Development of lung metastases in mouse models of tongue squamous cell carcinoma.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) represents 3%-4% of all cancers. Despite the increasing incidence of OSCC distant metastasis and poor prognosis, few animal models of OSCC distant metastasis have been reported. In this study, we established mouse models of OSCC lung metastasis by orthotopic and tail vein injection of new OSCC cell lines. METHODS: For the tail vein model, we used a novel cell line isolated from lung metastases reproduced in vivo after intravenous injection of HSC-3 GFP/luciferase cells and sorted for GFP expression (HSC-3 M1 GFP/luciferase). Lung metastases were assessed by imaging techniques and further confirmed by histology. For the orthotopic model, HSC-3 GFP/luciferase cells were injected into the tongue of athymic nude mice. The primary tumor and metastases were assessed by in vivo imaging, histology, and immunohistochemistry. RESULTS: The orthotopic model presented spontaneous lung metastases in 50% of the animals and lymph node metastases were present in 83% of cases. In the tail vein model, a lung metastasis rate of 60% was observed. CONCLUSIONS: Lung metastases were successfully reproduced by orthotopic and tail vein injection. Since lymph node metastases were present, the orthotopic model with HSC-3 GFP/luciferase cells may be suitable to investigate metastatic dissemination in OSCC.

Hybrid Polypyrrole and Polydopamine Nanosheets for Precise Raman/Photoacoustic Imaging and Photothermal Therapy.

The development of near-infrared light responsive conductive polymers provides a useful theranostic platform for malignant tumors by maximizing spatial resolution with deep tissue penetration for diagnosis and photothermal therapy. Herein, the self-assembly of ultrathin 2D polypyrrole nanosheets utilizing dopamine as a capping agent and a monolayer of octadecylamine as a template is demonstrated. The 2D polypyrrole-polydopamine nanostructure has tunable size distribution which shows strong absorption in the first and second near-infrared windows, enabling photoacoustic imaging and photothermal therapy. The hybrid double-layer is demonstrated to increase Raman intensity for 3D Raman imaging (up to two orders of magnitude enhancement and spatial resolution up to 1 µm). The acidic environment drives reversible doping of polypyrrole, which can be detected by Raman spectroscopy. The combined properties of the nanosheets can substantially enhance performance in dual-mode Raman and photoacoustic guided photothermal therapy, as shown by the 69% light to heat conversion efficiency and higher cytotoxicity against cancer spheroids. These pH-responsive features highlight the potential of 2D conductive polymers for applications in accurate, highly efficient theranostics.

Assembly of Fillable Microrobotic Systems by Microfluidic Loading with Dip Sealing.

Microrobots can provide spatiotemporally well-controlled cargo delivery that can improve therapeutic efficiency compared to conventional drug delivery strategies. Robust microfabrication methods to expand the variety of materials or cargoes that can be incorporated into microrobots can greatly broaden the scope of their functions. However, current surface coating or direct blending techniques used for cargo loading result in inefficient loading and poor cargo protection during transportation, which leads to cargo waste, degradation and non-specific release. Herein, a versatile platform to fabricate fillable microrobots using microfluidic loading and dip sealing (MLDS) is presented. MLDS enables the encapsulation of different types of cargoes within hollow microrobots and protection of cargo integrity. The technique is supported by high-resolution 3D printing with an integrated microfluidic loading system, which realizes a highly precise loading process and improves cargo loading capacity. A corresponding dip sealing strategy is developed to encase and protect the loaded cargo whilst maintaining the geometric and structural integrity of the loaded microrobots. This dip sealing technique is suitable for different materials, including thermal and light-responsive materials. The MLDS platform provides new opportunities for microrobotic systems in targeted drug delivery, environmental sensing, and chemically powered micromotor applications.

Intratumoral injection of hydrogel-embedded nanoparticles enhances retention in glioblastoma.

Intratumoral drug delivery is a promising approach for the treatment of glioblastoma multiforme (GBM). However, drug washout remains a major challenge in GBM therapy. Our strategy, aimed at reducing drug clearance and enhancing site-specific residence time, involves the local administration of a multi-component system comprised of nanoparticles (NPs) embedded within a thermosensitive hydrogel (HG). Herein, our objective was to examine the distribution of NPs and their cargo following intratumoral administration of this system in GBM. We hypothesized that the HG matrix, which undergoes rapid gelation upon increases in temperature, would contribute towards heightened site-specific retention and permanence of NPs in tumors. BODIPY-containing, infrared dye-labeled polymeric NPs embedded in a thermosensitive HG (HG-NPs) were fabricated and characterized. Retention and distribution dynamics were subsequently examined over time in orthotopic GBM-bearing mice. Results demonstrate that the HG-NPs system significantly improved site-specific, long-term retention of both NPs and BODIPY, with co-localization analyses showing that HG-NPs covered larger areas of the tumor and the peri-tumor region at later time points. Moreover, NPs released from the HG were shown to undergo uptake by surrounding GBM cells. Findings suggest that intratumoral delivery with HG-NPs has immense potential for GBM treatment, as well as other strategies where site-specific, long-term retention of therapeutic agents is warranted.

Nanomedicine for Imaging and Therapy of Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma has the worst outcome among all cancer types, with a 5-year survival rate as low as 10%. The lethal nature of this cancer is a result of its silent onset, resistance to therapies, and rapid spreading. As a result, most patients remain asymptomatic and present at diagnosis with an already infiltrating and incurable disease. The tumor microenvironment, composed of a dense stroma and of disorganized blood vessels, coupled with the dysfunctional signal pathways in tumor cells, creates a set of physical and biological barriers that make this tumor extremely hard-to-treat with traditional chemotherapy. Nanomedicine has great potential in pancreatic adenocarcinoma, because of the ability of nano-formulated drugs to overcome biological barriers and to enhance drug accumulation at the target site. Moreover, monitoring of disease progression can be achieved by combining drug delivery with imaging probes, resulting in early detection of metastatic patterns. This review describes the latest development of theranostic formulations designed to concomitantly treat and image pancreatic cancer, with a specific focus on their interaction with physical and biological barriers.