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Published on: February 9, 2019
Bioactive lipid-nanoparticles with inherent self-therapeutic and anti-angiogenic properties for cancer therapy
Shuwen Cao1, Wenyue Zhang1, Hehai Pan2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China 510120; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China.
Abstract:
Angiogenesis inhibition has become a promising therapeutical strategy for cancer treatment. Current clinical anti-angiogenesis treatment includes antibodies against vascular endothelial growth factor (VEGF) or VEGF receptor, fusion proteins with high affinity to VEGF receptor, and tyrosine kinase inhibitors of VEGF receptor. However, current treatments are prone to systemic toxicity or acquiring drug resistance. A natural bioactive lipid 1,2-dipalmitoyl-sn‑glycero-3-phosphate (dipalmitoyl phosphatidic acid, DPPA) was reported to exhibit anti-angiogenic and anti-tumoral activity. However, the hydrophobic property of DPPA largely restricted its clinical use, while systemic infusion of free DPPA could result in undesirable side effects. Herein, we successfully developed DPPA-based lipid-nanoparticles (DPPA-LNPs) which turns the "therapeutic payload into nanocarrier". This strategy could improve on DPPA's hydrophiliciy, thereby facilitating its systemic administration. . DPPA-LNPs not only retained the therapeutic anti-angiogenic and anti-tumoral bioactivity of parental DPPA, but also greatly improved its tumor targeting ability via enhanced permeability and retention (EPR) effect. This strategy not only eliminates the limitation of drug encapsulation rate, toxicity of the delivery vehicle; but also enhances DPPA bioacvtity in vitro and in vivo. Systemic administration of DPPA-LNPs significantly suppressed the blood vessel formation and tumor growth of triple negative breast cancer and liver cancer growth on both xenograft tumor models. STATEMENT OF SIGNIFICANCE: This is the first-in-kind self-therapeutic inherent lipid to be made into a nanocarrier, with inherent anti-angiogenic and anti-tumor properties. DPPA nanocarrier is fully natural, fully compatible with minimal systemic toxicity. DPPA nanocarrier can accumulate at high concentration at tumor via EPR effect, exerting both anti-angiogenic and anti-tumor effects in vivo. DPPA nanocarrier could be used to encapsulate biologics or small molecules for synergistic anti-cancer therapy.
Insights
A novel nanocarrier system using dipalmitoyl phosphatidic acid (DPPA) enhances its anti-angiogenic and anti-tumor properties. DPPA-LNPs improve tumor targeting and reduce toxicity for effective cancer therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Angiogenesis inhibition is a key cancer treatment strategy, but current therapies face toxicity and resistance issues.
- 1,2-dipalmitoyl-sn‑glycero-3-phosphate (DPPA), a natural lipid, shows anti-angiogenic and anti-tumoral activity but has poor solubility and potential side effects.
- Existing treatments for angiogenesis inhibition include antibodies, fusion proteins, and tyrosine kinase inhibitors, each with limitations.
Purpose of the Study:
- To develop a nanocarrier system for DPPA to improve its hydrophilicity, systemic administration, and tumor targeting.
- To evaluate the anti-angiogenic and anti-tumoral efficacy of DPPA-based lipid-nanoparticles (DPPA-LNPs) in preclinical cancer models.
- To assess the safety and therapeutic potential of DPPA-LNPs as a novel cancer treatment strategy.
Main Methods:
- Formulation of DPPA-based lipid-nanoparticles (DPPA-LNPs) to encapsulate the bioactive lipid.
- Evaluation of DPPA-LNPs' anti-angiogenic and anti-tumoral properties in vitro and in vivo.
- Assessment of tumor targeting via the enhanced permeability and retention (EPR) effect in xenograft tumor models.
- Systemic administration of DPPA-LNPs in triple negative breast cancer and liver cancer models.
Main Results:
- DPPA-LNPs successfully improved DPPA's hydrophilicity and facilitated systemic administration.
- DPPA-LNPs retained the anti-angiogenic and anti-tumoral bioactivity of DPPA while enhancing tumor targeting through the EPR effect.
- Systemic administration of DPPA-LNPs significantly suppressed blood vessel formation and tumor growth in triple negative breast cancer and liver cancer xenograft models.
- The DPPA nanocarrier demonstrated minimal systemic toxicity and high compatibility.
Conclusions:
- DPPA-LNPs represent a novel, self-therapeutic nanocarrier with inherent anti-angiogenic and anti-tumor properties.
- This nanocarrier system overcomes DPPA's limitations, offering improved efficacy, tumor targeting, and reduced toxicity.
- DPPA-LNPs hold significant potential for synergistic cancer therapy through encapsulation of other therapeutic agents.
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