Melanin-loaded biocompatible photosensitive nanoparticles for controlled drug release in combined photothermal-chemotherapy guided by photoacoustic/ultrasound dual-modality imaging.

Combined photothermal-chemotherapy guided by multimodal imaging is a promising strategy for cancer diagnosis and treatment. Multifunctional nanoparticles, such as those comprising organic and inorganic compounds, have been extensively investigated for combined photothermal-chemotherapy; however, their application is still limited by their potential long-term toxicity and lack of contrast properties. To solve these problems, in this study, a new type of multifunctional nanoparticle for combined photothermal-chemotherapy guided by dual-modality imaging was prepared with endogenous melanin by multistep emulsification to enhance tumor ablation. The nanoparticles were coated with poly(lactide-co-glycolic acid) (PLGA) and loaded with paclitaxel (PTX), encapsulated melanin and perfluoropentane (PFP). The materials in the nanoparticles were endogenous, ensuring high stability, biocompatibility, and biosafety. Nanoparticles irradiated with a laser, which induced their phase transformation into microbubbles, exhibited high photothermal conversion efficiency, thereby achieving photoacoustic (PA)/ultrasound (US) dual-modality imaging to determine tumor location, boundary, and size and to monitor drug distribution. Furthermore, optical droplet vaporization (ODV) of the nanoparticles could trigger the release of PTX; thus, these nanoparticles are a useful drug carrier. In vivo and in vitro experiments revealed that a strong synergistic antitumor effect was achieved by combining the photothermal properties of the nanoparticles with a chemotherapy drug. Importantly, the cavitation, thermoelastic expansion, and sonoporation caused by the phase transformation of the nanoparticles could directly damage the tumors. These processes also promoted the release, penetration and absorption of the drug, further enhancing the effect of combined photothermal-chemotherapy on tumor suppression. Therefore, the multifunctional nanoparticles prepared in this study provide a new strategy of using endogenous materials for controlled near-infrared (NIR)-responsive drug release and combined photothermal-chemotherapy guided by multimodal imaging.

Magnetic-responsive and targeted cancer nanotheranostics by PA/MR bimodal imaging-guided photothermally triggered immunotherapy.

While theranostic nanoparticle (TNP)-based photothermal therapy (PTT) exhibits prominent promise for cancer therapy, metastatic cancers remain one of the main obstacles of effective PTT. Immunotherapy has been developed vigorously to inhibit metastatic cancers, but the heterogeneity of patients and the complexities of manufacturing cancer vaccines significantly hinder its further clinical applications. Herein, a photothermally triggered immunotherapeutic paradigm under imaging guidance was designed based on magnetic-responsive immunostimulatory nanoagents (MINPs) loaded with superparamagnetic iron oxide (SPIO) nanoparticles and cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs). The fabricated MINPs with the clinically approved components acted not only as a contrast agent for photoacoustic (PA)/magnetic resonance (MR) bimodal imaging but also as a magnetic-targeting therapeutic agent for photothermally triggered immunotherapy. Under external magnetic fields, the MINPs showed a great magnetic-targeting ability, leading to high accumulation of the photoabsorber (SPIO) and the immunoadjuvant (CpG ODNs) in the tumors for precise bimodal imaging guidance. More importantly, the excellent photothermal conversion effect of the MINPs upon near-infrared (NIR) exposure enabled the effective photothermal destruction of the primary tumors, releasing tumor-associated antigens and showing 'autologous cancer vaccine'-like functions, thus activating robust antitumor immune responses, especially in the presence of CpG ODN-containing immunostimulatory nanoagents. Such generated immune responses can further attack the remaining tumors and distant metastatic tumors in mice. This work provides an imaging-guided photothermally triggered immunotherapeutic strategy based on multifunctional MINPs to effectively eliminate primary tumors and inhibit metastatic tumors simultaneously with high specificity, easy maneuverability and favorable biocompatibility. This strategy may potentially be applicable for precise individualized diagnosis and therapy of various tumors.

