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Preparation and Characterization of Individual and Multi-drug Loaded Physically Entrapped Polymeric Micelles
Published on: August 28, 2015
Pirfenidone-Loaded Polymeric Micelles as an Effective Mechanotherapeutic to Potentiate Immunotherapy in Mouse Tumor
Fotios Mpekris1, Petri Ch Papaphilippou2, Myrofora Panagi1
1Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678 Nicosia, Cyprus.
Abstract:
Ongoing research is actively exploring the use of immune checkpoint inhibitors to treat solid tumors by inhibiting the PD-1/PD-L1 axis and reactivating the function of cytotoxic T effector cells. Many types of solid tumors, however, are characterized by a dense and stiff stroma and are difficult to treat. Mechanotherapeutics have formed a recent class of drugs that aim to restore biomechanical abnormalities of the tumor microenvironment, related to increased stiffness and hypo-perfusion. Here, we have developed a polymeric formulation containing pirfenidone, which has been successful in restoring the tumor microenvironment in breast tumors and sarcomas. We found that the micellar formulation can induce similar mechanotherapeutic effects to mouse models of 4T1 and E0771 triple negative breast tumors and MCA205 fibrosarcoma tumors but with a dose 100-fold lower than that of the free pirfenidone. Importantly, a combination of pirfenidone-loaded micelles with immune checkpoint inhibition significantly delayed primary tumor growth, leading to a significant improvement in overall survival and in a complete cure for the E0771 tumor model. Furthermore, the combination treatment increased CD4+ and CD8+ T cell infiltration and suppressed myeloid-derived suppressor cells, creating favorable immunostimulatory conditions, which led to immunological memory. Ultrasound shear wave elastography (SWE) was able to monitor changes in tumor stiffness during treatment, suggesting optimal treatment conditions. Micellar encapsulation is a promising strategy for mechanotherapeutics, and imaging methods, such as SWE, can assist their clinical translation.
Insights
New micellar pirfenidone combined with immune checkpoint inhibitors effectively treats solid tumors by restoring the tumor microenvironment and enhancing anti-tumor immunity.
Area of Science:
- Oncology
- Biomaterials Science
- Immunotherapy
Background:
- Solid tumors often possess dense, stiff stroma, hindering treatment efficacy.
- Immune checkpoint inhibitors (ICIs) target the PD-1/PD-L1 axis to reactivate cytotoxic T cells.
- Mechanotherapeutics address tumor microenvironment biomechanical abnormalities like stiffness and hypo-perfusion.
Purpose of the Study:
- To develop a micellar formulation of pirfenidone for mechanotherapy.
- To evaluate the efficacy of pirfenidone micelles alone and in combination with ICIs against solid tumors.
- To assess the impact of combination therapy on tumor immunity and stiffness.
Main Methods:
- Development of pirfenidone-loaded polymeric micelles.
- In vivo studies using mouse models of triple-negative breast tumors (4T1, E0771) and fibrosarcoma (MCA205).
- Combination treatment with pirfenidone micelles and anti-PD-1 immune checkpoint inhibition.
- Assessment of tumor growth, survival, immune cell infiltration (CD4+, CD8+ T cells, myeloid-derived suppressor cells), and tumor stiffness using ultrasound shear wave elastography (SWE).
Main Results:
- Pirfenidone micelles achieved mechanotherapeutic effects at a 100-fold lower dose than free pirfenidone.
- Combination therapy significantly delayed tumor growth, improved overall survival, and achieved complete cure in the E0771 model.
- Treatment increased CD4+ and CD8+ T cell infiltration and reduced myeloid-derived suppressor cells, promoting an immunostimulatory environment and immunological memory.
- SWE effectively monitored changes in tumor stiffness, indicating optimal treatment conditions.
Conclusions:
- Micellar encapsulation is a promising strategy for delivering mechanotherapeutics.
- Combination therapy of pirfenidone micelles and ICIs demonstrates significant anti-tumor activity and potential for inducing long-term immunity.
- Ultrasound shear wave elastography can aid in monitoring treatment response and optimizing clinical translation of mechanotherapeutics.
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