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Updated: Jun 7, 2025
Anticancer Efficacy of Photodynamic Therapy with Lung Cancer-Targeted Nanoparticles
Published on: December 1, 2016
Dual targeting and bioresponsive nano-PROTAC induced precise and effective lung cancer therapy
Xiaoling Guan1, Xiaowei Xu1, Yiwen Tao1
1The Fifth Affiliated Hospital, The Affiliated Panyu Central Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, The School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
Abstract:
Epigenetic regulation has emerged as a promising therapeutic strategy for lung cancer treatment, which can facilitate the antitumor responses by modulating epigenetic dysregulation of target proteins in lung cancer. The proteolysis-targeting chimera (PROTAC) reagent, dBET6 shows effective inhibition of bromodomain-containing protein 4 (BRD4) that exerts antitumor efficacy by degrading BRD4 via the ubiquitin-proteasome system. Nevertheless, the low tissue specificity and bioavailability impede its therapeutic effects and clinical translation on lung cancer treatment. Herein, we developed a type of dual targeting and bioresponsive nano-PROTAC (c R GD/L LC membrane/D S-P LGA/d B ET6, named RLDPB), which was constructed by using the pH and glutathione (GSH)-responsive polymer, disulfide bond-linked poly(lactic-co-glycolic acid) (PLGA-S-S-PLGA, DS-PLGA) to load the PROTAC agent dBET6, and further camouflaged with the homotypic LLC cell membranes, followed by the conjugation with cRGD ligand to the surface of the nanoparticles. Notably, RLDPB showed enhanced celluar uptake by lung cancer cells in vitro and accumulation in the tumors via the dual targeting structure including cRGD and LLC membrane. The pH/GSH responsiveness improved the release of dBET6 from the DS-PLGA-based nanoparticles within the cells. RLDPB was demonstrated to facilitate tumor regression by inducing the apoptosis of lung cancer cells with the degradation of BRD4. Thus, RLDPB can be considered a powerful tool to suppress lung cancer, which opens a new avenue to treat lung cancer by PROTAC.
Insights
A novel nano-PROTAC (RLDPB) enhances lung cancer treatment by targeting bromodomain-containing protein 4 (BRD4) degradation. This dual-targeting, bioresponsive nanoparticle improves drug delivery and tumor regression, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Nanotechnology
- Biochemistry
Background:
- Epigenetic dysregulation is a key factor in lung cancer.
- Proteolysis-targeting chimera (PROTAC) reagents like dBET6 show potential by degrading bromodomain-containing protein 4 (BRD4).
- Limitations of current PROTACs include low tissue specificity and bioavailability, hindering clinical translation for lung cancer.
Purpose of the Study:
- To develop a dual-targeting, bioresponsive nano-PROTAC (RLDPB) for improved lung cancer therapy.
- To enhance the delivery and efficacy of the PROTAC agent dBET6.
- To overcome the limitations of traditional PROTACs in lung cancer treatment.
Main Methods:
- Constructed a nano-PROTAC (RLDPB) using pH/glutathione (GSH)-responsive disulfide bond-linked poly(lactic-co-glycolic acid) (DS-PLGA) to load dBET6.
- Camouflaged nanoparticles with homotypic LLC cell membranes and conjugated cRGD ligands for dual targeting.
- Evaluated in vitro cellular uptake, in vivo tumor accumulation, and therapeutic efficacy, including apoptosis induction and BRD4 degradation.
Main Results:
- RLDPB demonstrated enhanced cellular uptake by lung cancer cells and tumor accumulation.
- The pH/GSH responsiveness facilitated efficient release of dBET6 within cancer cells.
- RLDPB effectively induced lung cancer cell apoptosis and tumor regression through BRD4 degradation.
Conclusions:
- The developed nano-PROTAC, RLDPB, shows significant potential as a therapeutic strategy for lung cancer.
- Dual targeting and bioresponsiveness improve PROTAC delivery and antitumor efficacy.
- RLDPB represents a promising advancement in PROTAC-based lung cancer treatment.
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