Folate receptor-targeted RNAi nanoparticles for silencing STAT3 in tumor-associated macrophages and tumor cells.

We developed a STAT3 silencing siRNA to both tumor cells and M2 macrophages. The dual-targeting system prepared by electronic self-assembly was composed of folic acid-conjugated carboxymethyl chitosan for targeting and cationic chitosan derivatives for siRNA package. The effects of siRNA delivery was investigated in M2 macrophages and Lewis lung cancer cells (LLC). Due to the enhanced delivery efficiency, the dual-targeting delivery system exhibited a higher efficacy compared with non-targeting nanoparticles, resulting in a dramatically reduction of STAT3 expression in both cells, and a successful shift from M2 phenotypes (pro-tumor) to M1 phenotypes (anti-tumor) for macrophages. Additionally, the influence of the nanoparticles on LLC cells co-cultured with M2 macrophages was also investigated. The increased apoptosis and inhibition of proliferation of LLC cells were observed. In vivo therapeutic effect was also evaluated in s.c. tumor models, tumor growth was effectively inhibited and the level of M2 macrophages in tumor tissues was dramatically reduced.

Synthesis and Characterization of Quaternized Poly(ß-amino ester) for Highly Efficient Delivery of Small Interfering RNA.

The development of non-viral vectors for gene delivery has gained attention over the past decades. Specifically, poly(ß-amino ester) (PBAE) has shown great potential for improving the delivery of gene therapeutics. It has been observed that low-molecular-weight PBAE displayed low transfection activities, while quaternization could enhance the transgene expression efficacy of PBAE. Herein, PBAE quaternary ammonium salt (PBAEQAS) was synthesized to increase the positive charge of the polymers, which resulted in an increase in siRNA binding efficiency based on self-assembly electrostatic interaction. Specifically, the nanoparticle surface was positively charged, which increased the uptake ability of siRNA. Compared with acrylate-PBAEQAS/siNC nanoparticles and amine-PBAEQAS/siNC nanoparticles, acrylate-PBAEQAS/siSurvivin nanoparticles and amine-PBAEQAS/siSurvivin nanoparticles induced more-efficient cell apoptosis and gene silencing. All these results suggest that PBAEQAS would be a promising gene delivery vector for cancer treatment.

Nucleic Acid-Based Therapeutics for Pulmonary Diseases.

Nucleic acid-based therapeutics present huge potential in the treatment of pulmonary diseases ranging from lung cancer to asthma and chronic pulmonary diseases, which are often fatal and widely prevalent. The susceptibility of nucleic acids to degradation and the complex structure of lungs retard the effective pulmonary delivery of nucleic acid drug. To overcome these barriers, different strategies have been exploited to increase the delivery efficiency using chemically synthesized nucleic acids, vector encapsulation, proper formulation, and administration route. However, several limitations regarding off-target effects and immune stimulation of nucleic acid drugs hamper their translation into the clinical practice. Therefore, their successful clinical application will ultimately rely on well-developed carriers and methods to ensure safety and efficacy. In this review, we provide a comprehensive overview of the nucleic acid application for pulmonary diseases, covering action mechanism of the nucleic acid drugs, the novel delivery systems, and the current formulation for the administration to lungs. The latest advances of nucleic acid drugs under clinical evaluation to treat pulmonary disorders will also be detailed.

The Potential of Milk-Derived Exosomes for Drug Delivery.

BACKGROUND: Exosomes, one of the extracellular vesicles, are widely present in all biological fluids and play an important role in intercellular communication. Due to their hydrophobic lipid bilayer and aqueous hydrophilic core structure, they are considered a possible alternative to liposome drug delivery systems. Not only do they protect the cargo like liposomes during delivery, but they are also less toxic and better tolerated. However, due to the lack of sources and methods for obtaining enough exosomes, the therapeutic application of exosomes as drug carriers is limited. METHODS: A literature search was performed using the ScienceDirect and PubMed electronic databases to obtain information from published literature on milk exosomes related to drug delivery. RESULTS: Here, we briefly reviewed the current knowledge of exosomes, expounded the advantages of milk-derived exosomes over other delivery vectors, including higher yield, the oral delivery characteristic and additional therapeutic benefits. The purification and drug loading methods of milk exosomes, and the current application of milk exosomes were also introduced. CONCLUSION: The emergence of milk-derived exosomes is expected to break through the limitations of exosomes as therapeutic carriers of drugs. We hope to raise awareness of the therapeutic potential of milk-derived exosomes as a new drug delivery system.

Apoptosis of A549 cells by small interfering RNA targeting survivin delivery using poly-ß-amino ester/guanidinylated O-carboxymethyl chitosan nanoparticles.

Gene-based therapeutics has emerged as a promising approach for human cancer therapy. Among a variety of non-viral vectors, polymer vectors are particularly attractive due to their safety and multivalent groups on their surface. This study focuses on guanidinylated O-carboxymethyl chitosan (GOCMCS) along with poly-ß-amino ester(PBAE) for siRNA delivery. Binding efficiency of PBAE/siRNA/GOCMCS nanoparticles were characterized by gel electrophoresis. The siRNA-loaded nanoparticles were found to be stable in the presence of RNase A, serum and BALF respectively. Fine particle fraction (FPF) which was determined by a two-stage impinger (TSI) was 57.8% ±â€¯2.6%. The particle size and zeta potential of the nanoparticles were 153.8 ±â€¯12.54 nm and + 12.2 ±â€¯4.94 mV. In vitro cell transfection studies were carried out with A549 cells. The cellular uptake was significantly increased. When the cells were incubated with siSurvivin-loaded nanoparticles, it could induce 26.83% ±â€¯0.59% apoptosis of A549 cells and the gene silencing level of survivin expression in A549 cells were 30.93% ±â€¯2.27%. The results suggested that PBAE/GOCMCS nanoparticle was a very promising gene delivery carrier.