Lipeng Gao

Characterization of Fe3O4/SiO2/Gd2O(CO3)2 core/shell/shell nanoparticles as T1 and T2 dual mode MRI contrast agent.

Core/shell/shell structured Fe3O4/SiO2/Gd2O(CO3)2 nanoparticles were successfully synthesized. Their properties as a new type of T1-T2 dual model contrast agent for magnetic resonance imaging were investigated. Due to the introduce of a separating SiO2 layer, the magnetic coupling between Gd2O(CO3)2 and Fe3O4 could be modulated by the thickness of SiO2 layer and produce appropriate T1 and T2 signal. Additionally, the existence of Gd(3+) enhances the transverse relaxivity of Fe3O4 possibly because of the magnetic coupling between Gd(3+) and Fe3O4. The Fe3O4/SiO2/Gd2O(CO3)2 nanoparticles exhibit good biocompatibility, showing great potential for biomedical applications.

Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia

Currently, conventional therapies for acute myeloid leukemia (AML) have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR) T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML.

An effective intracellular delivery system of monoclonal antibody for treatment of tumors: erythrocyte membrane-coated self-associated antibody nanoparticles

Antibody-based drugs have attracted much attention for their targeting ability, high efficacy and low toxicity. But it is difficult for those intrabodies, a kind of antibody whose targets are intracellular biomarkers, to become effective drugs due to the lack of intracellular delivery strategy and their short circulation time in blood. Human telomerase reverse transcriptase (hTERT), an important biomarker for tumors, is expressed only in cytoplasm instead of on cell membrane. In this study, the anti-hTERT blocking monoclonal antibody (mAb), as the model intrabody, was used to prepare nanoparticles (NPs), followed by the encapsulation of erythrocyte membrane (EM), to obtain the EM-coated anti-hTERT mAb NPs delivery system. The final NPs showed a z-average hydrodynamic diameter of about 197.3 nm. The in vitro cellular uptake by HeLa cells confirmed that compared with free anti-hTERT mAb, the EM-coated anti-hTERT mAb NPs exhibited a significantly increased uptake by tumor cells. Besides, the pharmacokinetic study confirmed that the EM encapsulation can remarkably prolong the circulation time and increase the area under curve (AUC) of NPs in blood. The EM-coated anti-hTERT mAb NPs exhibited a remarkably decreased uptake by macrophages than uncoated NPs, which may be responsible for the prolonged circulation time and increased AUC. Furthermore, the frozen section of tumor tissue was performed and proved that the EM-coated anti-hTERT mAb NPs can be more effectively accumulated in tumor tissues than the free mAb and uncoated NPs. In summary, this study indicated that EM-coated anti-hTERT mAb NPs are an effective delivery system for the long circulation and intracellular delivery of an intrabody, and make it possible for the intracellular biomarkers to become the potential targets of drugs.

iNGR-Modified Liposomes for Tumor Vascular Targeting and Tumor Tissue Penetrating Delivery in the Treatment of Glioblastoma

The tumor vascular barrier and tumor stroma barrier become the two main obstacles in the in vivo delivery of nanomedicines. In this study, to overcome the two barriers, we used iNGR, a tumor-penetrating peptide, to modify the liposomes to increase their accumulation and penetration in tumor tissues. First, iNGR-modified sterically stabilized liposomes (iNGR-SSL) were prepared, which showed vesicle sizes of about 100 nm and narrow size distribution. The uptake of iNGR-SSL by U87MG cells and HUVECs were significantly more than that of unmodified liposome. The in vivo imaging study demonstrated that iNGR modification remarkably increased the accumulation of the liposome in orthotopic tumor tissues of animal model. The immunofluorescence staining analysis proved that iNGR-SSL could penetrate through tumor blood vessels and into the deep tumor tissues. The cytotoxicity of iNGR-modified doxorubicin-loaded liposomes (iNGR-SSL/DOX) on U87MG and HUVECs cells in vitro was significantly enhanced than that of unmodified doxorubicin-loaded liposomes (SSL/DOX). The iNGR-SSL/DOX also showed comparatively (p < 0.05) stronger cytotoxicity on tumor than SSL/DOX, which should be resulted from the increased tumor accumulation and penetration mediated by iNGR. This study proved that iNGR peptide modification might be an effective method to enhance the tumor penetrating ability of liposomes in tumor tissue and their antitumor effect.

