Polyglutamate-based nanoconjugates for image-guided surgery and post-operative melanoma metastases prevention

• Published in: Theranostics Vol. 12; no. 14; pp. 6339 - 6362
• Main Authors: Epshtein, Yana, Blau, Rachel, Pisarevsky, Evgeni, Koshrovski-Michael, Shani, Ben-Shushan, Dikla, Pozzi, Sabina, Shenbach-Koltin, Gal, Fridrich, Lidar, Buzhor, Marina, Krivitsky, Adva, Dey, Pradip, Satchi-Fainaro, Ronit
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2022; Ivyspring International Publisher
• Subjects: Animals; Antigens; Cathepsins; Clinical trials; Drugs; FDA approval; Glutamic Acid; Immune Checkpoint Inhibitors; Immunotherapy; Kinases; Melanoma; Melanoma - drug therapy; Metastasis; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular weight; Mutation; Nanoconjugates; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - prevention & control; Peptides; Polyglutamic Acid - therapeutic use; Prevention; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf; Research Paper; Skin cancer; Skin Neoplasms - pathology; Surgery; Surgery, Computer-Assisted; Tumors; Polymeric nanomedicine; Immune checkpoint inhibitors; Image-guided surgery; PGA; BRAF/MEK inhibitors
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.72941

Cutaneous melanoma is the most aggressive and deadliest of all skin malignancies. Complete primary tumor removal augmented by advanced imaging tools and effective post-operative treatment is critical in the prevention of tumor recurrence and future metastases formation. To meet this challenge, we designed novel polymeric imaging and therapeutic systems, implemented in a two-step theranostic approach. Both are composed of the biocompatible and biodegradable poly(α,L-glutamic acid) (PGA) nanocarrier that facilitates extravasation-dependent tumor targeting delivery. The first system is a novel, fluorescent, Turn-ON diagnostic probe evaluated for the precise excision of the primary tumor during image-guided surgery (IGS). The fluorescence activation of the probe occurs via PGA degradation by tumor-overexpressed cathepsins that leads to the separation of closely-packed, quenched FRET pair. This results in the emission of a strong fluorescence signal enabling the delineation of the tumor boundaries. Second, therapeutic step is aimed to prevent metastases formation with minimal side effects and maximal efficacy. To that end, a targeted treatment containing a BRAF (Dabrafenib - mDBF)/MEK (Selumetinib - SLM) inhibitors combined on one polymeric platform (PGA-SLM-mDBF) was evaluated for its anti-metastatic, preventive activity in combination with immune checkpoint inhibitors (ICPi) αPD1 and αCTLA4. IGS in melanoma-bearing mice led to a high tumor-to-background ratio and reduced tumor recurrence in comparison with mice that underwent surgery under white light (23% 33%, respectively). Adjuvant therapy with PGA-SLM-mDBF combined with ICPi, was well-tolerated and resulted in prolonged survival and prevention of peritoneal and brain metastases formation in BRAF-mutated melanoma-bearing mice. The results reveal the great clinical potential of our PGA-based nanosystems as a tool for holistic melanoma treatment management.