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Dual PLGA nanoparticles co-encapsulating P5091 and Resveratrol synergistically target the USP7-MDM2-P53 axis for
1Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India..
Abstract:
Glioma, a Grade-IV brain tumor, often exhibits functional suppression of P53 signaling due to aberrant stabilization of MDM2 by the deubiquitinase USP7, presenting a therapeutically exploitable vulnerability that remains under-utilised because of poor drug bioavailability and limited blood-brain barrier penetration. Here, we developed a rationally designed PLGA-based dual-loaded nanoformulation co-encapsulating USP7 inhibitor P5091 and P53-modulating polyphenol Resveratrol, to significantly attenuate the USP7-MDM2-P53 axis. Guided by synergy analysis, nanoparticles were formulated at an optimized molar ratio enabling controlled and sustained drug release with favourable physicochemical stability. Dual nanoencapsulation significantly enhanced synergistic cytotoxicity in glioma cells and 3D spheroids by inducing apoptosis through significant P53 restoration. Dual co-encapsulation improves pharmacokinetics and suppresses tumor growth with improved survival in orthotopic glioma model without any obvious vital organs histological damage. These findings highlight a mechanism-guided nanotherapeutic strategy for glioma treatment.
Insights
This study developed a dual-drug nanoparticle to treat glioma by restoring P53 signaling. The nanotherapy effectively suppressed tumor growth and improved survival in preclinical models.
Area of Science:
- Oncology
- Nanotechnology
- Biochemistry
Background:
- Glioma (Grade-IV brain tumor) often shows suppressed P53 signaling via MDM2 stabilization by USP7.
- This USP7-MDM2-P53 axis presents a therapeutic target, but drug delivery challenges limit efficacy.
- Poor drug bioavailability and blood-brain barrier penetration hinder current glioma treatments.
Purpose of the Study:
- To develop a PLGA-based nanoformulation co-encapsulating a USP7 inhibitor (P5091) and Resveratrol.
- To investigate the synergistic therapeutic potential of this dual-drug delivery system for glioma treatment.
- To enhance P53 signaling and overcome drug delivery limitations in glioma.
Main Methods:
- Rational design of PLGA nanoparticles with optimized molar ratios for controlled drug release.
- Synergy analysis to determine the ideal drug combination ratio.
- In vitro cytotoxicity assays on glioma cells and spheroids.
- In vivo studies using an orthotopic glioma mouse model to assess pharmacokinetics, tumor suppression, and survival.
Main Results:
- Optimized nanoparticles demonstrated controlled and sustained release of P5091 and Resveratrol.
- Dual nanoencapsulation achieved synergistic cytotoxicity in glioma cells and spheroids via P53 restoration and apoptosis induction.
- The nanotherapy improved pharmacokinetics, significantly suppressed tumor growth, and enhanced survival in vivo.
- No significant histological damage was observed in vital organs, indicating a favorable safety profile.
Conclusions:
- PLGA-based dual nanoformulation effectively targets the USP7-MDM2-P53 axis in glioma.
- This nanotherapeutic strategy offers improved bioavailability and blood-brain barrier penetration for glioma treatment.
- The findings support a mechanism-guided approach for developing novel glioma therapies.
