Yanxiu Li

Development of both methotrexate and mitomycin C loaded PEGylated chitosan nanoparticles for targeted drug codelivery and synergistic anticancer effect.

Codelivery of multiple drugs with one kind of drug carriers provided a promising strategy to suppress the drug resistance and achieve the synergistic therapeutic effect in cancer treatment. In this paper, we successfully developed both methotrexate (MTX) and mitomycin C (MMC) loaded PEGylated chitosan nanoparticles (CS-NPs) as drug delivery systems, in which MTX, as a folic acid analogue, was also employed as a tumor-targeting ligand. The new drug delivery systems can coordinate the early phase targeting effect with the late-phase anticancer effect. The (MTX+MMC)-PEG-CS-NPs possessed nanoscaled particle size, narrow particle size distribution, and appropriate multiple drug loading content and simultaneously sustained drug release. In vitro cell viability tests indicated that the (MTX+MMC)-PEG-CS-NPs exhibited concentration- and time-dependent cytotoxicity. Moreover, in vitro cellular uptake suggested that the (MTX+MMC)-PEG-CS-NPs could be efficiently taken up by cancer cells by FA receptor-mediated endocytosis. On the other hand, the (MTX+MMC)-PEG-CS-NPs can codelivery MTX and MMC to not only achieve the high accumulation at the tumor site but also more efficiently suppress the tumor cells growth than the delivery of either drug alone, indicating a synergistic effect. In fact, the codelivery of two anticancer drugs with distinct functions and different anticancer mechanisms was key to opening the door to their targeted drug delivery and synergistic anticancer effect. Therefore, the (MTX+MMC)-PEG-CS-NPs as targeted drug codelivery systems might have important potential in clinical implications for combination cancer chemotherapy.

Self-Assembled Nanoparticles Based on Amphiphilic Anticancer Drug–Phospholipid Complex for Targeted Drug Delivery and Intracellular Dual-Controlled Release

Integrating advantages of mitomycin C (MMC)-phospholipid complex for increased drug encapsulation efficiency and reduced premature drug release, DSPE-PEG-folate (DSPE-PEG-FA) for specific tumor targeting, we reported a simple one-pot self-assembly route to prepare the MMC-phospholipid complex-loaded DSPE-PEG-based nanoparticles (MP-PEG-FA NPs). Both confocal imaging and flow cytometry demonstrated that MMC was distributed into nuclei after cellular uptake and intracellular drug delivery. More importantly, the systemically administered MP-PEG-FA NPs led to increased blood persistence and enhanced tumor accumulation in HeLa tumor-bearing nude mice. This study introduces a simple and effective strategy to design the anticancer drug-phospholipid complex-based targeted drug delivery system for sustained/controlled drug release.

Bacillus-Shape Design of Polymer Based Drug Delivery Systems with Janus-Faced Function for Synergistic Targeted Drug Delivery and More Effective Cancer Therapy

The particle shape of the drug delivery systems had a strong impact on their in vitro and in vivo performance, but there was limited availability of techniques to produce the specific shaped drug carriers. In this article, the novel methotrexate (MTX) decorated MPEG-PLA nanobacillus (MPEG-PLA-MTX NB) was prepared by the self-assembly technique followed by the extrusion through SPG membrane with high N2 pressure for targeted drug delivery, in which Janus-like MTX was not only used as a specific anticancer drug but could also be served as a tumor-targeting ligand. The MPEG-PLA-MTX NBs demonstrated much higher in vitro and in vivo targeting efficiency compared to the MPEG-PLA-MTX nanospheres (MPEG-PLA-MTX NSs) and MPEG-PLA nanospheres (MPEG-PLA NSs). In addition, the MPEG-PLA-MTX NBs also displayed much more excellent in vitro and in vivo antitumor activity than the MPEG-PLA-MTX NSs and free MTX injection. To our knowledge, this work provided the first example of the integration of the shape design (which mediated an early phase tumor accumulation and a late-phase cell internalization) and Janus-faced function (which mediated an early phase active targeting effect and a late-phase anticancer effect) on the basis of nanoscaled drug delivery systems. The highly convergent and cooperative drug delivery strategy opens the door to more drug delivery systems with new shapes and functions for cancer therapy.

