Combination of polythyleneimine regulating autophagy prodrug and Mdr1 siRNA for tumor multidrug resistance.

Multidrug resistance (MDR) has been restricting the efficacy of chemotherapy, which mainly include pump resistance and non-pump resistance. In order to fight overall MDR, a novel targeted gene/drug co-deliver nano system is developed, which can suppress the drug efflux pumps and modulate autophagy to overcoming both pump and non-pump resistance. Here, small interfere RNA (siRNA) is incorporated into polymer-drug conjugates (PEI-PTX, PP) which are composed of polyethyleneimine (PEI) and paclitaxel (PTX) via covalent bonds, and hyaluronic acid (HA) is coated on the surface of PP/siRNA to achieve long blood cycle and CD44-targeted delivery. The RNA interference to mdr1 gene is combined with autophagy inhibition by PP, which efficiently facilitate apoptosis of Taxol-resistant lung cancer cells (A549/T). Further study indicates that PEI in PP may play a significant role to block the autophagosome-lysosome fusion process by means of alkalizing lysosomes. Both in vitro and in vivo studies confirm that the nanoassemblies can successfully deliver PTX and siRNA into tumor cells and significantly inhibited A549/T tumor growth. In summary, the polymeric nanoassemblies provide a potential strategy for combating both pump and non-pump resistance via the synergism of RNAi and autophagy modulation.

Efficiency co-delivery of ellagic acid and oxygen by a non-invasive liposome for ameliorating diabetic retinopathy.

Diabetic retinopathy (DR) is one of the serious complications of diabetes, which has become the fourth leading cause of vision loss worldwide. Current treatment of DR relies on intravitreal injections of antiangiogenic agents, which has made considerable achievements in reducing visual impairment. However, long-term invasive injections require advanced technology and can lead to poor patient compliance as well as the incidence of ocular complications including bleeding, endophthalmitis, retinal detachment and others. Hence, we developed non-invasive liposomes (EA-Hb/TAT&isoDGR-Lipo) for efficiency co-delivery of ellagic acid and oxygen, which can be administered intravenously or by eye drops. Among that, ellagic acid (EA), as an aldose reductase inhibitor, could remove excessive reactive oxygen species (ROS) induced by high glucose for preventing retinal cell apoptosis, as well as reduce retinal angiogenesis through the blockage of VEGFR2 signaling pathway; carried oxygen could ameliorate DR hypoxia, and further enhanced the anti-neovascularization efficacy. Our results showed that EA-Hb/TAT&isoDGR-Lipo not only effectively protected retinal cells from high glucose-induced damage, but also inhibited VEGF-induced vascular endothelial cells migration, invasion, and tube formation in vitro. In addition, in a hypoxic cell model, EA-Hb/TAT&isoDGR-Lipo could reverse retinal cell hypoxia, thereby reducing the expression of VEGF. Significantly, after being administered as an injection or eye drops, EA-Hb/TAT&isoDGR-Lipo obviously ameliorated the structure (central retinal thickness and retinal vascular network) of retina by eliminating ROS and down-regulating the expression of GFAP, HIF-1α, VEGF and p-VEGFR2 in a DR mouse model. In summary, EA-Hb/TAT&isoDGR-Lipo holds great potentials in improvement of DR, which provides a novel approach for the treatment of DR.

Effects of polymer carriers on the occurrence and development of autophagy in drug delivery.

Autophagy is an evolutionarily conserved catabolic process that can degrade cytoplasmic materials and recycle energy to maintain metabolite homeostasis in cells. Autophagy is closely related to various physiological or pathological processes. Macromolecular materials are widely used in drug delivery systems and disease treatments due to their intrinsic effects, such as altered pharmacokinetics and biodistribution. Interaction of autophagic flux or the signal pathway with macromolecules may cause autophagy inhibition or autophagy cell death. This review covers autophagy regulation pathways and macromolecular materials (including functional micelles, biodegradable and pH-sensitive polymers, biomacromolecules, dendrimers, coordination polymers, and hybrid nanoparticles) mediated autophagy modulation.

