Tumor acidity-sensitive linkage-bridged block copolymer for therapeutic siRNA delivery.

The design of ideal nanoparticle delivery systems should be capable of meeting the requirements of several stages of drug delivery, including prolonged circulation, enhanced accumulation and penetration in the tumor, facilitated cellular internalization and rapid release of the active drug in the tumor cells. However, among the current design strategies, meeting the requirements of one stage often conflicts with the other. Herein, a tumor pH-labile linkage-bridged block copolymer of poly(ethylene glycol) with poly(lacide-co-glycolide) (PEG-Dlinkm-PLGA) was used for siRNA delivery to fulfill all aforementioned requirements of these delivery stages. The obtained siRNA-encapsulating PEG-Dlinkm-PLGA nanoparticle gained efficiently prolonged circulation in the blood and preferential accumulation in tumor sites via the PEGylation. Furthermore, the PEG surface layer was detached in response to the tumor acidic microenvironment to facilitate cellular uptake, and the siRNA was rapidly released within tumor cells due to the hydrophobic PLGA layer. Hence, PEG-Dlinkm-PLGA nanoparticles met the requirements of several stages of drug delivery, and resulted in the enhanced therapeutic effect of the nanoparticular delivery systems.

Xu CF ，Zhang HB ，Sun CY ，Liu Y ，Shen S ，Yang XZ ，Zhu YH ，Wang J ... -  《-》

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 《-》

Matrix metalloproteinase 2-responsive micelle for siRNA delivery.

Systemic delivery of small interfering RNA (siRNA) into cancer cells remains the major obstacle to siRNA drug development. An ideal siRNA delivery vehicle for systemic administration should have long circulation time in blood, accumulate at tumor site, and sufficiently internalize into cancer cells for high-efficiency of gene silence. Herein, we report a core-shell Micelleplex delivery system that made from block copolymer bearing poly(ethylene glycol) (PEG), matrix metalloproteinase 2 (MMP-2)-degradable peptide PLG*LAG, cationic cell penetrating peptide polyarginine r9 and poly(ε-caprolactone) (PCL) for siRNA delivery. We show clear evidences in vitro and in vivo to prove that the micelle carrying siRNA can circulate enough time in blood, enrich accumulation at tumor sites, shed the PEG layer when triggered by tumor overexpressing MMP-2, and then the exposing cell penetrating peptide r9 enhanced cellular uptake of siRNA. Accordingly, this design strategy enhances the inhibition of breast tumor growth following systemic injection of this system carrying siRNA against Polo-like kinase 1, which demonstrating this Micelleplex can be a potential delivery system for systemic siRNA delivery in cancer therapy.

Wang HX ，Yang XZ ，Sun CY ，Mao CQ ，Zhu YH ，Wang J ... -  《-》

Glucose-linked sub-50-nm unimer polyion complex-assembled gold nanoparticles for targeted siRNA delivery to glucose transporter 1-overexpressing breast cancer stem-like cells.

Cancer stem-like cells (CSCs) treatment is a plausible strategy for enhanced cancer therapy. Here we report a glucose-installed sub-50-nm nanocarrier for the targeted delivery of small interfering RNA (siRNA) to CSCs through selective recognition of the glucose ligand to the glucose transporter 1 (GLUT1) overexpressed on the CSC surface. The siRNA nanocarrier was constructed via a two-step assembling process. First, a glucose-installed poly(ethylene glycol)-block-poly(l-lysine) modified with lipoic acid (LA) at the ω-end (Glu-PEG-PLL-LA) was associated with a single siRNA to form a unimer polyion complex (uPIC). Second, a 20 nm gold nanoparticle (AuNP) was decorated with ~65 uPICs through AuS bonding. The glucose-installed targeted nanoparticles (Glu-NPs) exhibited higher cellular uptake of siRNA payloads in a spheroid breast cancer (MBA-MB-231) cell culture compared with glucose-unconjugated control nanoparticles (MeO-NPs). Notably, the Glu-NPs became more efficiently internalized into the CSC fraction, which was defined by aldehyde dehydrogenase (ALDH) activity assay, than the other fractions, probably due to the higher GLUT1 expression level on the CSCs. The Glu-NPs elicited significantly enhanced gene silencing in a CSC-rich orthotopic MDA-MB-231 tumor tissue following systemic administration to tumor-bearing mice. Ultimately, the repeated administrations of polo-like kinase 1 (PLK1) siRNA-loaded Glu-NPs significantly suppressed the growth of orthotopic MDA-MB-231 tumors. These results demonstrate that Glu-NP is a promising nanocarrier design for CSC-targeted cancer treatment.

Yi Y ，Kim HJ ，Zheng M ，Mi P ，Naito M ，Kim BS ，Min HS ，Hayashi K ，Perche F ，Toh K ，Liu X ，Mochida Y ，Kinoh H ，Cabral H ，Miyata K ，Kataoka K ... -  《-》

Long circulating chitosan/PEG blended PLGA nanoparticle for tumor drug delivery.

Polymeric nanoparticles have long been sought after as carriers for systemic and targeted drug delivery. The ability of these particles to circulate in the bloodstream for a prolonged period of time is often a prerequisite for successful targeted delivery. To achieve this, paclitaxel loaded chitosan and polyethylene glycol coated PLGA (PLGA-CS-PEG) nanoparticles were formulated and characterized that could efficiently encapsulate hydrophobic drugs, and also evade the phagocytic uptake by reducing opsonization by blood proteins, hence increasing the bioavailability of the drug. In our study, we primarily assessed a rational approach for designing and formulating ideal long-circulating nanoparticles by optimizing the concentration of chitosan (CS) and polyethylene glycol (PEG). Uptake efficiency and in vitro cytotoxicity of the formulated nanoparticles was also evaluated in different cancer cell lines (retinoblastoma, breast cancer and pancreatic cancer). PLGA-CS-PEG nanoparticles showed dramatic prolongation in blood circulation, as well as reduced macrophage uptake, with only a small amount of the nanoparticles sequestered in the liver, when compared to PLGA-CS and PLGA nanoparticles. Superior anti-proliferative effect and cell cycle inhibition was observed in case of PLGA-CS nanoparticles and PLGA-CS-PEG nanoparticles over PLGA nanoparticles and native paclitaxel, which may be due to higher cellular uptake resulting in greater antiproliferative activity of nanoparticles. The present results thus suggest that, a combinational coating of PEG and chitosan may represent a significant step in the development of long-circulating drug delivery carriers for tumor drug delivery.

Parveen S ，Sahoo SK 《-》