作者: Lamy, Laureline ; Piffoux, Max ; Gazeau, Florence ; Yakavets, Ilya ; Silva, Amanda K A ; Francois, Aurelie ; Wilhelm, Claire ; Zorin, Vladimir ; Bezdetnaya, Lina

AbstractBackgroundDespite the highly expected clinical application of nanoparticles (NPs), the translation of NPs from lab to the clinic has been relatively slow. Co-culture 3D spheroids account for the 3D arrangement of tumor cells and stromal components, e.g., cancer-associated fibroblasts (CAFs) and extracellular matrix, recapitulating microenvironment of head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated how the stroma-rich tumor microenvironment affects the uptake, penetration, and photodynamic efficiency of three lipid-based nanoformulations of approved in EU photosensitizer temoporfin (mTHPC): Foslip® (mTHPC in conventional liposomes), drug-in-cyclodextrin-in-liposomes (mTHPC-DCL) and extracellular vesicles (mTHPC-EVs).ResultsCollagen expression in co-culture stroma-rich 3D HNSCC spheroids correlates with the amount of CAFs (MeWo cells) in individual spheroid. The assessment of mTHPC loading demonstrated that Foslip®, mTHPC-DCL and mTHPC-EVs encapsulated 0.05 × 10− 15 g, 0.07 × 10− 15 g, and 1.3 × 10− 15 g of mTHPC per nanovesicle, respectively. The mid-penetration depth of mTHPC NPs in spheroids was 47.8 µm (Foslip®), 87.8 µm (mTHPC-DCL), and 49.7 µm (mTHPC-EVs), irrespective of the percentage of stromal components. The cellular uptake of Foslip® and mTHPC-DCL was significantly higher in stroma-rich co-culture spheroids and was increasing upon the addition of serum in the culture medium. Importantly, we observed no significant difference between PDT effect in monoculture and co-culture spheroids treated with lipid-based NPs. Overall, in all types of spheroids mTHPC-EVs demonstrated outstanding total cellular uptake and PDT efficiency comparable to other NPs.ConclusionsThe stromal microenvironment strongly affects the uptake of NPs, while the penetration and PDT efficacy are less sensitive to the presence of stromal components. mTHPC-EVs outperform other lipid nanovesicles due to the extremely high loading capacity. The results of the present study enlarge our understanding of how stroma components affect the delivery of NPs into the tumors.

2021-02-23·ACS Nano1区 · 材料科学

Immune Reprogramming Precision Photodynamic Therapy of Peritoneal Metastasis by Scalable Stem-Cell-Derived Extracellular Vesicles

1区 · 材料科学

Article

作者: Sarda-Mantel, Laure ; Pinto, Amandine ; Lavieu, Grégory ; Pocard, Marc ; Marangon, Iris ; Méreaux, Julie ; Wilhelm, Claire ; Gazeau, Florence ; Nicolás-Boluda, Alba ; Silva, Amanda K. A.

The dissemination of tumor metastasis in the peritoneal cavity, also called peritoneal metastasis (PM) or carcinomatosis, represents a late stage of gastrointestinal and gynecological cancer with very poor prognosis, even when cytoreductive surgery is effective, due to residual microscopic disease. Photodynamic therapy (PDT) in the management of peritoneal metastasis has been clinically limited by the low tumor selectivity of photosensitizers (PS) and important adverse effects. Here, we propose extracellular nanovesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) as the fourth generation of immune active PS vectors that are able to target peritoneal metastasis with superior selectivity, potentiate PDT cytotoxicity at the tumor site without affecting healthy tissues, modulate the tumor microenvironment of immunocompetent colorectal and ovarian carcinomatosis models, and promote an antitumor immune response. A pioneering strategy was developed for high yield, large-scale production of MSC-EVs encapsulating the drug meta(tetrahydroxyphenyl)chlorin (mTHPC) (EVs-mTHPC) that is compatible with requirements of clinical translation and also preserves the topology and integrity of naturally produced EVs. Intraperitoneal injection of EVs-mTHPC showed an impressive enhancement of tumoral selectivity in comparison to the free drug and to the liposomal formulation Foslip (mean ratio of PS in tumors/organs of 40 for EVs-mTHPC versus 1.5 for the free PS and 5.5 for Foslip). PDT mediated by EVs-mTHPC permitted an important tumoral necrosis (55% of necrotic tumoral nodules versus 18% for Foslip (p < 0.0001)) and promoted antitumor immune cell infiltration, mainly proinflammatory M1-like CD80+ and CD8+ T cell effector. Intratumor proliferation was significantly decreased after PDT with EVs-mTHPC. Overall EVs vectorization of mTHPC afforded important tumoral selectivity while overcoming the PDT toxicity of the free drug and prolonged mice survival in the colorectal carcinomatosis model. MSC-EVs produced by our scalable manufacturing method appears like the clinically relevant fourth-generation PDT vehicle to overcome current limitations of PDT in the treatment of peritoneal metastasis and promote a hot tumor immune environment in PM.

2020-09-01·Photodiagnosis and Photodynamic Therapy3区 · 医学

Effect of Foslip® mediated photodynamic therapy on 5-fluorouracil resistant human colorectal cancer cells

3区 · 医学

Article

作者: Huang, Zheng ; Chu, Esm ; Law, Eric ; Yow, Cmn ; Wu, Rwk

Colorectal cancer (CRC) is the commonest cancer in Hong Kong and is often treated with 5-fluorouracil (5-FU). However the clinical application of 5-FU was limited by drug resistance in CRC. Photodynamic therapy (PDT) is a novel treatment combating CRC via the combination of photosensitizer, molecular oxygen and light activation. In this study, 5-FU resistant HT29 (HT29FU) was established and its susceptibility to Foslip® PDT tested. Effect of 5-FU to HT29 cells was measured via qPCR. Efficacy of Foslip® PDT on HT29 and HT29FU cells were measured via photosensitizer uptake, cellular localization, cytotoxicity, cell cycle distribution and signal proteins expression. 5-FU significantly induced ABCB1 mRNA expression in HT29 cells; whereas with a 24 fold increase in HT29FU cells. Both cells responded similarly to Foslip® PDT, with the inhibitory concentration IC₂₀, IC₅₀ and IC₇₀ achieved at 1 ng/mL, 2 ng/mL and 5 ng/mL with 2 J/cm² light activation respectively. Foslip® PDT triggered apoptosis and reduced JNK protein expression at IC₇₀ on both cells. Effect of Foslip® PDT on HT29 cells was independent to 5-FU resistance properties. Therefore, Foslip® PDT could be a potential treatment for 5-FU resistant cancer patients. Further investigations on the Foslip® PDT mediated molecular changes in HT29FU cells deserve to be explored.

100 项与 Foslip 相关的药物交易

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