Synergistic effects of multidrug/material combination deliver system for anti-mutidrug-resistant tumor.

Multidrug resistance (MDR) is a public health issue of particular concern, for which nanotechnology-based multidrug delivery systems are considered among the most effective suppressive strategies for such resistance in tumors. However, for such strategies to be viable, the notable shortcomings of reduced loading efficiency and uncontrollable drug release ratio need to be addressed. To this end, we developed a novel "multidrug/material" co-delivery system, using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS, P-gp efflux pump inhibitor) and poly(amidoamine) (PAMAM) to fabricate a precursor material with the properties of reversing MDR and having a long-cycle. Further, to facilitate multidrug co-delivery, we loaded doxorubicin(Dox) and curcumin(Cur, cardiotoxicity modifier and P-gp inhibitor) into PAMAM-TPGS nano-micelles respectively, and mixed in appropriate proportions. The multidrug/material co-delivery system thus obtained was characterized by high drug loading and a controllable drug release ratio in the physiological environment. More importantly, in vitro and in vivo pharmacodynamic studies indicated that the multidrug/material co-delivery system facilitated the reversal of MDR. Moreover, the system has increased anti-tumor activity and is biologically safe. We accordingly propose that the "multidrug/material" co-delivery system developed in this study could serve as a potential platform for reversing MDR and achieving safe and effective clinical treatment.

Meniscus-Induced Directional Self-Transport of Submerged Bubbles on a Slippery Oil-Infused Pillar Array with Height-Gradient.

Directional manipulation of submerged bubbles is fundamental for both theoretical research and industrial production. However, most current strategies are limited to the upward motion direction, complex surface topography, and additional apparatuses. Here, we report a meniscus-induced self-transport platform, namely, a slippery oil-infused pillar array with height-gradient (SOPAH) by combining femtosecond laser drilling and replica mold technology. Owing to the unbalanced capillary force and Laplace pressure difference, bubbles on SOPAH tend to spontaneously transport along the meniscus gradient toward a higher elevation. The self-transport performances of bubbles near the pillars depend on the complex meniscus shape. Significantly, to understand the underlying transport mechanism, the 3D meniscus profile is simulated by solving the Young-Laplace equation. It is found that the concave valleys formed between the adjacent pillars can change the gradient direction of the meniscus and lead to the varied transport performances. Finally, by taking advantage of a water electrolysis system, the assembled SOPAH serving as a bubble-collecting device is successfully deployed. This work should not only bring new insights into the meniscus-induced self-transport dynamics but also benefit potential applications in the field of intelligent bubble manipulation.

Enzyme-responsive nano-drug delivery system for combined antitumor therapy.

Efficient drug loading, tumor targeting, intratumoral penetration, and cellular uptake are the main factors affecting the effectiveness of drug delivery systems in oncotherapy. Based on the tumor microenvironment, we proposed to develop Curcumin (Cur)-loaded matrix metalloproteinase (MMP)-responsive nanoparticles (Cur-P-NPs) by static electricity, to enhance tumor targeting, cellular uptake, and drug loading efficiency. These nanoparticles combine the properties of both PEG-peptides (cleaved peptide + penetrating peptide) and star-shaped polyester (DPE-PCL) nanoparticles. Cur-P-NPs displayed good entrapment efficiency, drug loading and biocompatibility. Additionally, they showed an enhanced release rate, cellular uptake, and anti-proliferative activity by activating peptides under the simulated tumor microenvironment. Furthermore, intraperitoneal injection of losartan (LST) successfully enhanced intratumoral drug penetration by collagen I degradation. In vivo studies based on the systematic administration of the synergistic LST + Cur-P-NPs combination to mice confirmed that combined antitumor therapy with LST and Cur-P-NPs could further improve intratumor distribution, enhance anticancer efficacy, and reduce the toxicity and side effects. Therefore, LST + Cur-P-NPs represent a new and efficient system for clinical oncotherapy.

A Biocompatible Vibration-Actuated Omni-Droplets Rectifier with Large Volume Range Fabricated by Femtosecond Laser.

High-performance droplet transport is crucial for diverse applications including biomedical detection, chemical micro-reaction, and droplet microfluidics. Despite extensive progress, traditional passive and active strategies are restricted to limited liquid types, small droplet volume ranges, and poor biocompatibilities. Moreover, more challenges occur for biological fluids due to large viscosity and low surface tension. Here, a vibration-actuated omni-droplets rectifier (VAODR) consisting of slippery ratchet arrays fabricated by femtosecond laser and vibration platforms is reported. Through the relative competition between the asymmetric adhesive resistance originating from the lubricant meniscus on the VAODR and the periodic inertial driving force originating from isotropic vibration, the fast (up to ≈60 mm s-1 ), programmable, and robust transport of droplets is achieved for a large volume range (0.05-2000 µL, Vmax /Vmin  ≈ 40 000) and in various transport modes including transport of liquid slugs in tubes, programmable and sequential transport, and bidirectional transport. This VAODR is general to a high diversity of biological and medical fluids, and thus can be used for biomedical detection including ABO blood-group tests and anticancer drugs screening. These strategies provide a complementary and promising platform for maneuvering omni-droplets that are fundamental to biomedical applications and other high-throughput omni-droplet operation fields.

