Sequential delivery of VEGF siRNA and paclitaxel for PVN destruction, anti-angiogenesis, and tumor cell apoptosis procedurally via a multi-functional polymer micelle.

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.

Yang Y ，Meng Y ，Ye J ，Xia X ，Wang H ，Li L ，Dong W ，Jin D ，Liu Y ... -  《-》

A theranostic micelleplex co-delivering SN-38 and VEGF siRNA for colorectal cancer therapy.

The development of an efficient colorectal cancer therapy is currently a public health priority. In the present work, we proposed a multifunctional theranostic micellar drug delivery system utilizing cationic PDMA-block-poly(ε-caprolactone) (PDMA-b-PCL) micelles as nanocarriers of SN-38 (7-ethyl-10-hydroxycamptothecin), ultra-small superparamagnetic iron oxide nanoparticles (USPIO), and small interfering RNA (siRNA) that targets human vascular endothelial growth factor (VEGF). The VEGF siRNA was conjugated to polyethylene glycol (PEG) (siRNA-PEG) before complexation with the micelles in order to improve the siRNA's stability and to prolong its retention time in the blood circulation. To further improve the in vivo biosafety, we prepared mixed micelles using mPEG-PCL together with PDMA-b-PCL copolymer. The SN-38/USPIO-loaded siRNA-PEG mixed micelleplexes passively targeted to tumor regions and synergistically facilitated VEGF silencing and chemotherapy, thus efficiently suppressing tumor growth via a multi-dose therapy regimen. Additionally, the SN-38/USPIO-loaded siRNA-PEG mixed micelleplexes acted as a negative magnetic resonance imaging (MRI) contrast agent in T2-weighted imaging, resulting in a powerful tool for the diagnosis and for tracking of the therapeutic outcomes. In summary, we established a theranostic micellar drug and gene delivery system that not only synergistically combined gene silencing and chemotherapy but also served as a negative MRI contrast agent, which reveal its potential as a novel colorectal cancer therapy.

Lee SY ，Yang CY ，Peng CL ，Wei MF ，Chen KC ，Yao CJ ，Shieh MJ ... -  《-》

Synergistic inhibition of breast cancer by co-delivery of VEGF siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles.

A somatostatin analog, vapreotide (VAP), can be used as a ligand for targeting drug delivery based on its high affinity to somatostatin receptors (SSTRs), which is overexpressed in many tumor cells. RNA interference plays an important role on downregulation of vascular endothelial growth factor (VEGF), which is important for tumor growth, progression and metastasis. To improve tumor therapy efficacy, the vapreotide-modified core-shell type nanoparticles co-encapsulating VEGF targeted siRNA (siVEGF) and paclitaxel (PTX), termed as VAP-PLPC/siRNA NPs, were developed in this study. When targeted via somatostatin receptors to tumor cells, the VAP-PLPC/siRNA NPs could simultaneously delivery siVEGF and PTX into cells and achieve a synergistic inhibition of tumor growth. Interestingly, in vitro cell uptake and gene silencing experiments demonstrated that the targeted VAP-PLPC/siRNA NPs exhibited significant higher intracellular siRNA accumulation and VEGF downregulation in human breast cancer MCF-7 cells, compared to those of the non-targeted PEG-PLPC/siRNA NPs. More importantly, in vivo results further demonstrated that the targeted VAP-PLPC/siRNA NPs had significant stronger drug distribution in tumor tissues and tumor growth inhibition efficacy via receptor-mediated targeting delivery, accompany with an obvious inhibition of neovascularization induced by siVEGF silencing. These results suggested that the co-delivery of siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles would be a promising approach for tumor targeted therapy.

Feng Q ，Yu MZ ，Wang JC ，Hou WJ ，Gao LY ，Ma XF ，Pei XW ，Niu YJ ，Liu XY ，Qiu C ，Pang WH ，Du LL ，Zhang Q ... -  《-》

Natural Particulates Inspired Specific-Targeted Codelivery of siRNA and Paclitaxel for Collaborative Antitumor Therapy.

Wang R ，Zhao Z ，Han Y ，Hu S ，Opoku-Damoah Y ，Zhou J ，Yin L ，Ding Y ... -  《-》

Combination antitumor immunotherapy with VEGF and PIGF siRNA via systemic delivery of multi-functionalized nanoparticles to tumor-associated macrophages and breast cancer cells.

Given that vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), over-expressed in breast cancer cells and M2-like tumor-associated macrophages (M2-TAMs) within tumor microenvironment (TME), work synergistically and independently in mediating tumor progression and immunosuppression, combinatorial immune-based approaches targeting them are expected to be a potent therapeutic modality for patients. Here, polyethylene glycol (PEG) and mannose doubly modified trimethyl chitosan (PEG = MT) along with citraconic anhydride grafted poly (allylamine hydrochloride) (PC)-based nanoparticles (NPs) (PEG = MT/PC NPs) with dual pH-responsiveness were developed to deliver VEGF siRNA (siVEGF)/PIGF siRNA (siPIGF) to both M2-TAMs and breast cancer cells for antitumor immunotherapy. With prolonged blood circulation and intelligent pH-sensitivity, PEG = MT/PC NPs were highly accumulated in tumor tissues and then internalized in M2-TAMs and breast cancer cells via mannose-mediated active targeting and passive targeting, respectively. With the charge-reversal of PC, PEG = MT/PC NPs presented effective endosomal/lysosomal escape and intracellular siRNA release, resulting in efficient gene silencing. Due to the synergism between siVEGF and siPIGF in anti-proliferation of tumor cells and reversal of the TME from pro-oncogenic to anti-tumoral, PEG = MT/PC/siVEGF/siPIGF NPs (PEG = MT/PC/siV-P NPs) exerted robust suppression of breast tumor growth and lung metastasis. This combination strategy may provide a promising alternative for breast cancer therapy.

Song Y ，Tang C ，Yin C 《-》