCs, PLA was used to load perfluorooctyl bromide (PFOB) inside to form echogenic nano-scaled microcapsules (nanocapsules) using an adapted oil-in-water emulsion solvent evaporation process, followed by the formation of gold nanoshell via a surface seeding method and surface PEGylation to generate gold nanoshelled nanocapsules (PGsP NCs). In vivo imaging evaluation proved the capabilities of PGsP NCs to serve as dual-modal ultrasound/CT contrast agents. Human glioblastoma tumor bearing nude mice were used to confirm the photothermal tumor ablation feature of PGsP NCs.Magnetic resonance imaging (MRI) was applied to replace CT imaging to avoid the radiation injury of X-ray. By incorporation of superparamagnetic iron oxide nanoparticles (SPIOs) in the PFOB nanocapsules, the gold nanoshelled magnetic nanocapsules (PGS-SP NCs) were fabricated by surface seeding method and PEGylation. By passive targeting to the tumor area after intravenous injection, such a theranostic agent could efficiently ablate the human fibrosarcoma xenografted tumors via the NIR laser irradiation under the guidance of contrast enhanced ultrasound/MRI dual-modal imaging, achieving great therapeutic efficacy without systemic damage to the animals.These theranostic agents could display dynamic complementary information about the tumors by multimodal imaging methods to help alter the treatment accordingly with personalization and high efficiency. In the early future, the multifunctional microcapsules may provide an alternative methodology for noninvasive cancer diagnosis and therapy.