Star polyester-based folate acid-targeting nanoparticles for doxorubicin and curcumin co-delivery to combat multidrug-resistant breast cancer.

Chemotherapeutic treatments are indispensable in the treatment of breast cancer. However, the emergence of multidrug-resistance, strong cell toxicity, and poor targeting selection has inhibited their clinical application. In this study, two synergistic drugs, doxorubicin (DOX) and curcumin (CUR), were co-administered to overcome multidrug resistance (MDR). Based on the characteristics of the tumor microenvironment, we developed folic acid-modified nanoparticles ((DOX + CUR)-FA-NPs) based on a star-shaped polyester (FA-TRI-CL) to enhance the tumor targeting selectivity and drug loading (DL) capacity. The (DOX + CUR)-FA-NPs displayed a characteristic spheroid morphology with an ideal diameter (186.52 nm), polydispersity index (0.024), zeta potential (-18.87 mV), and good entrapment efficiency (97.64%/78.13%, DOX/CUR) and DL (20.27%/11.29%, DOX/CUR) values. In vitro pharmacokinetic and pharmacodynamic experiments demonstrated that the (DOX + CUR)-FA-NPs were gradually released, and they displayed the highest cell apoptosis and cellular uptake in MCF-7/ADR cells. Additionally, in vivo results illustrated that (DOX + CUR)-FA-NPs not only displayed significant tumor targeting and anticancer efficacy, but also induced less pathological damage to the normal tissue. In summary, co-administered DOX and CUR appeared to reverse MDR, and this targeted combinational nanoscale delivery system could thus be a promising carrier for tumor therapies in the future.

Curcumin-Loaded Hybrid Nanoparticles: Microchannel-Based Preparation and Antitumor Activity in a Mouse Model.

PURPOSE: To develop microchannel-based preparation of curcumin (Cur)-loaded hybrid nanoparticles using enzyme-targeted peptides and star-shaped polycyclic lipids as carriers, and to accomplish a desirable targeted drug delivery via these nanoparticles, which could improve the bioavailability and antitumor effects of Cur. METHODS: The amphiphilic tri-chaintricarballylic acid-poly (ε-caprolactone)-methoxypolyethylene glycol (Tri-CL-mPEG) and the enzyme-targeted tetra-chain pentaerythritol-poly (ε-caprolactone)-polypeptide (PET-CL-P) were synthesized. The Cur-loaded enzyme-targeted hybrid nano-delivery systems (Cur-P-NPs) were prepared by using the microfluidic continuous granulation technology. The physicochemical properties, release behavior in vitro, and stability of these Cur-P-NPs were investigated. Their cytotoxicity, cellular uptake, anti-proliferative efficacy in vitro, biodistribution, and antitumor effects in vivo were also studied. RESULTS: The particle size of the prepared Cur-P-NPs was 146.1 ± 1.940 nm, polydispersity index was 0.175 ± 0.014, zeta potential was 10.1 ± 0.300 mV, encapsulation rate was 74.66 ± 0.671%, and drug loading capacity was 5.38 ± 0.316%. The stability of Cur-P-NPs was adequate, and the in vitro release rate increased with the decrease of the environmental pH. Seven days post incubation, the cumulative release values of Cur were 52.78%, 67.39%, and 98.12% at pH 7.4, pH 6.8 and pH 5.0, respectively. Cur-P-NPs exhibited better cell entry and antiproliferation efficacy against U251 cells than the Cur-solution and Cur-NPs and were safe for use. Cur-P-NPs specifically targeted tumor tissues and inhibited their growth (78.63% tumor growth inhibition rate) with low toxic effects on normal tissues. CONCLUSION: The enzyme-targeted hybrid nanoparticles prepared in the study clearly have the tumor-targeting ability. Cur-P-NPs can effectively improve the bioavailability of Cur and have potential applications in drug delivery and tumor management.

Pitcher plant-bioinspired bubble slippery surface fabricated by femtosecond laser for buoyancy-driven bubble self-transport and efficient gas capture.

Functional materials with specific bubble wettability play an important role in manipulating the behavior of underwater gas bubbles. Inspired by the natural Pitcher plant, we designed a large area lubricated slippery surface (LSS) by femtosecond laser processing for buoyancy-driven bubble self-transport and efficient gas capture. The mechanism of bubble self-transport involves a competition between the buoyancy and the resistance due to drag force and hysteresis. The transportation velocity of the bubbles on the LSS is strongly associated with the surface tension of the lubricants. The lower the surface tension, the higher the sliding velocity. On the basis of sufficient bubble adhesion, the shaped LSS tracks are fabricated to guide the bubble movement and achieve continuous manipulation between bubble merging and detachment. We demonstrate that these designable pathways on the LSS not only manipulate bubble behavior in a two-dimensional space but also realize three-dimensional movement of bubbles on the Mobius-striped LSS. Finally, a gas catcher decorated with large area LSS is manufactured for underwater bubble capture, which maintains a high capture efficiency (more than 90%) with an air output of ∼3.4 L min-1. This finding reveals a meaningful interaction between the underwater bubbles and the LSS surface, accelerating the applications of bubble slippery surfaces in underwater flammable gas collection and tail gas treatment.