A light-controllable specific drug delivery nanoplatform for targeted bimodal imaging-guided photothermal/chemo synergistic cancer therapy.

Breast cancer is a severe threat to the health and lives of women due to its difficult early diagnosis and the unsatisfactory therapeutic efficacy of breast cancer treatments. The development of theranostic strategies to combat breast cancer with high accuracy and effectiveness is therefore urgently needed. In this study, we describe a near-infrared (NIR) light-controllable, targeted and biocompatible drug delivery nanoplatform (PFH-PTX@PLGA/SPIO-Her) for photoacoustic (PA)/ultrasound (US) bimodal imaging-guided photothermal (PTT)/chemo synergistic cancer therapy of breast cancer. Carboxyl-modified PEGylated poly (lactic-co-glycolic acid) (PLGA-PEG-COOH) constituted the skeleton of the nanoplatform. Especially, the antibody Herceptin was modified onto the surface of nanoplatform for active HER2-targing to facilitate the tumor accumulation of the nanoplatform. The encapsulated superparamagnetic iron oxide (SPIO) nanoparticles could be employed as an excellent PA imaging agent to guide tumor therapy. When exposed to NIR light, the SPIO also could transform NIR light into thermal energy for photothermal ablation of tumor. The NIR-induced thermal effect subsequently triggered the optical droplet vaporization (ODV) of perfluorohexane (PFH) to generate PFH gas bubbles, which not only achieved the US imaging enhancement, but also contributed to the release of loaded paclitaxel (PTX) from the nanoplatform for significantly improving PTT therapeutic efficacy. Our results demonstrated that the targeted tumor accumulation, accurate real-time bimodal imaging, and the abundant drug release at the tumor site were all closely associated with the PTT therapeutic efficacy. Therefore, the theranostic nanoplatform is a very promising strategy for targeted imaging-guided photothermal/chemo synergistic tumor therapy with high therapeutic efficacy and minimized side effects. STATEMENT OF SIGNIFICANCE: Breast cancer is the most frequent cancer in women. Herein, we successfully developed a light-controllable and HER2 targeted theranostic nanoparticels (PFH-PTX@PLGA/SPIO-Her) as a specific drug delivery nanoplatform to overcome the low accuracy of tumor detection and the low specificity of traditional chemo-therapeutic protocols. The study demonstrated that PFH-PTX@PLGA/SPIO-Her could actively target to breast cancer cells with positive HER2 expression. The biocompatible PFH-PTX@PLGA/SPIO-Her nanoparticles as both photoacoustic/ultrasound bimodal imaging agents, photothermal-conversion nanomaterials (photothermal hyperthermia) and controllable drug delivery nanoagents (optical droplet vaporization) have completely eradicated the tumor without severe side effects. The theranostic strategy not only integrates strengthens of traditional imaging or therapeutic modalities, but also paves a new way for the efficient cancer treatment by taking the advantage of quickly-developing nanomedicine.

Folate-receptor-targeted laser-activable poly(lactide-co-glycolic acid) nanoparticles loaded with paclitaxel/indocyanine green for photoacoustic/ultrasound imaging and chemo/photothermal therapy.

