Rutian Li

Covalently Combining Carbon Nanotubes with Anticancer Agent: Preparation and Antitumor Activity

A multiwalled carbon nanotube (MWNT)-based drug delivery system was developed by covalently combining carbon nanotubes with the antitumor agent 10-hydroxycamptothecin (HCPT) using hydrophilic diaminotriethylene glycol as the spacer between nanotube and drug moieties. The surface functionalizations of the nanotube were carried out by enrichment of carboxylic groups with optimized oxidization treatment, followed by covalently linking hydrophilic diaminotriethylene glycol via amidation reaction, and then HCPT was chemically attached to carbon nanotubes through a cleavable ester linkage. It is demonstrated that the obtained MWNT-HCPT conjugates are superior in antitumor activity both in vitro and in vivo to clinical HCPT formulation. In vivo single photon emission computed tomography (SPECT) imaging and ex vivo gamma scintillation counting analyses reveal that MWNT-HCPT conjugates have relatively long blood circulation and high drug accumulation in the tumor site. These properties together with the enhanced cell uptake and multivalent presentation of HCPT on a single nanotube benefit substantially the antitumor effects and would boost significantly the applications of carbon nanotubes in the biomedicine field.

Multifunctional Nanocarriers for Cell Imaging, Drug Delivery, and Near-IR Photothermal Therapy

Multifunctional nanocarriers based on chitosan/gold nanorod (CS-AuNR) hybrid nanospheres have been successfully fabricated by a simple nonsolvent-aided counterion complexation method. Anticancer drug cisplatin was subsequently loaded into the obtained hybrid nanospheres, utilizing the loading space provided by the chitosan spherical matrix. In vitro cell experiments demonstrated that the CS-AuNR hybrid nanospheres can not only be utilized as contrast agents for real-time cell imaging but also serve as a near-infrared (NIR) thermotherapy nanodevice to achieve irradiation-induced cancer cell death owing to the unique optical properties endowed by the encapsulated gold nanorods. In addition, an effective attack on the cancer cells by the loaded anticancer drug cisplatin has also been observed, rendering the obtained nanocarriers an all-in-one system possessing drug delivery, cell imaging, and photothermal therapy functionalities.

Paclitaxel-loaded poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) nanoparticles: Preparation and antitumor activity in vivo

Paclitaxel (PTX)-loaded poly(N-vinylpyrrolidone)-b-poly(epsilon-caprolactone) (PVP-b-PCL) nanoparticles with high drug payload were successfully prepared by a modified nano-precipitation method and characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS) and zeta potential. The satisfactory drug loading content (>25%) and high encapsulation efficiency (>85%) were achieved. The in vivo real-time biodistribution of PTX-loaded nanoparticles was investigated using near-infrared fluorescence (NIRF) imaging. The antitumor effect of PTX-loaded nanoparticles was evaluated, both, in vitro on three different cancer cell lines and in vivo on hepatic H22 tumor bearing mice model via intravenous administration (i.v.). It is found that PTX-loaded nanoparticles exhibit significant superior in vivo antitumor effect than the commercially available Taxol formulation by combining the tumor volumes and survival rates measurement, intravital positron emission tomography and computed tomography (PET/CT) imaging.

The antitumor effect of novel docetaxel-loaded thermosensitive micelles.

To further evaluate the novel docetaxel-loaded micelle based on the biodegradable thermosensitive copolymer poly(N-isopropylacrylamide-co-acrylamide)-b-poly(dl-lactide) that we had synthesized before, in this paper, we studied its in vitro cytotoxicity in three different tumor cell lines by standard MTT assays using different tumor cell lines, followed by studies of acute toxicity and the tumor distribution studies which were conducted in Kunming mice. Meanwhile, the in vivo antitumor efficacy as well as toxicity of the micelle was evaluated in C57BL/6 mice. According to our findings, the in vitro cytotoxicity of docetaxel-loaded micelles was lower than that of the conventional docetaxel formulation at 37 degrees C, while hyperthermia greatly enhanced the efficacy of drug-loaded micelles. The acute toxicity study showed reduced toxicity of docetaxel-loaded micelle compared to that of conventional docetaxel formulation. Moreover, docetaxel-loaded micelle enabled a prominent higher docetaxel concentration in tumor than conventional docetaxel formulation. Furthermore, a significantly higher antitumor efficacy was observed in mice treated with docetaxel-loaded micelles accompanied by hyperthermia; docetaxel-loaded micelles also caused less body weight loss of mice. This study demonstrates an increased antitumor efficacy and reduced toxicity of the novel docetaxel-loaded micelle and indicates its prospect of clinical applications.

