All-stage precisional glioma targeted therapy enabled by a well-designed D-peptide
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Updated: Dec 25, 2025
Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression
Published on: February 3, 2023
Danni Ran1, Jianfen Zhou1, Zhilan Chai1
1Department of Pharmaceutics, School of Pharmacy, Fudan University, and Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, & State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Abstract:
Uncontrollable cell proliferation and irreversible neurological damage make glioma one of the most deadly diseases in clinic. Besides the multiple biological barriers, glioma stem cells (GSCs) that are responsible for the maintenance and recurrence of tumor tissues also hinder the therapeutic efficacy of chemotherapy. Therefore, all-stage precisional glioma targeted therapy regimens that could efficiently deliver drugs to glioma cells and GSCs after overcoming multiple barriers have received increasing scrutiny. Methods: A polymeric micelle-based drug delivery system was developed by modifying a "Y-shaped" well-designed ligand of both GRP78 protein and quorum sensing receptor to achieve all-stage precisional glioma targeting, then we evaluated the targeting ability and barrier penetration ability both in vitro and in vivo. In order to achieve all-stage precisional therapy, we need kill both GSCs and glioma related cells. Parthenolide (PTL) has been investigated for its selective toxicity to glioma stem cells while Paclitaxel (PTX) and Temozolomide (TMZ) are widely used in experimental and clinical therapy of glioma respectively. So the in vivo anti-glioma effect of combination therapy was evaluated by Kaplan-Meier survival analysis and immunohistochemical (IHC) examination of tumor tissues. Results: The "Y-shaped" well-designed peptide, termed DWVAP, exhibited excellent glioma (and GSCs) homing and barrier penetration ability. When modified on micelle surface, DWVAP peptide significantly enhanced accumulation of micelles in brain and glioma. In addition, DWVAP micelles showed no immunogenicity and cytotoxicity, which could guarantee their safety when used in vivo. Treatment of glioma-bearing mice with PTL loaded DWVAP modified PEG-PLA micelles plus PTX loaded DWVAP modified PEG-PLA micelles or PTL loaded DWVAP modified PEG-PLA micelles plus TMZ showed improved anti-tumor efficacy in comparison to PTL and PTX loaded unmodified micelles or PTL loaded unmodified micelles plus TMZ. Conclusion: Combination of all-stage targeting strategy and concomitant use of chemotherapeutics and stem cell inhibitors could achieve precise targeted therapy for glioma.
Insights
A novel drug delivery system using a "Y-shaped" peptide effectively targets glioma cells and glioma stem cells, overcoming biological barriers. This combination therapy enhances anti-glioma efficacy for improved patient outcomes.
Area of Science:
- Neuro-oncology
- Nanomedicine
- Drug Delivery Systems
Background:
- Glioma presents significant challenges due to uncontrollable cell proliferation and neurological damage.
- Glioma stem cells (GSCs) contribute to tumor recurrence and chemotherapy resistance.
- Existing therapies face limitations in overcoming biological barriers and precisely targeting both glioma cells and GSCs.
Purpose of the Study:
- To develop an all-stage precisional glioma-targeted drug delivery system.
- To evaluate the targeting, barrier penetration, and therapeutic efficacy of the novel system in vitro and in vivo.
- To assess the combination therapy's effectiveness against glioma and GSCs.
Main Methods:
- Development of a polymeric micelle-based drug delivery system modified with a "Y-shaped" peptide (DWVAP) targeting GRP78 and quorum sensing receptors.
- Evaluation of DWVAP micelle targeting and barrier penetration in vitro and in vivo.
- In vivo assessment of combination therapy using Parthenolide (PTL), Paclitaxel (PTX), and Temozolomide (TMZ) loaded micelles.
Main Results:
- The DWVAP peptide demonstrated excellent glioma and GSC homing and barrier penetration capabilities.
- DWVAP-modified micelles showed enhanced brain and glioma accumulation with no observed immunogenicity or cytotoxicity.
- Combination therapy with DWVAP micelles loaded with PTL and PTX, or PTL and TMZ, significantly improved anti-tumor efficacy compared to unmodified micelles.
Conclusions:
- The DWVAP peptide-modified micelle system achieves precise, all-stage glioma targeting.
- Combining targeted drug delivery with chemotherapeutics and stem cell inhibitors offers a promising strategy for precise glioma therapy.
- This approach holds potential for overcoming therapeutic challenges in glioma treatment.
