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Polyglutamate-based nanoconjugates for image-guided surgery and post-operative melanoma metastases prevention
Yana Epshtein1, Rachel Blau1,2, Evgeni Pisarevsky1
1Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Abstract:
Rationale: 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. Methods: 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. Results: 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% versus 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. Conclusions: The results reveal the great clinical potential of our PGA-based nanosystems as a tool for holistic melanoma treatment management.
Insights
Novel polymeric nanosystems offer a two-step theranostic approach for melanoma. Image-guided surgery with a fluorescent probe reduced tumor recurrence, while combination therapy prevented metastases and prolonged survival in mice.
Area of Science:
- Oncology
- Materials Science
- Nanotechnology
Background:
- Cutaneous melanoma is an aggressive skin cancer requiring complete tumor removal and effective post-operative treatment to prevent recurrence and metastasis.
- Advanced imaging and targeted therapies are crucial for improving melanoma management and patient outcomes.
Purpose of the Study:
- To develop and evaluate novel polymeric imaging and therapeutic nanosystems for a two-step theranostic approach in melanoma treatment.
- To assess the efficacy of a "Turn-ON" fluorescent diagnostic probe for image-guided surgery (IGS) and a combination therapy for preventing melanoma metastasis.
Main Methods:
- Designed poly(α,L-glutamic acid) (PGA) nanocarriers for tumor targeting.
- Developed a "Turn-ON" fluorescent probe activated by cathepsins for IGS.
- Formulated a combination therapy (PGA-SLM-mDBF) with BRAF/MEK inhibitors and immune checkpoint inhibitors (ICPi) for anti-metastatic activity.
Main Results:
- IGS using the fluorescent probe achieved a high tumor-to-background ratio and reduced tumor recurrence (23% vs. 33%) compared to white light surgery.
- Adjuvant therapy with PGA-SLM-mDBF and ICPi was well-tolerated, prolonged survival, and prevented peritoneal and brain metastases in BRAF-mutated melanoma mouse models.
Conclusions:
- PGA-based nanosystems demonstrate significant clinical potential for comprehensive melanoma treatment.
- The developed theranostic approach offers a promising strategy for improving surgical precision and preventing melanoma metastasis.
