An Integrated Nanotechnology-Enabled Transbronchial Image-Guided Intervention Strategy for Peripheral Lung Cancer.

Early detection and efficient treatment modality of early-stage peripheral lung cancer is essential. Current nonsurgical treatments for peripheral lung cancer show critical limitations associated with various complications, requiring alternative minimally invasive therapeutics. Porphysome nanoparticle-enabled fluorescence-guided transbronchial photothermal therapy (PTT) of peripheral lung cancer was developed and demonstrated in preclinical animal models. Systemically administered porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast, as confirmed in three subtypes of orthotopic human lung cancer xenografts (A549, H460, and H520) in mice and in an orthotopic VX2 tumor in rabbits. An in-house prototype fluorescence bronchoscope demonstrated the capability of porphysomes for in vivo imaging of lung tumors in the mucosal/submucosal layers, providing real-time fluorescence guidance for transbronchial PTT. Porphysomes also enhanced the efficacy of transbronchial PTT significantly and resulted in selective and efficient tumor tissue ablation in the rabbit model. A clinically used cylindrical diffuser fiber successfully achieved tumor-specific thermal ablation, showing promising evidence for the clinical translation of this novel platform to impact upon nonsurgical treatment of early-stage peripheral lung cancer. Cancer Res; 76(19); 5870-80. ©2016 AACR.

Nanoparticle-Enabled Selective Destruction of Prostate Tumor Using MRI-Guided Focal Photothermal Therapy.

BACKGROUND: The Magnetic Resonance Imaging (MRI)-guided focal laser therapy has shown early promise in Phase 1 trial treating low/intermediate-risk localized prostate cancer (PCa), but the lack of tumor selectivity and low efficiency of heat generation remain as drawbacks of agent-free laser therapy. Intrinsic multifunctional porphyrin-nanoparticles (porphysomes) have been exploited to treat localized PCa by MRI-guided focal photothermal therapy (PTT) with significantly improved efficiency and tumor selectivity over prior methods of PTT, providing an effective and safe alternative to active surveillance or radical therapy. METHODS: The tumor accumulation of porphysomes chelated with copper-64 was determined and compared with the clinic standard (18) F-FDG in an orthotropic PCa mouse model by positron emission tomography (PET) imaging, providing quantitative assessment for PTT dosimetry. The PTT was conducted with MRI-guided light delivery and monitored by MR thermometry, mimicking the clinical protocol. The efficacy of treatment and adverse effects to surround tissues were evaluated by histology analysis and tumor growth in survival study via MRI. RESULTS: Porphysomes showed superior tumor-to-prostate selectivity over (18) F-FDG (6:1 vs. 0.36:1). MR thermometry detected tumor temperature increased to ≥55°C within 2 min (671 nm at 500 mW), but minimal increase in surrounding tissues. Porphysome enabled effective PTT eradication of tumor without damaging adjacent organs in orthotropic PCa mouse model. CONCLUSIONS: Porphysome-enabled MRI-guided focal PTT could be an effective and safe approach to treat PCa at low risk of progression, thus addressing the significant unmet clinical needs and benefiting an ever-growing number of patients who may be over-treated and risk unnecessary side effects from radical therapies. Prostate 76:1169-1181, 2016. © 2016 Wiley Periodicals, Inc.

One minute, sub-one-watt photothermal tumor ablation using porphysomes, intrinsic multifunctional nanovesicles.

We recently developed porphysomes as intrinsically multifunctional nanovesicles. A photosensitizer, pyropheophorbide α, was conjugated to a phospholipid and then self-assembled to liposome-like spherical vesicles. Due to the extremely high density of porphyrin in the porphyrin-lipid bilayer, porphysomes generated large extinction coefficients, structure-dependent fluorescence self-quenching, and excellent photothermal efficacy. In our formulation, porphysomes were synthesized using high pressure extrusion, and displayed a mean particle size around 120 nm. Twenty-four hr post-intravenous injection of porphysomes, the local temperature of the tumor increased from 30 °C to 62 °C rapidly upon one minute exposure of 750 mW (1.18 W/cm(2)), 671 nm laser irradiation. Following the complete thermal ablation of the tumor, eschars formed and healed within 2 weeks, while in the control groups the tumors continued to grow and all reached the defined end point within 3 weeks. These data show how porphysomes can be used as potent photothermal therapy (PTT) agents.

Ablation of hypoxic tumors with dose-equivalent photothermal, but not photodynamic, therapy using a nanostructured porphyrin assembly.

Tumor hypoxia is increasingly being recognized as a characteristic feature of solid tumors and significantly complicates many treatments based on radio-, chemo-, and phototherapies. While photodynamic therapy (PDT) is based on photosensitizer interactions with diffused oxygen, photothermal therapy (PTT) has emerged as a new phototherapy that is predicted to be independent of oxygen levels within tumors. It has been challenging to meaningfully compare these two modalities due to differences in contrast agents and irradiation parameters, and no comparative in vivo studies have been performed until now. Here, by making use of recently developed nanostructured self-quenched porphysome nanoparticles, we were able to directly compare PDT and PTT using matched light doses and matched porphyrin photosensitizer doses (with the photosensitizer being effective for either PTT or PDT based on the existence of nanostructure or not). Therefore, we demonstrated the nanostructure-driven conversion from the PDT singlet oxygen generating mechanism of porphyrin to a completely thermal mechanism, ideal for PTT enhancement. Using a novel hypoxia tumor model, we determined that nanostructured porphyrin PTT enhancers are advantageous to overcome hypoxic conditions to achieve effective ablation of solid tumors.