[Show abstract][Hide abstract] ABSTRACT: Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications.
[Show abstract][Hide abstract] ABSTRACT: Breast cancer has been considered as a serious threat to females' life. Active targeting drug delivery is a potential strategy in cancer therapy, which however is hindered by the targeting efficiency. Herein, a 14-mer peptide (TKD) derived from the oligomerization domain of membrane heat-shock protein 70 (memHsp70), for the first time, was exploited as a tumor-targeting ligand to modify polymeric micelles. NMR results demonstrated the successful synthesis of TKD-PEG-PLGA polymer. No difference was observed in the drug release between TKD-modified doxorubicin (DOX)-loaded micelles (TKD-D-M) and unmodified counterparts. The modification of TKD mediated apparently higher cellular uptake within memHsp70-positive MCF-7 cells, compared to normal MCF-10A cells. Excessive TKD pretreatment significantly inhibited the cellular uptake of TKD-D-M, indicating the receptor-mediated mechanism. Enhanced accumulation of TKD-D-M within the tumor of MCF-7 bearing mice further demonstrated the targeting ability of TKD in vivo. CCK-8 assay showed that the modification of TKD significantly increase the anti-proliferation effect against MCF-7 cells. The findings demonstrated that TKD peptide is a potential ligand which can target drug delivery systems to memHsp70-positive breast cancer.
No preview · Article · Dec 2015 · International Journal of Pharmaceutics
[Show abstract][Hide abstract] ABSTRACT: Multiple diagnosis of cancer by a facile fluorescent sensor is extremely attractive. Herein, a Cy3-labeled ssDNA probe (P0-Cy3) was π-π stacked on the surface of oxidized mesoporous carbon nanospheres (OMCN) to construct the fluorescent "turn-on" aptasensor. Attributing to the intrinsic properties of OMCN, the OMCN-based aptasensor can not only be used to detect mucin1 protein in liquid with a wide range of 0.1 - 10.6 μmol/L, a low detection limit of 6.52 nmol/L, and good selectivity, but also can quantify the cancer cells in solution with the linear range of 104 - 2 × 106 cells/mL and a detection limit of 8,500 cells/mL. Fascinatingly, this OMCN-based aptasensor was exploited to image cancer via solid tissues such as cells, tissue sections, ex vivo and in vivo tumors, in which the obvious distinguishability between cancer and normal tissues was clearly demonstrated. This is a robust and simple detection technique, which can well achieve the multiple diagnosis of cancer in vitro and in vivo.
[Show abstract][Hide abstract] ABSTRACT: Tumor site-directed multifunctional therapeutic platforms such as photothermochemotherapy which respond to tumor-focused physical and biological stimuli are highly demanded for effective cancer therapy. Herein, targeting peptide-conjugated core-shell graphitic carbon@silica nanospheres with dual-ordered mesopores (MMPS) were successfully fabricated and developed as antitumoral doxorubicin (DOX) delivery system (MMPSD) for synergistic targeted photothermal chemotherapy of breast cancer. The hydrophilic mesoporous silica shell guarantees good water dispersity of MMPSD. The hydrophobic-graphitic mesoporous carbon core provides excellent hydrophobic drug loading, immediate contact between the drug and photothermal hotspots, and high NIR photothermal conversion efficiency. SP13 peptide facilitates MMPSD for targeted and enhanced delivery of DOX within HER2-positive SK-BR-3 breast cancer cells, while PEGylation ensures the biocompatibility. Thus, the MMPSD system exhibited efficient drug loading capacity, high targeting ability, sensitive NIR/pH-responsive DOX release, sustained release and excellent combined antitumor activity.
[Show abstract][Hide abstract] ABSTRACT: A general strategy is developed for dual-triggered chemo-photothermal tumor therapy based on template semi-graphitized mesoporous silica nanoparticles (TsGMSN). The strategy endues classic MSN with new charming properties, while easily escaping from toxicity of the surfactant. The doxorubicin-loaded system (TsGMSND) exhibits synergistic heat-stimulative, pH-responsive, and sustained release, and effective combined tumor therapy.