Erythrocyte Membrane-Wrapped pH Sensitive Polymeric Nanoparticles for Non-Small Cell Lung Cancer Therapy

The application of nano drug delivery systems (NDDSs) may enhance the effectiveness of chemotherapeutic drugs in vivo. However, the short blood circulation time and poor drug release profile in vivo are still two problems with them. Herein, by using red blood cell membrane (RBCm) wrapping and pH sensitive technology, we prepared RBCm wrapped pH sensitive poly(l-γ-glutamylcarbocistein)-paclitaxel (PGSC-PTX) nanoparticles (PGSC-PTX@RBCm NPs), to prolong the circulation time in blood and release PTX timely and adequately in acidic tumor environment. The PGSC-PTX NPs and PGSC-PTX@RBCm NPs showed spherical morphology with average sizes about 50 and 100 nm, respectively. The cytotoxicity of PGSC-PTX@RBCm NPs was considerably decreased compared with that of PGSC-PTX NPs. PTX release from PGSC-PTX and PGSC-PTX@RBCm NPs at pH 6.5 was remarkably higher than those at pH 7.4, respectively. The PGSC-PTX@RBCm NPs exhibited remarkably decreased uptake by macrophages than PGSC-PTX NPs. The area under the curve within 72 h (AUC0-72h) for is significantly higher than PGSC-PTX NPs. The PGSC-PTX@RBCm NPs also showed significantly stronger growth-inhibiting effect on tumor than PGSC-PTX NPs. These results indicated that PGSC-PTX@RBCm NPs have acidic drug release sensitivity, the characteristics of long circulation, and remarkable tumor growth inhibiting effect. This study may provide an effective strategy for improving the antitumor effect of NDDS.

Tumor-penetrating Peptide Conjugated and Doxorubicin Loaded T1-T2 Dual Mode MRI Contrast Agents Nanoparticles for Tumor Theranostics

The conventional chemotherapeutics could not be traced in vivo and provide timely feedback on the clinical effectiveness of drugs. Methods: In this study, a tumor-penetrating peptide RGERPPR (RGE) modified, Gd-DTPA conjugated, and doxorubicin (DOX) loaded Fe3O4@SiO2@mSiO2 nanoparticle drug delivery system (Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs) was prepared for tumor theranostics. Results: The Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs showed a z-average hydrodynamic diameter of about 90 nm, and a pH-sensitive DOX release profile. The 3 T MRI results confirmed the relaxivity of the NPs (r1 = 6.13 mM-1S-1, r2 = 36.89 mM-1S-1). The in vitro cellular uptake and cytotoxicity assays on U87MG cells confirmed that the conjugation of RGERPPR played a significant role in increasing the cellular uptake and cytotoxicity of the NPs. The near-infrared fluorescence in vivo imaging results showed that the NPs could be significantly accumulated in the U87MG tumor tissue, which should result from the mediation of the tumor-penetrating peptide RGERPPR. The MRI results showed that the NPs offered a T1-T2 dual mode contrast imaging effect which would lead to a more precise diagnosis. Compared with unmodified NPs, the RGE-modified NPs showed significantly enhanced MR imaging signal in tumor tissue and antitumor effect, which should also be attributed to the tumor penetrating ability of RGERPPR peptide. Furthermore, the Hematoxylin and Eosin (H&E) staining and TUNEL assay proved that the NPs produced obvious cell apoptosis in tumor tissue. Conclusions: These results indicated that Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs are an effective targeted delivery system for tumor theranostics, and should have a potential value in the personalized treatment of tumor.

A Novel Gd-DTPA-conjugated Poly(L-γ-glutamyl-glutamine)-paclitaxel Polymeric Delivery System for Tumor Theranostics.

The conventional chemotherapeutics could not be traced in vivo and provide timely feedback on the clinical effectiveness of drugs. In this study, poly(L-γ-glutamyl-glutamine)-paclitaxel (PGG-PTX), as a model polymer, was chemically conjugated with Gd-DTPA (Gd-diethylenetriaminepentaacetic acid), a T1-contrast agent of MRI, to prepare a Gd-DTPA-conjugated PGG-PTX (PGG-PTX-DTPA-Gd) delivery system used for tumor theranostics. PGG-PTX-DTPA-Gd can be self-assembled to NPs in water with a z-average hydrodynamic diameter about 35.9 nm. The 3 T MRI results confirmed that the relaxivity of PGG-PTX-DTPA-Gd NPs (r1 = 18.98 mM−1S−1) was increased nearly 4.9 times compared with that of free Gd-DTPA (r1 = 3.87 mM−1S−1). The in vivo fluorescence imaging results showed that PGG-PTX-DTPA-Gd NPs could be accumulated in the tumor tissue of NCI-H460 lung cancer animal model by EPR effect, which was similar to PGG-PTX NPs. The MRI results showed that compared with free Gd-DTPA, PGG-PTX-DTPA-Gd NPs showed significantly enhanced and prolonged signal intensity in tumor tissue, which should be attributed to the increased relaxivity and tumor accumulation. PGG-PTX-DTPA-Gd NPs also showed effective antitumor effect in vivo. These results indicated that PGG-PTX-DTPA-Gd NPs are an effective delivery system for tumor theranostics, and should have a potential value in personalized treatment of tumor.