Superior antitumor efficiency of cisplatin-loaded nanoparticles by intratumoral delivery with decreased tumor metabolism rate

cis-Dichlorodiamminoplatinum (II) (cisplatin) has demonstrated extraordinary activities against a variety of solid tumors. However, the clinical efficacy is contrasted by its toxicity profile. To reduce the toxicity and enhance the circulation time of cisplatin, core-shell structure nanoparticles were prepared from block copolymer of methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL). Cisplatin was incorporated into the nanoparticles with high encapsulation efficiency more than 75%. Controlled release of cisplatin was observed in a sustained manner. In vitro cytotoxicity studies proved the efficacy of cisplatin-loaded nanoparticles against BGC823 and H(22) cells in a dose and time-dependent manner. Furthermore, intratumoral administration was applied to improve the tumor-targeted delivery in the in vivo evaluation. Compared with free cisplatin, cisplatin-loaded nanoparticles exhibited superior antitumor effect by delaying tumor growth when delivered intratumorally, while no significant improvement was observed when they were administrated intraperitoneally. Positron emission tomography/computed tomography (PET/CT) imaging was utilized for the first time to detect the declined (18)F-labeled 2-fluoro-2-deoxy-d-glucose ((18)F-FDG) uptake of the tumor in mice receiving cisplatin-loaded nanoparticles intratumorally. These results suggest that polymeric nanoparticles with core-shell structures are promising for further studies as drug delivery carriers, and intratumoral delivery of drug-loaded nanoparticles could be a probable clinically useful therapeutic regimen.

Nanospheres-Incorporated Implantable Hydrogel as a Trans-Tissue Drug Delivery System

The objective of this study is to investigate the anticancer efficacy of a drug delivery system comprised of gelatin hydrogel (jelly) containing cisplatin (CDDP)-loaded gelatin/poly(acrylic acid) nanoparticles by peritumoral implantation and to compare the treatment response between the implantation administration of the jelly and intravenous (i.v.) administration of the nanoparticles. It is found that the implantation of the jelly containing CDDP-loaded nanoparticles on tumor tissue exhibited significantly superior efficacy in impeding tumor growth and prolonging the lifetime of mice than that of i.v. injection of CDDP-loaded nanoparticles in a murine hepatoma H(22) cancer model. An in vivo biodistribution assay performed on tumor-bearing mice demonstrated that the jelly implant caused much higher concentration and retention of CDDP in tumor and lower CDDP accumulation in nontarget organs than that of i.v. injected nanoparticles. Immunohistochemical analysis demonstrated that the nanoparticles from the jelly can be distributed in tumor tissue not only by their diffusion but also by the vasculature in the implantation region into tumor interior, enabling CDDP to efficiently reach more viable cells of tumor compared with i.v. injected nanoparticles. Thus, nanoparticles for peritumoral chemotherapy are promising for higher treatment efficacy due to increased tumor-to-normal organ drug uptake ratios and improved drug penetration in tumors.

Preparation and evaluation of PEG–PCL nanoparticles for local tetradrine delivery

To establish a satisfactory delivery system for local delivery of Tetradrine (Tet), four kinds of core-shell nanoparticles were prepared from di-block copolymer of methoxy poly(ethylene glycol)-polycaprolactone (MePEG-PCL) and tri-block copolymer of polycaprolactone-poly(ethylene glycol)-polycaprolactone (PCL-PEG-PCL). The physiochemical traits of the four kinds of nanoparticles including morphology, particle size, zeta-potential, drug-loading content, stability, and in vitro release profile were studied. We also evaluated the four kinds of nanoparticles by in vitro cellular uptake experiment, cytotoxicity assay against LoVo cells, and biocmpatibility study. Histoculture Drug Response Assay (HDRA), a more predictive method usually used to evaluate chemosensitivity was firstly applied in our study to evaluate the antitumor potency of polymeric nanoparticles. The current study showed that all the four kinds of copolymers exhibited remarkable in vitro antitumor effects, especially in HDRA assay. The configuration and composition of the copolymers were important for the properties and functions of the nanoparticles. Nanoparticles prepared from the di-block copolymer with a particle size around 300nm and the hydrophobic composition about 80% was determined as the most effective drug carrier for further studies.