BACKGROUND: Cancer is one of the most serious threats to human health. Precision medicine is an innovative approach to treatment, as part of which theranostic nanomedicine has been studied extensively. However, the required biocompatibility and substantial cost for the approval of nanomedicines hinder their clinical translation. PURPOSE: We designed a novel type of theranostic nanoparticle (NP) folate-receptor-targeted laser-activatable poly(lactide-co-glycolic acid) (PLGA) NPs loaded with paclitaxel (Ptx)/indo-cyanine green (ICG)-folic acid-polyethylene glycol (PEG)-PLGA-Ptx@ICG-perfluorohexane (Pfh)- using safe and approved materials and drugs, which would facilitate clinical translation. With laser irradiation, highly efficient photothermal therapy can be achieved. Additionally, targeted NPs can be activated by near-infrared laser irradiation at a specific region, which leads to the sharp release of Ptx at areas of high folate-receptor expression and ensures a higher Ptx concentration within the tumor region, thereby leading to chemo/photothermal synergistic antitumor efficacy. Meanwhile, the NPs can be used as a dual-modality contrast agent for photoacoustic and ultrasound imaging. MATERIALS AND METHODS: FA-PEG-PLGA-Ptx@ICG-Pfh NPs were prepared by sonification method and characterized for physicochemical properties. Cytotoxicity and in vivo biocompatibility were evaluated respectively by CCK8 assay and blood analysis. NPs as dual-modality contrast agents were evaluated by photoacoustic/ultrasound imaging system in vitro and in vivo. In vitro anticancer effect and in vivo anticancer therapy was evaluated by CCK8 assay and MDA-MB231 tumor-bearing mice model. RESULTS: FA-PEG-PLGA-Ptx@ICG-Pfh NPs were in the size of 308±5.82 nm with negative zeta potential and showed excellent photothermal effect. The NPs could be triggered sharp release of Ptx by laser irradiation, and showed the good biocompatibility in vitro and in vivo. Through photoacoustic/ultrasound imaging, the NPs showed an excellent ability as dual-modality contrast agents in vitro and in vivo. FA-PEG-PLGA-Ptx@ICG-Pfh NPs with laser irradiation showed the best anticancer efficacy in vitro and in vivo. CONCLUSION: Such a biocompatible and novel theranostic NP is expected to integrate dual-modality imaging with improved therapeutic efficacy and provide a promising paradigm for cancer therapy.

PA/US dual-modality imaging to guide VEGFR-2 targeted photothermal therapy using ZnPc-/PFH-loaded polymeric nanoparticles.

Angiogenesis is a common pathological characteristic of many solid tumors and vulnerable atherosclerotic plaques. Photothermal therapy (PTT) is a promising method to reduce neovascularization. To increase the targeting ability and efficiency of PTT, a novel polymeric nanosystem that encapsulates phthalocyanine zinc (ZnPc) and perfluorohexane (PFH) was developed to target the new blood vessels of breast tumors. After being conjugated to the anti-VEGFR-2 antibody, the polymeric nanoparticles (NPs) targeted vascular endothelial cells efficiently. The photosensitizer (PS) in the NPs could convert laser energy into heat, generating local high temperatures to kill the surrounding cells under laser irradiation. In addition, the liquid-gas phase transition of PFH was induced, and an enhanced ultrasound (US) and photoacoustic (PA) image could be obtained. US/PA imaging enables visualization of the location of NPs, and laser irradiation position can be guided to the optimal location, resulting in fewer side effects than those from traditional treatments with a high targeting ability and an efficient synergistic effect from the PTT.

Phase-Transition Nanodroplets for Real-Time Photoacoustic/Ultrasound Dual-Modality Imaging and Photothermal Therapy of Sentinel Lymph Node in Breast Cancer.

Pathological status of lymph nodes (LNs) plays a critical role in staging and treatment for the patients with breast cancer. Sentinel lymph node biopsy has become the standard method in determining pathological status of axillary LNs. Therefore, the determination of sentinel lymph nodes (SLNs) and therapy of metastatic LNs are highly desirable in clinic. Herein, an unprecedented carbon nanoparticles (CNs)-incorporated liquid-gas phase-transition nanodroplets (CNPs) with strong near-infrared (NIR) absorption, good biocompatibility, excellent photoacoustic (PA) and ultrasound (US) contrast, and high photothermal-conversion efficiency are reported in this study. Upon laser irradiation, liquid-gas phase transition of the CNPs has been demonstrated to provide excellent contrasts for PA/US dual-modality imaging both in vitro and in vivo. Additionally, the CNPs are capable of staining lymph nodes, which can contribute significantly to the identification of LNs with naked eyes. With increased laser energy, the CNPs exhibit the high performance in killing the breast cancer cells both in vitro and in vivo, due to the photothermal effect induced from the CNs within CNPs. These results suggest that the developed multifunctional phase-transition nanodroplets have high potential to act as the theranostic agents in both SLNs detection and therapy of metastatic LNs.