Hydrotropic polymer-based paclitaxel-loaded self-assembled nanoparticles: preparation and biological evaluation

The poor compatibility of carrier materials with drugs is one of the main obstacles in the drug encapsulation of nano-drug delivery system (NDDS), hindering the clinical translation of NDDS. In this study, using paclitaxel (PTX) as the insoluble model drug, we conjugated N,N-diethylniacinamide (DENA), a hydrotropic agent of PTX, to the backbone of poly(L-γ-glutamyl-glutamine) (PGG), a water-soluble polymer, to prepare the “hydrotropic polymer” PGG–DENA to improve its compatibility with PTX. By virtue of the hydrotropic effect of the DENA group, PTX was encapsulated by PGG–DENA to obtain the hydrotropic polymeric nanoparticles (PGG–DENA/PTX NPs). PTX-conjugated poly(L-γ-glutamyl-glutamine) acid (PGG–PTX) NPs previously reported were used as the control in the study. The PGG–DENA/PTX NPs showed a z-average hydrodynamic diameter of about 70 nm, and good long-term stability in PBS solution at 4 °C. The cumulative release rate of PTX from PGG–DENA/PTX NPs reached 79.10% at 96 h, while that of PGG–PTX NPs was 22.96%. PGG–DENA/PTX NPs showed significantly increased in vitro cytotoxicity on NCI-H460 lung cancer cells compared with PGG–PTX NPs. The hemolysis study proved that the PGG–DENA/PTX NPs has good biocompatibility. These results indicated that by introducing the hydrotropic agent DENA, the hydrotropic polymer PGG–DENA becomes an effective carrier material of PTX. This study provides a solution to increase the compatibility of carrier materials with insoluble drugs, and also may provide an effective way to develop a series of personalized carrier materials suitable for different insoluble drugs.

Poly (l-γ-glutamylglutamine) Polymer Enhances Doxorubicin Accumulation in Multidrug Resistant Breast Cancer Cells

Background: Drug resistance is one of the bottlenecks of cancer chemotherapy in the clinic. Polymeric nanomedicine is one of the most promising strategies for overcoming poor chemotherapy responses due to the multidrug resistance (MDR). Methods: In this study, a new polymer-based drug delivery system, poly (l-γ-glutamylglutamine)-doxorubicin (PGG-Dox) conjugate, was studied in both drug-induced resistant human breast cancer MDA-MB-231/MDR cells and their parent human breast cancer MDA-MB-231 cells. The effect of PGG on facilitating the growth inhibition of Dox against multidrug resistant cells were investigated by evaluating the cytotoxicity of PGG-Dox conjugate, PGG/Dox unconjugated complex and free Dox on both cells. The underlying mechanisms in resistant cells were further studied via the intracellular traffic studies. Results: Both conjugated and unconjugated PGG significantly increased Dox uptake, prolonged Dox retention and reduced Dox efflux in the MDA-MB-231/MDR cells. The PGG-Dox conjugate is taken up by tumor cells mainly by pinocytosis pathway, in which PGG-Dox conjugate-containing vesicles are formed and enter the cells. Conclusions: This study indicated that both polymer-drug conjugate and unconjugated complex are promising strategies of overcoming resistance of anti-tumor drugs.

pPB peptide-mediated siRNA-loaded stable nucleic acid lipid nanoparticles on targeting therapy of hepatic fibrosis

Hepatic fibrosis is a necessary process in the development of liver diseases such as hepatic cirrhosis and its complications, which has become a serious threat to human health. Currently, antifibrotic drug treatment is ineffective, and one reason should be the lack of liver targeting ability. In this report, polypeptide pPB-modified stable nucleic acid lipid nanoparticles (pPB-SNALPs) were prepared to selectively deliver siRNAs against heat shock protein 47 to the liver for targeted therapy of hepatic fibrosis. First, siRNA sequences with high silencing efficiency were screened based on siRNA transfection efficacy. Then, pPB-SNALPs were prepared, which showed a narrow size distribution with a diameter in the range of 110-130 nm and a neutral z-potential of 0 mV. As evidenced by the in vitro and in vivo targeting study, compared with unmodified SNALP, pPB-SNALP showed increased uptake by LX-2 cells and primary hepatic stellate cells (HSC) of mice in vitro and showed increased liver distribution and HSC uptake in vivo. In addition, pPB-SNALP also exhibited an enhanced inhibitory effect on TAA-induced hepatic fibrosis mice with high gp46 mRNA expression in vivo. In summary, our results demonstrated that pPB-SNALP is an effective liver-targeted delivery system. This study could lay a good foundation for the targeted gene therapy of hepatic fibrosis.