Self-targeted, bacillus-shaped, and controlled-release methotrexate prodrug polymeric nanoparticles for intratumoral administration with improved therapeutic efficacy in tumor-bearing mice

Poor drug distribution and inefficient drug concentrations within the tumor intracellular environment still limit the therapeutic efficacy of drugs for cancer chemotherapy. Local drug delivery (physical targeting) combined with receptor-mediated drug delivery (chemical targeting) and assistance by a novel shape design is a promising strategy to treat the infiltrating tumor (even those that persist post surgery). In this paper, we prepared dye and methotrexate (MTX) functionalized nanobacilli (MPEG-PLA-MTX-Cy5.5 NB) by a self-assembly technique combined with extrusion through a SPG membrane for intratumoral administration, in which the bacillus-shaped MPEG-PLA-MTX-Cy5.5 NB were armed with a dual-acting MTX that can specifically and efficiently enhance their cellular uptake, while avoiding their dispersion from tumor sites. After intratumoral administration to a H22 xenograft mouse model, the MPEG-PLA-MTX-Cy5.5 NB delivered the drug more effectively to the tumor compared to the MPEG-PLA-Cy5.5 nanospheres (MPEG-PLA-Cy5.5 NSs) and MPEG-PLA-MTX-Cy5.5 nanospheres (MPEG-PLA-MTX-Cy5.5 NSs). Compared to the free MTX and MPEG-PLA-MTX-Cy5.5 NSs, the controlled-release MPEG-PLA-MTX-Cy5.5 NB also significantly inhibited the tumor growth and improved therapeutic efficacy. The platforms are highly convergent, flexible and simplified systems that may serve as guides in the further design of nanoparticles with a revolutionary new shape and function for clinical applications.

Tumor-targeted co-delivery of mitomycin C and 10-hydroxycamptothecin via micellar nanocarriers for enhanced anticancer efficacy

Lipophilicity enhancement of mitomycin C (MMC) was achieved by the introduction of soybean phosphatidyhlcholine (SPC, a kind of phospholipid) (Molecular Pharmaceutics, 2013, 10, 90–101). In addition, the co-delivery of both drugs with one kind of nanoscale drug carrier provided a promising strategy to realize synergistic therapeutic effects and overcome drug resistance in cancer therapy. In this work, we developed folate (FA) functionalized MMC–SPC phospholipid complexes and 10-hydroxycamptothecin (HCPT)-loaded micelles (MMC/HCPT loaded FA-micelles) by film hydration followed by a dialysis and extrusion technique. The MMC/HCPT loaded FA-micelles possessed a nanoscale particle size, a well-controllable drug loading efficiency, and simultaneously sustained and pH-dependent drug release. In vitro cellular uptake analysis suggested that the MMC/HCPT loaded FA-micelles could be efficiently taken up by cancer cells via FA receptor-mediated endocytosis. In vitro cell viability studies demonstrated that the MMC/HCPT loaded FA-micelles showed time- and concentration-dependent cytotoxicity, and significantly enhanced the cytotoxicity compared to both free drugs. Moreover, the MMC/HCPT loaded FA-micelles can simultaneously deliver both MMC and HCPT to not only efficiently promote their accumulation in the tumor as a result of passive and active targeting, but also sufficiently inhibit the tumor growth compared to treatment with both free drugs while reducing the toxicity. The both MMC and HCPT anticancer drug-loaded FA-micelles can be considered as effective therapeutic systems for targeted drug co-delivery and combination cancer chemotherapy.

