Liya Xie

Both FA- and mPEG-conjugated chitosan nanoparticles for targeted cellular uptake and enhanced tumor tissue distribution

Both folic acid (FA)- and methoxypoly(ethylene glycol) (mPEG)-conjugated chitosan nanoparticles (NPs) had been designed for targeted and prolong anticancer drug delivery system. The chitosan NPs were prepared with combination of ionic gelation and chemical cross-linking method, followed by conjugation with both FA and mPEG, respectively. FA-mPEG-NPs were compared with either NPs or mPEG-/FA-NPs in terms of their size, targeting cellular efficiency and tumor tissue distribution. The specificity of the mPEG-FA-NPs targeting cancerous cells was demonstrated by comparative intracellular uptake of NPs and mPEG-/FA-NPs by human adenocarcinoma HeLa cells. Mitomycin C (MMC), as a model drug, was loaded to the mPEG-FA-NPs. Results show that the chitosan NPs presented a narrow-size distribution with an average diameter about 200 nm regardless of the type of functional group. In addition, MMC was easily loaded to the mPEG-FA-NPs with drug-loading content of 9.1%, and the drug releases were biphasic with an initial burst release, followed by a subsequent slower release. Laser confocal scanning imaging proved that both mPEG-FA-NPs and FA-NPs could greatly enhance uptake by HeLa cells. In vivo animal experiments, using a nude mice xenograft model, demonstrated that an increased amount of mPEG-FA-NPs or FA-NPs were accumulated in the tumor tissue relative to the mPEG-NPs or NPs alone. These results suggest that both FA- and mPEG-conjugated chitosan NPs are potentially prolonged drug delivery system for tumor cell-selective targeting treatments.

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.

Development of multifunctional folate-poly(ethylene glycol)-chitosan-coated Fe3O4 nanoparticles for biomedical applications

AbstractThe efficacy of magnetic nanoparticles (MNPs) for biomedical applications depends on the specic targeting capacity, blood circulation time and magnetic susceptibility. Functionalized chitosan-coated Fe3O4 nanoparticles (CS-coated Fe3O4 NPs) were synthesized by a non-solvent-aided coacervation procedure followed by a chemical crosslinking procedure. The surfaces of CS-coated Fe3O4 NPs were successfully functionalized with folate-poly(ethylene glycol)-COOH (FA-PEG) to obtain novel FA-PEG-CS-coated Fe3O4 NPs endowed with long blood circulation and specic targeting capacity. The as-synthesized NPs were characterized by dynamic light scattering, transmission electron microscope, X-ray diffraction, thermal gravimetric analysis, vibration sample magnetometer, Fourier transform infrared spectroscopy, and confocal laser scanning microscopy. As a result, the novel FA-PEG-CS-coated Fe3O4 NPs showed excellent biocompatibility, magnetic properties, good dispersibility, and proper hydrodynamic sizes in an aqueous medium. The specific targeting capacity of the as-synthesized NPs to cancer cells was also investigated. It was observed that the uptake of the FA-PEG-CS-coated Fe3O4 NPs by HeLa cells was significantly enhanced compared to the CS-coated Fe3O4 NPs and mPEG-CS-coated Fe3O4 NPs. These results clearly indicate that our novel FA-PEG-CS-coated Fe3O4 NPs with remarkable specific targeting capacity, long blood circulation, and superparamagnetism hold great promise for biomedical applications, including targeted drug delivery and hyperthermia therapy.

A comparative in vitro evaluation of self-assembled PTX-PLA and PTX-MPEG-PLA nanoparticles

We present a dialysis technique to direct the self-assembly of paclitaxel (PTX)-loaded nanoparticles (NPs) using methoxypolyethylene glycol-poly(d,l-lactide) (MPEG-PLA) and PLA, respectively. The composition, morphology, particle size and zeta potential, drug loading content, and drug encapsulation efficiency of both PTX-PLA NPs and PTX-MPEG-PLA NPs were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, dynamic light scattering, electrophoretic light scattering, and high-performance liquid chromatography. The passive targeting effect and in vitro cell viability of the PTX-MPEG-PLA NPs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PTX-PLA NPs. The results showed that the PTX-MPEG-PLA NPs and PTX-PLA NPs presented a hydrodynamic particle size of 179.5 and 441.9 nm, with a polydispersity index of 0.172 and 0.189, a zeta potential of −24.3 and −42.0 mV, drug encapsulation efficiency of 18.3% and 20.0%, and drug-loaded content of 1.83% and 2.00%, respectively. The PTX-MPEG-PLA NPs presented faster release rate with minor initial burst compared to the PTX-PLA NPs. The PTX-MPEG-PLA NPs presented superior cell cytotoxicity and excellent cellular uptake compared to the PTX-PLA NPs. These results suggested that the PTX-MPEG-PLA NPs presented more desirable characteristics for sustained drug delivery compared to PTX-PLA NPs.

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.