[Show abstract][Hide abstract] ABSTRACT: Targeting peptide-modified magnetic graphene-based mesoporous silica (MGMSPI) are synthesized, characterized, and developed as a multifunctional theranostic platform. This system exhibits many merits, such as biocompatibility, high near-infrared photothermal heating, facile magnetic separation, large T2 relaxation rates (r2), and a high doxorubicin (DOX) loading capacity. In vitro and in vivo results demonstrate that DOX-loaded MGMSPI (MGMSPID) can integrate magnetic resonance imaging, dual-targeting recognition (magnetic targeting and receptor-mediated active targeting), and chemo-photothermal therapy into a single system for a visualized-synergistic therapy of glioma. In addition, it is observed that the MGMSPID system has heat-stimulated, pH-responsive, sustained release properties. All of these characteristics would provide a robust multifunctional theranostic platform for visualized glioma therapy.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson's disease (PD).
Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations.
The successful synthesis of DPA was demonstrated via (1)H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119 ± 12 nm and zeta potential of 8.2 ± 0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups.
This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.
No preview · Article · May 2013 · Pharmaceutical Research
[Show abstract][Hide abstract] ABSTRACT: Current therapy of malignant glioma in clinic is unsatisfactory with poor patient compliance due to low therapeutic efficiency and strong systemic side effects. Herein, we combined chemo-photothermal targeted therapy of glioma within one novel multifunctional drug delivery system. A targeting peptide (IP)-modified mesoporous silica-coated graphene nanosheet (GSPI) was successfully synthesized and characterized, and first introduced to the drug delivery field. A doxorubicin (DOX)-loaded GSPI-based system (GSPID) showed heat-stimulative, pH-responsive, and sustained release properties. Cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of glioma cells compared to that of single chemotherapy or photothermal therapy. Furthermore, the IP modification could significantly enhance the accumulation of GSPID within glioma cells. These findings provided an excellent drug delivery system for combined therapy of glioma due to the advanced chemo-photothermal synergistic targeted therapy and good drug release properties of GSPID, which could effectively avoid frequent and invasive dosing and improve patient compliance.
No preview · Article · Mar 2013 · Journal of the American Chemical Society
[Show abstract][Hide abstract] ABSTRACT: Receptor-mediated delivery of hydrophobic antitumor drugs is of great interest in chemotherapy of tumors such as glioma. Specific expression of interleukin-13 (IL-13) receptor has been characterized in glioma. In this work, a specific peptide corresponding to the residues within IL-13 protein, designated as IP, was exploited, for the first time, as a glioma-targeting ligand. IP was conjugated to mesoporous silica nanoparticles (MSN) via bifunctional polyethyleneglycol (PEG), constructing the vector MSN–PEG–IP. The successful synthesis of MSN–PEG–IP was demonstrated via Fourier transform infrared spectroscopy. The transmission electron microscopy result showed that the size of MSN–PEG–IP was about 160 nm with an average pore diameter of around 2.6 nm. The cellular uptake of doxorubicin (DOX)-loading IP-modified system (MSN–PEG–IP/DOX) was concentration-dependent in glioma U251 cells. IP modification could significantly enhance the cellular uptake of the drug delivery system in U251 cells but not in normal astrocyte 1800 cells, compared to unmodified counterparts. This effect was further verified by cytotoxicity analysis. Furthermore, the intracellular trafficking result indicated that the loaded DOX was mostly accumulated in nuclei, even at very short incubation time (5 min). All the results suggested that IP could be applied as a special glioma-targeting ligand, and MSN–PEG–IP is a potential vector for delivering hydrophobic chemotherapeutic drugs to IL-13 receptor-overexpressed tumors.