Design of a novel curcumin-soybean phosphatidylcholine complex-based targeted drug delivery systems

Abstract Recently, the global trend in the field of nanomedicine has been toward the design of combination of nature active constituents and phospholipid (PC) to form a therapeutic drug-phospholipid complex. As a particular amphiphilic molecular complex, it can be a unique bridge of traditional dosage-form and novel drug delivery system. In thisarticle, on the basis of drug-phospholipid complex technique and self-assembly technique, we chose a pharmacologically safe and low toxic drug curcumin (CUR) to increase drug-loading ability, achieve controlled/sustained drug release and improve anticancer activity. A novel CUR-soybean phosphatidylcholine (SPC) complex and CUR-SPC complex self-assembled nanoparticles (CUR-SPC NPs) were prepared by a co-solvent method and a nanoprecipitation method. DSPE-PEG-FA was further functionalized on the surface of PEG-CUR-SPC NPs (designed as FA-PEG-CUR-SPC NPs) to specifically increase cellular uptake and targetability. The FA-PEG-CUR-SPC NPs showed a spherical shape, a mean diameter of about 180 nm, an excellent physiological stability and pH-triggered drug release. The drug entrapment efficiency and drug-loading content was up to 92.5 and 16.3%, respectively. In vitro cellular uptake and cytotoxicity studies demonstrated that FA-PEG-CUR-SPC NPs and CUR-SPC NPs presented significantly stronger cellular uptake efficacy and anticancer activity against HeLa cells and Caco-2 cells compared to free CUR, CUR-SPC NPs and PEG-CUR-SPC NPs. More importantly, FA-PEG-CUR-SPC NPs showed the prolonged systemic circulation lifetime and enhanced tumor accumulation compared with free CUR and PEG-CUR-SPC NPs. These results suggest that the FA targeted PEGylated CUR-SPC complex self-assembled NPs might be a promising candidate in cancer therapy.

Self-assembly of multifunctional integrated nanoparticles loaded with a methotrexate–phospholipid complex: combining simplicity and efficacy in both targeting and anticancer effects

Recently, the global trend in the field of nanomedicine has been toward the design of highly sophisticated drug delivery systems with active targeting and therapeutic functions, as well as responsiveness to biological stimuli for improving therapeutic efficacy. But offering sophistication generally increases their complexity that might be disadvantageous in pharmaceutical development. In this paper, we hypothesize that using a clinical anticancer drug methotrexate (MTX) as both a targeting ligand and a therapeutic agent to interact with natural product phospholipid (PC) and thus self-assemble will lead to an efficient but simple and flexible, moreover, multifunctional integrated system. The methotrexate (MTX)–phospholipid (PC) complex is prepared by a co-solvent method and can be self-assembled into nanoparticles (MTX–PC NPs), which significantly increases the drug-loading ability and reduces the burst drug release compared with free MTX and MTX-loaded liposomes. The MTX–PC complex and its self-assembled MTX–PC NPs were evaluated by UV, TGA, DSC, XRD, FTIR, 1H-NMR, SEM, TEM, AFM, and in an in vitro drug release study. The MTX-PC NPs had a particle size of 152.5 ± 3.2 nm, a narrow size distribution, a high drug-loading efficiency of 20.7 ± 2.4%, and a controlled and sustained release behavior. The in vitro cellular uptake results showed that a vital advantage of this system is that MTX-PC NPs with pH-triggered drug release can exert an early-phase good active targeting efficiency (attributed to the surface-absorbed MTX) cooperating with a late-phase excellent anticancer efficiency (was attributed to the core-dispersed MTX). The concept of the self-targeted anticancer effect based on drug–lipid hybrid systems might be a promising candidate for cancer therapy compared with traditional drug delivery systems.