Single-step assembly of polymer-lipid hybrid nanoparticles for mitomycin C delivery

Mitomycin C is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its clinical use is still hindered by the mitomycin C (MMC) delivery systems. In this study, the MMC-loaded polymer-lipid hybrid nanoparticles (NPs) were prepared by a single-step assembly (ACS Nano 2012, 6:4955 to 4965) of MMC-soybean phosphatidyhlcholine (SPC) complex (Mol. Pharmaceutics 2013, 10:90 to 101) and biodegradable polylactic acid (PLA) polymers for intravenous MMC delivery. The advantage of the MMC-SPC complex on the polymer-lipid hybrid NPs was that MMC-SPC was used as a structural element to offer the integrity of the hybrid NPs, served as a drug preparation to increase the effectiveness and safety and control the release of MMC, and acted as an emulsifier to facilitate and stabilize the formation. Compared to the PLA NPs/MMC, the PLA NPs/MMC-SPC showed a significant accumulation of MMC in the nuclei as the action site of MMC. The PLA NPs/MMC-SPC also exhibited a significantly higher anticancer effect compared to the PLA NPs/MMC or free MMC injection in vitro and in vivo. These results suggested that the MMC-loaded polymer-lipid hybrid NPs might be useful and efficient drug delivery systems for widening the therapeutic window of MMC and bringing the clinical use of MMC one step closer to reality.

Preparation and in vitro evaluation of an ultrasound-triggered drug delivery system: 10-Hydroxycamptothecin loaded PLA microbubbles

10-Hydroxycamptothecin (HCPT) loaded PLA microbubbles, used as an ultrasound-triggered drug delivery system, were fabricated by a double emulsion-solvent evaporation method. The obtained microbubbles were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and confocal laser scanning microscope (CLSM). In addition, the effect of diagnostic ultrasound exposure on BEL-7402 cells combined with HCPT-loaded PLA microbubbles was evaluated using cytotoxicity assay, CLSM and flow cytometry (FCM). It was found that the HCPT-loaded PLA microbubbles showed smooth surface and spherical shape, and the drug was amorphously dispersed within the shell and the drug loading content reached up to 1.69%. Nearly 20% of HCPT was released upon exposure to diagnostic ultrasound at frequency of 3.5MHz for 10min. Moreover, HCPT fluorescence in the cells treated only with the HCPT-loaded PLA microbubbles was discernible, but less intense, while those treated with the microbubbles in conjunction with ultrasound exposure was evident and intense, indicating an increased cellular uptake of HCPT by ultrasound exposure. Cytotoxicity test on BEL-7402 cells indicated that the HCPT-loaded PLA microbubbles combined with ultrasound exposure were more cytotoxic than the microbubbles alone. The results suggest that the combination of drug loaded PLA microbubbles and diagnostic ultrasound exposure exhibit an effective intracellular drug uptake by tumor cells, indicating their great potential for antitumor therapy.

Dual-acting, function-responsive, and high drug payload nanospheres for combining simplicity and efficacy in both self-targeted multi-drug co-delivery and synergistic anticancer effect.

Recently, the global trend in the field of nanomedicine has been toward the design of highly sophisticated drug delivery systems with specific targeting and synergistic therapeutic functions for improving therapeutic efficacy. But offering sophistication generally increases their complexity that might be disadvantageous in pharmaceutical development. We hypothesize that using a macromolecular prodrug with a dual role will be conductive to integrating its dual function into self-targeted multidrug co-delivery and combination cancer therapy. In this paper, the on-off switching function-responsive, macromolecular methotrexate (MTX) prodrug-self-targeted, controlled-/sustained-release, and high drug-loading hydroxylcamptothecin (HCPT) drug nanospheres were prepared and characterized. The self-targeting system can co-deliver multi-drug to different action sites with distinct anticancer mechanisms to specifically target folate receptors-overexpressing cancer cells with synergistic therapeutic efficiency.

Self-assembly of the active lactone form of a camptothecin–phospholipid complex for sustained nuclear drug delivery

10-Hydroxycamptothecin (CPT) is considered as one of the most promising anticancer drugs against a broad spectrum of human cancers. However, it is difficult to apply CPT clinically, because of its poor water solubility and reversible instability between the active lactone and inactive carboxylate forms at neutral pH. In this paper, to overcome these limitations, the active lactone form of CPT–soybean phosphatidylcholine (SPC) complex self-assembled nanoparticles (CPT–SPC NPs) is prepared by a co-solvent method combined with a self-assembly technique. The CPT–SPC complex is characterized by solubility, UV-vis, 1H NMR, FTIR, XRD, and fluorescence analysis. These results prove the efficient complexation between active lactone form of CPT and SPC (complexation rate was high as approximately 98%). The self-assembled CPT–SPC NPs show a hydrodynamic particle size of 210.7 ± 6.1 nm, a zeta potential of −24.9 ± 3.1 mV, a spherical shape, and a high drug-loading content of 16.3 ± 0.5%. CPT is released from the CPT–SPC NPs in a biphasic way with an initial burst release followed by a subsequent sustained release. Additionally, in comparision with the free CPT, the CPT–SPC NPs, because of the improved drug stability and enhanced drug transport across cellular membranes, present significantly higher cellular uptake efficiency and cell-killing effect of the drug. Moreover, both confocal imaging and fluorescence measurements demonstrate that CPT is able to be delivered to nuclei by the CPT–SPC NPs after their cellular uptake, by real-time monitoring of drug release and intracellular drug delivery. Furthermore, in vivo animal imaging results indicate that the systemically administered CPT–SPC NPs exhibit excellent tumor targetability in HeLa tumor-bearing nude mice. These results demonstrate that the CPT–SPC complex-based self-assembled NPs hold great potential as effective drug delivery systems for cancer treatment.