Predictive value of thymidylate synthase expression in advanced colorectal cancer patients receiving fluoropyrimidine-based chemotherapy: Evidence from 24 studies

The published data about thymidylate synthase (TS) expression and its predictive value in advanced colorectal cancer (CRC) patients receiving fluoropyrimidine‐based chemotherapy seemed inconclusive. To derive a more precise estimation of the relationship, a metaanalysis was performed. Studies have been identified by searching PubMed and Embase. Inclusion criteria were advanced CRC patients, received fluoropyrimidine‐based chemotherapy and evaluation of TS expression and overall response rate (ORR). The relative ratio (RR) for ORR in patients with low‐TS expression over those with high‐TS expression with 95% confidence interval (CI) was calculated for each study as an estimation of the predictive effect of TS. A total of 24 studies including 1,112 patients were involved in this metaanalysis. The overall RR was 2.20 (95% CI, 1.82–2.66; p = 0.000). For studies evaluating TS expression in metastatic lesions, the pooled RR was 3.23 (95% CI, 2.27–4.59; p = 0.000); for studies testing TS expression in primary lesions, a pooled RR of 1.89 (95% CI, 1.45–2.48; p = 0.000) was estimated. Focusing the analysis on immunohistochemistry (IHC)‐based or RTPCR‐based assessments, the pooled RR was 1.83 (95% CI, 1.44–2.34; p = 0.000) and 2.96 (95% CI, 2.07–4.22; p = 0.000), respectively. The results indicated that low‐TS expression tumors in advanced CRC patients were more sensitive to fluoropyrimidine‐based chemotherapy. Subgroup analyses indicated that the predictive value of TS expression evaluated in metastases was more prominent than that of primary lesions, and that TS expression tested by RTPCR was also of greater predictive value than by IHC.

Enhanced antitumor efficacy, biodistribution and penetration of docetaxel-loaded biodegradable nanoparticles

To investigate the antitumor effect, biodistribution and penetration in tumors of docetaxel (DOC)-loaded polyethylene glycol-poly(caprolactone) (mPEG-PCL) nanoparticles on hepatic cancer model, DOC-loaded nanoparticles (DOC-NPs) were prepared with synthesized mPEG-PCL by nano-precipitated method with satisfactory encapsulation efficiency, loading capacity and size distribution. The fabricated nano-drugs were effectively transported into tumoral cells through endocytosis and localized around the nuclei in the cytoplasm. In vitro cytotoxicity test showed that DOC-NPs inhibited the murine hepatic carcinoma cell line H22 in a dose-dependent manner, which was similar to Taxotere, the commercialized formulation of docetaxel. The in vivo biodistribution performed on tumor-bearing mice by NIRF real-time imaging demonstrated that the nanoparticles achieved higher concentration and longer retention in tumors than in non-targeted organs after intravenous injection. The immunohistochemical analysis demonstrated that the nanoparticles located not only near the tumoral vasculatures, but also inside the tumoral interior. Therefore, DOC-NPs could penetrate into tumor parenchyma, leading to high intratumoral concentration of DOC. More importantly, the in vivo anti-tumor evaluation showed that DOC-NPs significantly inhibited tumor growth by tumor volume measurement and positron emission tomography and computed tomography (PET/CT) imaging observation. Taken together, the reported drug delivery system here could shed light on the future targeted therapy against hepatic carcinoma.

Dual‐Functional Alginic Acid Hybrid Nanospheres for Cell Imaging and Drug Delivery

An effective and facile approach to prepare gold-nanoparticle-encapsulated alginic acid-poly[2-(diethylamino)ethyl methacrylate] monodisperse hybrid nanospheres (ALG-PDEA-Au) is developed by using monodisperse ALG-PDEA nanospheres as a precursor nanoparticulate reaction system. This approach utilizes particle-interior chemistry, which avoids additional reductant or laborious separation process and, moreover, elegantly ensures that all the gold nanoparticles are located inside the hybrid nanospheres and every nanosphere is loaded with gold nanoparticles. These obtained ALG-PDEA-Au hybrid nanospheres have not only uniform size, similar surface properties, and good biocompatibility but also unique optical properties provided by the embedded gold nanoparticles. It is demonstrated that negatively charged ALG-PDEA-Au hybrid nanospheres can be internalized by human colorectal LoVo cancer cells and hence act as novel optical-contrast reagents in tumor-cell imaging by optical microscopy. Moreover, these hybrid nanospheres can also serve as biocompatible carriers for the loading and delivery of an anti-cancer drug doxorubicin. In vitro cell viability tests reveal that drug-loaded ALG-PDEA-Au hybrid nanospheres exhibit similar tumor cell inhibition to the free drug doxorubicin. Therefore, the obtained hybrid nanospheres successfully combine two functions, that is, cell imaging and drug delivery, into one single system, and may be of great application potential in other biomedical-related areas.