Validation of a dual role of methotrexate-based chitosan nanoparticles in vivo

A compound with a dual role has the potential to integrate its dual functions into a single nanoscale drug delivery system. Here, based on the methotrexate (MTX)-based PEGylated chitosan (CS) nanoparticles, we validated this dual role in vivo and explored the in vivo efficiency of MTX as an early-phase tumor-targeting ligand and also as a late-phase anticancer drug. Following intravenous administration, compared with the (FA + PEG)–CS–NPs and PEG–CS–NPs, the (MTX + PEG)–CS–NPs exhibited a slower blood clearance profile, longer systemic circulation time, and significantly greater tumor accumulation. Furthermore, with the aide of folate (FA) receptor-mediated endocytosis (ability to turn cellular uptake “off” in normal cells, whereas it is “on” in cancer cells) and pH/intracellular protease-mediated hydrolyzing peptide bonds (able to turn drug release “off” in systemic circulation whereas it is “on” inside endo/lysosomes), the (MTX + PEG)–CS–NPs showed remarkably superior therapeutic efficiency compared to the commercially available MTX. More importantly, this work would stimulate interest in the use of the clinically useful MTX as a synergistically self-targeted therapeutic agent in the design of a highly convergent, flexible and simplified nanoscale drug delivery system for simultaneously targeting and treating FA receptor-overexpressing tumors.

Dually folate/CD44 receptor-targeted self-assembled hyaluronic acid nanoparticles for dual-drug delivery and combination cancer therapy

Nanoparticles (NPs) functionalized with targeting ligands have shown promise, but are still limited by their nonspecific uptake by certain healthy tissues and cells that express low or even comparable levels of receptors. To increase their accumulation at tumor sites while decreasing the unintended toxicity, a possible solution is the involvement of two separate tumor-specific ligands in the localization. In this study, a dual tumor-targeting drug-loaded NP system was self-assembled by the amphiphilic conjugate of methotrexate-hyaluronic acid-octadecylamine (MTX-HA-OCA) with curcumin (CUR) encapsulated within the hydrophobic core (designated as MTX-HA-OCA/CUR NPs). The advantages of this nanosystem are that the anticancer drug MTX can be utilized as a tumor-targeting ligand toward folate receptors due to its structural similarity to folic acid (FA), and HA can serve as another tumor-targeting ligand toward CD44 receptors. The MTX-HA-OCA/CUR NPs are ∼70 nm in diameter and have sustained/controlled drug release behavior. An in vitro cellular uptake and competition inhibition study exhibited that MTX-HA-OCA/CUR NPs could significantly enhance the internalization efficiency in HeLa cells via folate/CD44 receptor-mediated endocytosis as compared to HA-OCA/CUR NPs. More importantly, the in vitro cytotoxicity of MTX-HA-OCA/CUR NPs was significantly enhanced as compared to those of the HA-OCA/CUR NPs, both free drugs, and individual free drug. Furthermore, the real-time in vivo and ex vivo fluorescence imaging of HeLa tumor-bearing mice showed that MTX-HA-OCA/CUR NPs could more efficiently enhance their accumulation and improve the penetration at the tumor site as compared to HA-OCA/CUR NPs. Therefore, these dually folate/CD44 receptor-targeted self-assembled HA NPs for the co-delivery of both anticancer drugs might provide a promising strategy for dual-targeted combination cancer therapy.

Examining the effect of ions and proteins on the heat dissipation of iron oxide nanocrystals

In this paper, the effect and contribution of physiological components like ions and proteins under an applied alternating magnetic field (AMF) towards heat dissipation of superparamagnetic iron oxide nanoparticles (SPIONs) are discussed. Our results have shown that under an applied AMF, magnetic hyperthermia efficiency could be significantly enhanced if SPIONs were suspended in 1× phosphate buffered saline (PBS) compared to a suspension in de-ionized (DI) water. However, no heat enhancement was found when SPIONs were suspended in blood which is an amalgamation of physiological ions and proteins. Closer investigations have revealed that the presence of physiological ions can contribute positively to heating efficiency, and the heating efficiency increases with concentration of ions, ionic mass and solubility. However, the heating efficiency of ions can be suppressed to an insignificant level (comparable with measurement error), in the presence of physiological proteins in 1×PBS. Our electrochemical studies also showed that ionic mobility can be reduced significantly if proteins were present in the solution, thus retarding the heating efficiency.