Sequential delivery of VEGF siRNA and paclitaxel for PVN destruction, anti-angiogenesis, and tumor cell apoptosis procedurally via a multi-functional polymer micelle
Abstract
Co-delivery of chemotherapy drugs and VEGF siRNA (siVEGF) to control tumor growth has been a research hotspot for improving cancer treatment. Current systems co-deliver siVEGF and chemo drugs into tumor cells simultaneously. Although effective, these systems do not flow to the abnormal blood vessels around tumor cells (vascular niche, PVN), which play an important role in the metastasis and deterioration of the tumor. Thus, we custom-synthesized triblock copolymer poly(ε-caprolactone)-polyethyleneglycol-poly(L-histidine) (PCL-PEG-PHIS) with previously synthesized folate-PEG-PHIS to construct a targeted multifunctional polymer micelle (PTX/siVEGF-CPPs/TMPM) to sequentially deliver siVEGF-CPPs (disulfide bond-linked siVEGF and cell-penetrating peptides) and paclitaxel (PTX). The sequential delivery vesicles showed the anticipated three-layered TEM structure and dual-convertible (surface charge- and particle size-reversible) features in the tumor environment (pH 6.5), which guaranteed the sequential release of siVEGF-CPPs and PTX in the tumor extracellular environment and tumor cells, respectively. To mimic the in vivo tumor environment, a double cell model was employed by co-culturing HUVECs and MCF-7 cells. Improved cell endocytosis efficiency, VEGF gene silence efficacy, and in vitro anti-proliferation activity were achieved. An in vivo study on MCF-7 tumor-bearing female nude mice also indicated that sequential delivery vesicles could lead to significant induction of tumor cell apoptosis, loss of VEGF expression, and destruction of tumor blood vessels (PVN and neovascularization). These sequential delivery vesicles show potential as an effective co-delivery platform for siVEGF and chemo drugs to improve cancer therapy efficacy.
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Polymeric micelles formed by amphiphilic block copolymers have gained attention due to their core/shell structure, excellent stability, and ideal encapsulation and delivery efficiency of hydrophobic drugs.
“Among them, polymeric micelles formed by amphiphilic block copolymers have gained more attention due to their unique properties such as the core/shell structure, excellent stability, and ideal encapsulation and delivery efficiency of hydrophobic drugs.34–37”
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- Authors
- Yang, Y., Meng, Y., Ye, J., Xia, X., Wang, H., Li, L., Dong, W., Jin, D., & Liu, Y.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Liu, Yuling
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 287
- Pages
- 103-120
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2888584728
- Cited by
- 49
- References
- 40
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 5 · 2022: 14 · 2021: 12 · 2020: 5 · 2019: 4
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Beijing Natural Science Foundation (7162135)
- PUMC Youth Fund (3332015139)
- Fundamental Research Funds for the Central Universities (2017350020)
- China Postdoctoral Science Foundation (2017M620679)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- VEGF siRNA, paclitaxel, sequential drug delivery, polymeric micelles, folate targeting, cell-penetrating peptides, disulfide bonds, pH-responsive drug release, tumor vasculature, angiogenesis inhibition, tumor cell apoptosis, MCF-7 breast cancer
- MeSH terms
- RNAi Therapeutics, Animals, Antineoplastic Agents, Phytogenic, Breast Neoplasms, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Micelles, Neovascularization, Pathologic, Polyesters, Polyethylene Glycols, Drug Delivery Systems, Apoptosis, Paclitaxel, Gene Transfer Techniques, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Human Umbilical Vein Endothelial Cells, MCF-7 Cells
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