Recent advances in anti-multidrug resistance for nano-drug delivery system.

Chemotherapy for tumors occasionally results in drug resistance, which is the major reason for the treatment failure. Higher drug doses could improve the therapeutic effect, but higher toxicity limits the further treatment. For overcoming drug resistance, functional nano-drug delivery system (NDDS) has been explored to sensitize the anticancer drugs and decrease its side effects, which are applied in combating multidrug resistance (MDR) via a variety of mechanisms including bypassing drug efflux, controlling drug release, and disturbing metabolism. This review starts with a brief report on the major MDR causes. Furthermore, we searched the papers from NDDS and introduced the recent advances in sensitizing the chemotherapeutic drugs against MDR tumors. Finally, we concluded that the NDDS was based on several mechanisms, and we looked forward to the future in this field.

Normalization of the tumor microvasculature based on targeting and modulation of the tumor microenvironment.

Angiogenesis is an essential process for tumor development. Owing to the imbalance between pro- and anti-angiogenic factors, the tumor vasculature possesses the characteristics of tortuous, hyperpermeable vessels and compressive force, resulting in a reduction in the effect of traditional chemotherapy and radiotherapy. Anti-angiogenesis has emerged as a promising strategy for cancer treatment. Tumor angiogenesis, however, has been proved to be a complex process in which the tumor microenvironment (TME) plays a vital role in the initiation and development of the tumor microvasculature. The host stromal cells in the TME, such as cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and Treg cells, contribute to angiogenesis. Furthermore, the abnormal metabolic environment, such as hypoxia and acidosis, leads to the up-regulated expression of angiogenic factors. Indeed, normalization of the tumor microvasculature via targeting and modulating the TME has become a promising strategy for anti-angiogenesis and anti-tumor therapy. In this review, we summarize the abnormalities of the tumor microvasculature, tumor angiogenesis induced by an abnormal metabolic environment and host stromal cells, as well as drug delivery therapies to restore the balance between pro- and anti-angiogenic factors by targeting and normalizing the tumor vasculature in the TME.

Layered Double Hydroxide Modified with Deoxycholic and Hyaluronic Acids for Efficient Oral Insulin Absorption.

INTRODUCTION: This study aimed to construct a layered double hydroxide (LDH) nanoparticle delivery system that was modified by deoxycholic acid (DCA) and hyaluronic acid (HA) to increase the bioavailability of oral insulin. METHODS: LDH-DCA-HA was synthesized by the hybridization of DCA and HA with LDH. Subsequently, insulin was loaded onto LDH-DCA-HA, resulting in the formation of INS@LDH-DCA-HA. The in vivo and in vitro mechanisms of insulin release, as well as the efficiency of insulin absorption, were analyzed before and after DCA-HA modification. RESULTS: MTT assay showed that there was satisfactory biocompatibility between LDH-DCA-HA and Caco-2 cells at a concentration below 1000 µg/mL. Flow cytometry analysis revealed that Caco-2 cells absorbed INS@LDH-DCA-HA more readily than insulin. Measurement of transepithelial electrical resistance indicated that INS@LDH-DCA-HA induced the reversible opening of tight cell junctions, thereby facilitating its absorption. This was confirmed via laser confocal microscopy analysis, revealing that a large amount of zonula occludens-1 tight junction (TJ) protein was utilized for the paracellular pathway of nanoparticles. We also measured the blood glucose levels of type I diabetic mice and found that oral INS@LDH-DCA-HA exerted a steady hypoglycemic effect lasting 12 h, with a small range of postprandial blood glucose fluctuation. Immunofluorescence analysis showed that the strong penetration ability of INS@LDH-DCA-HA allowed insulin to enter epithelial cells more readily than free insulin. Finally, immunohistochemical analysis of anti-SLC10A1 protein confirmed that the cholic acid transporter receptor protein played a key role in the functioning of INS@LDH-DCA-HA. CONCLUSION: LDH nanoparticles modified by DCA and HA improved the absorption efficiency of insulin by opening the TJs of cells and interacting with the cholic acid transporter receptor protein.