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Gypenoside A-loaded mPEG-PLGA nanoparticles ameliorate high-glucose-induced retinal microvasculopathy by inhibiting
Qin Chen1, Fen-Sheng Qiu2, Wei Xie3
1Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou 310003, China.
Abstract:
Diabetic retinopathy (DR) is one of the chronic microvascular complications of type 2 diabetes mellitus (T2DM), which will cause retinal detachment and blindness without ideal therapies. Gypenoside A (GPA) are the main bioactive compound from Gynostemma pentaphyllum, and have various pharmacological effects. However, it suffered from poor bioavailability and potential cardiotoxicity in the clinical application. To overcome those limitations, in this study, nearly spherical nanoparticles (GPA-NP) with a mean particle size of 140.6 ± 22.4 nm were prepared by encapsulating GPA into mPEG-PLGA. This encapsulation efficiency was 84.4 ± 6.9 %, and the drug load was 4.02 %±0.35 %. The results showed that GPA-NP displayed more prolonged GPA release and higher bioavailability in vitro than GPA. GPA-NP obviously reduced the levels of oxidative stress markers and inflammatory cytokines in both retinal tissues of DR mice and high glucose-exposed HRMEC better than GPA alone. Mechanismly, GPA blocked the Nrf2-Keap1 interaction by binding with Kelch domain of Keap1 via alkyl and hydrogen bonds. Therefore, GPA-NP exerted more potent protectivity effects against high glucose-induced retinal microvascular endothelial ferroptosis in vitro and in vivo by activating Nrf2/HO-1/GPX4 pathway. It could be a promising therapeutic agent for preventing DR.
Insights
Gypenoside A nanoparticles (GPA-NP) improve bioavailability and reduce oxidative stress and inflammation, offering a promising treatment for diabetic retinopathy (DR). GPA-NP activate the Nrf2/HO-1/GPX4 pathway, protecting against retinal microvascular endothelial ferroptosis.
Area of Science:
- Biomedical Engineering
- Pharmacology
- Ophthalmology
Background:
- Diabetic retinopathy (DR) is a severe complication of type 2 diabetes mellitus (T2DM), leading to vision loss.
- Gypenoside A (GPA), a compound from Gynostemma pentaphyllum, shows therapeutic potential but suffers from poor bioavailability and cardiotoxicity.
- Existing therapies for DR are insufficient, necessitating novel treatment strategies.
Purpose of the Study:
- To develop Gypenoside A nanoparticles (GPA-NP) to enhance bioavailability and therapeutic efficacy for diabetic retinopathy.
- To investigate the protective mechanisms of GPA-NP against high glucose-induced retinal microvascular endothelial ferroptosis.
- To evaluate the in vitro and in vivo efficacy of GPA-NP in a mouse model of DR.
Main Methods:
- GPA was encapsulated into mPEG-PLGA to form nanoparticles (GPA-NP) with controlled particle size and high encapsulation efficiency.
- In vitro studies assessed GPA release, bioavailability, and effects on oxidative stress markers and inflammatory cytokines in high glucose-exposed human retinal microvascular endothelial cells (HRMEC).
- In vivo studies evaluated GPA-NP's efficacy in a DR mouse model, examining oxidative stress, inflammation, and ferroptosis markers, and elucidated the Nrf2/HO-1/GPX4 pathway activation.
Main Results:
- GPA-NP exhibited prolonged GPA release and significantly higher bioavailability compared to free GPA.
- GPA-NP demonstrated superior reduction of oxidative stress markers and inflammatory cytokines in retinal tissues of DR mice and high glucose-exposed HRMEC.
- GPA-NP effectively inhibited high glucose-induced retinal microvascular endothelial ferroptosis in vitro and in vivo by activating the Nrf2/HO-1/GPX4 pathway, with GPA blocking Nrf2-Keap1 interaction.
Conclusions:
- GPA-NP formulation overcomes the limitations of free GPA, offering enhanced bioavailability and therapeutic effects.
- GPA-NP shows potent protective effects against diabetic retinopathy by mitigating oxidative stress, inflammation, and ferroptosis via Nrf2/HO-1/GPX4 pathway activation.
- GPA-NP represents a promising therapeutic candidate for the prevention and treatment of diabetic retinopathy.
