Cancer-derived EVs show tropism for tissues at early stage of neoplastic transformation

Abstract

From the past decade, extracellular vesicles (EVs) have attracted considerable attention as tools for the selective delivery of anti-neoplastic drugs to cancer tissues. Compared to other nanoparticles, EVs display interesting unique features including immune compatibility, low toxicity and the ability to encapsulate a large variety of small-and macro-molecules. However, in virtually all studies, investigations on EVs have been focused on fully transformed cancers: the possibility to apply EV technology also to early-stage tumors has never been explored. Methods: Herein, we studied the ability of cancer-derived EVs to recognize and deliver their cargo also to incipient cancers. To this purpose, EV biodistribution was studied in MMTV-NeuT genetically modified mice during early mammary transformation, in fully developed breast tumors and in the normal gland of wild type syngeneic mice. EVs were loaded with indocyanine green (ICG), a near-infrared (NIR) dye together with oncolytic viruses and i.v. injected in mice. The nanoparticle biodistribution was assayed by in vivo and ex vivo optical imaging (detecting the ICG) and semiquantitative real-time PCR (measuring the adenoviral genome) in different tissues. Results: Our results demonstrate the ability of cancer-derived EVs to recognize early-stage neoplastic tissues opening the possibility to selectively deliver theranostics also for tumor prevention. Conclusions: Taken together our study demonstrates the ability of EVs to recognize and deliver diagnostic and therapeutic agents not only to fully transformed tissues but also to early stage tumors. These findings pave the way for the synthesis of "universal" EVs-based formulation for targeted cancer therapy.

Polymer Coated Oncolytic Adenovirus to Selectively Target Hepatocellular Carcinoma Cells

“…1 H NMR (400 MHz, CDCl 3 , δ): 4.07 (s, 6H, OCH 3 ). 13 C{ 1 H}NMR (100 MHz, CDCl 3 , δ): 56.20 (2C, OCH 3 ), 172.24 (2C, CO), 172.91 (1C, CCl).…”

“…In a 2-neck round bottom flask, 9.6 mL of a 0.5 mg/mL NaOH aqueous solution (0.12 mol) was added dropwise over 5 min under nitrogen atmosphere to a stirred solution of ethanethiol (7.4 mL, 0.10 mol) in a mixture of water/acetone 20:5 (25 mL) cooled on ice. Carbon disulfide (CS 2 ) (8.37 g, 0.11 mol) was added to the reaction with cooling and constant stirring over a 1-h period, and the reaction was stirred until total consumption of CS 2 , which was checked by extended range 13 C NMR. Potassium ferrocyanide (36.21 g, 0.11 mol) was immediately added and stirred for 30 min at 0 • C until the solution turned dark yellow, and a precipitate was observed.…”

“…BF 3 Et 2 O (13.65 g, 96 mmol, 12 mL) was added dropwise over 1 h to the reaction mixture pre-cooled on an ice bath. The reaction was left under stirring at room temperature for 48 h. At scheduled times (every 24 h), the progress of the reaction was monitored by 13 C NMR analysis in DMSO-d 6 of samples withdrawn from the reaction solution by checking the shift of the anomeric carbon from 89 to 100. At full conversion, the reaction mixture was poured into saturated aqueous NaHCO 3 .…”

“…In this realm, a novel and effective approach to treating HCC can be represented by oncolytic virotherapy, which embodies a selective and powerful tool for cancer treatment. Oncolytic adenoviruses (OVs) are able to selectively replicate in tumor cells while sparing the healthy ones [ 10 , 11 , 12 , 13 , 14 ], inducing cytotoxic effects only in cancer cells by selective tumor cell lysis and boosting antitumor immunity [ 15 , 16 , 17 , 18 , 19 , 20 ]. In addition, OVs have shown encouraging clinical outcomes in terms of safety and efficacy [ 21 ], thus entering into the golden age of their utilization since IMLYGIC™ (T-VEC/Talimogene Laherparepvec) was approved, both in the United States and Europe, for the treatment of advanced-stage melanoma.…”

Current Strategies for Cancer Cell-Derived Extracellular Vesicles for Cancer Therapy

“…In the bright side, the newest researches showed the CEVs were able to be used for the trace of the early stage of neoplastic transformation (94) as well as the intracranial tumor may also can apply the CEVs because they can penetrate the bloodbrain barrier (BBB) and have an extraordinarily high brain delivery efficiency (95).…”