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Oral Poly(N-oxide) zwitterionic nanoplatform for Gambogenic Acid Enhances Mucosal penetration for potentiated
Shuo Tang1, Yu Tao1, Laiting Gong1
1Key Laboratory of Xin'an Medicine, the Ministry of Education, Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, National Center for Translational Medicine (Shanghai) Hefei Branch, Functional Activity and Resource Utilization on Edible and Medicinal Fungi Joint Laboratory of Anhui Province, Anhui University of Chinese Medicine, Hefei, Anhui 230038, China.
Abstract:
Oral anti-angiogenic therapy for hepatocellular carcinoma is fundamentally constrained by poor mucus penetration and enterocyte uptake, which limits intestinal absorption and systemic exposure. Moreover, anti-angiogenic therapy inherently reduces tumor vascular density, further restricting intratumoral drug accumulation and creating a therapeutic delivery paradox. Here, we report an oral poly(N-oxide) zwitterionic nanoplatform for gambogenic acid (GNA), termed POC-GNA, that could mechanistically overcome these sequential delivery barriers. POC-GNA nanoparticles confer strong non-fouling properties and a near-neutral surface to facilitate efficient mucus penetration and enterocyte uptake for improved intestinal absorption, while modulating tumor vasculature by reducing the density and increasing the permeability, ultimately enhancing their intratumoral accumulation. Consequently, oral POC-GNA exhibited markedly enhanced intestinal absorption, prolonged systemic circulation, and preferential accumulation in hepatic tumors. The improved bioavailability translated into potent antitumor efficacy through synergistic anti-angiogenic, vascular-disruptive, pro-apoptotic, and immunoregulatory effects. In both subcutaneous and orthotopic HCC models, oral POC-GNA achieved remarkable tumor inhibition rates, surpassing PEGylated formulations administered orally or intravenously. Importantly, oral delivery effectively eliminates the vascular irritation associated with intravenous GNA administration. Collectively, this study addresses a vascular density-dependent drug accumulation bottleneck and establishes a clinically translatable oral nanomedicine strategy for potentiated anti-angiogenic therapy.
Insights
This study introduces POC-GNA, an oral nanomedicine for hepatocellular carcinoma (HCC) treatment. It enhances drug delivery to tumors, improving absorption and efficacy while reducing side effects.
Area of Science:
- Nanomedicine
- Hepatocellular Carcinoma Research
- Drug Delivery Systems
Background:
- Oral anti-angiogenic therapy for hepatocellular carcinoma (HCC) faces challenges with poor mucus penetration and limited intestinal absorption.
- Reduced tumor vascular density in anti-angiogenic therapy restricts intratumoral drug accumulation, creating a delivery paradox.
Purpose of the Study:
- To develop an oral nanoplatform (POC-GNA) for gambogenic acid (GNA) that overcomes sequential delivery barriers in HCC.
- To enhance intestinal absorption, systemic exposure, and intratumoral accumulation of oral anti-angiogenic drugs.
Main Methods:
- Development of a poly(N-oxide) zwitterionic nanoplatform (POC-GNA) for gambogenic acid (GNA).
- Evaluation of POC-GNA's mucus penetration, enterocyte uptake, and intestinal absorption.
- Assessment of POC-GNA's effects on tumor vasculature (density and permeability) and intratumoral accumulation.
- Testing antitumor efficacy in subcutaneous and orthotopic HCC models compared to PEGylated formulations.
Main Results:
- POC-GNA demonstrated efficient mucus penetration and enterocyte uptake, leading to improved intestinal absorption and systemic circulation.
- POC-GNA modulated tumor vasculature, reducing density and increasing permeability, which enhanced intratumoral drug accumulation.
- Oral POC-GNA achieved significant tumor inhibition in HCC models, outperforming oral and intravenous PEGylated formulations.
- Oral delivery of POC-GNA avoided vascular irritation associated with intravenous GNA administration.
Conclusions:
- The developed POC-GNA nanoplatform effectively overcomes oral drug delivery barriers for HCC treatment.
- This strategy enhances anti-angiogenic therapy by improving drug accumulation and efficacy while offering a safer administration route.
- POC-GNA represents a clinically translatable nanomedicine strategy for potentiated oral anti-angiogenic therapy in HCC.
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