No preview · Article · Jul 2012 · Journal of Materials Chemistry
[Show abstract][Hide abstract] ABSTRACT: The combination of gene therapy and chemotherapy is a promising treatment strategy for brain gliomas. In this paper, we designed a co-delivery system (DGDPT/pORF-hTRAIL) loading chemotherapeutic drug doxorubicin and gene agent pORF-hTRAIL, and with functions of pH-trigger and cancer targeting. Peptide HAIYPRH (T7), a transferrin receptor-speciﬁc peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. T7-modiﬁed co-delivery system showed higher efﬁciency in cellular uptake and gene expression than unmodiﬁed co-delivery system in U87 MG cells, and accumulated in tumor more efﬁciently in vivo. DOX was covalently conjugated to carrier though pH-trigged hydrazone bond. In vitro incubation of the conjugates in buffers led to a fast DOX release at pH 5.0 (intracellular environment) while at pH 7.4 (blood) the conjugates are relatively stable. The combination treatment resulted in a synergistic growth inhibition (combination index, CI < 1) in U87 MG cells. The synergism effect of DGDPT/pORF-hTRAIL was verified in vitro and in vivo. In vivo anti-glioma efﬁcacy study confirmed that DGDPT/pORF-hTRAIL displayed anti-glioma activity but was less toxic.
[Show abstract][Hide abstract] ABSTRACT: The choline transporter (ChT) is used to transport choline-derivate-modified nanoparticles across the blood-brain barrier. It is demonstrated that ChT is an ideal Trojan horse. The choline-derivate-modified nanoparticles exhibit higher permeability across the brain capillary endothelial cells (BCECs) monolayer in vitro and higher gene distribution and expression in vivo.
Full-text · Article · Oct 2011 · Advanced Materials
[Show abstract][Hide abstract] ABSTRACT: Clinical diagnosis of cancers using magnetic resonance imaging (MRI) is highly dependent on contrast agents, especially for brain tumors which contain blood-brain barrier (BBB) at the early stage. However, currently mostly used low molecular weight contrast agents such as Gd-DTPA suffer from rapid renal clearance, non-specificity, and low contrast efficiency. The aim of this paper is to investigate the potential of a macromolecular MRI contrast agent based on dendrigraft poly-l-lysines (DGLs), using chlorotoxin (CTX) as a tumor-specific ligand. The contrast agent using CTX-modified conjugate as the main scaffold and Gd-DTPA as the payload was successfully synthesized. The results of fluorescent microscopy showed that the modification of CTX could markedly enhance the cellular uptake in C6 glioma and liver tumor cell lines, but not in normal cell line. Significantly increased accumulation of CTX-modified conjugate within glioma and liver tumor was further demonstrated in tumor-bearing nude mice using in vivo imaging system. The MRI results showed that the signal enhancement of mice treated with CTX-modified contrast reached peak level at 5 min for both glioma and liver tumor, 144.97% ± 19.54% and 158.69% ± 12.41%, respectively, significantly higher than that of unmodified counterpart and commercial control. And most importantly, the signal enhancement of CTX-modified contrast agent maintained much longer compared to that of controls, which might be useful for more exact diagnosis for tumors. CTX-modified dendrimer-based conjugate might be applied as an efficient MRI contrast agent for targeted and accurate tumor diagnosis. This finding is especially important for tumors such as brain glioma which is known hard to be diagnosed due to the presence of BBB.
[Show abstract][Hide abstract] ABSTRACT: Gene therapy offers a promising cure of brain glioma and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to induce cell apoptosis of glioma selectively without affecting the normal cells. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the principal vector. Angiopep-2, which can target to the low-density lipoprotein receptor-related protein-1 (LRP1) expressed on BCECs and glial cells, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG) and then complexed with the DNA, designated as PAMAM-PEG-Angiopep/DNA nanoparticles (NPs). The cellular uptake mechanism explored in glial cells showed that the DNA of PAMAM-PEG-Angiopep/DNA NPs entered into the nuclei through the endosome/lysosome pathway. The in vivo biodistribution of PAMAM-PEG-Angiopep/DNA NPs in the brain especially the tumor site was higher than that of PAMAM-PEG/DNA NPs and PAMAM/DNA NPs. Furthermore, the TUNEL analysis showed a more wide-extended apoptosis in the PAMAM-PEG-Angiopep/pORF-TRAIL NPs treated group, compared to other groups including commercial Temozolomide-treated one. The median survival time of PAMAM-PEG-Angiopep/pORF-TRAIL NPs and Temozolomide treated on brain tumor-bearing mice was 61 and 49 days respectively, significantly longer than that of other groups. Besides, the NPs suggested low cytotoxicity after in vitro transfection. Thus, the results showed that Angiopep-2 could be exploited as a specific ligand to cross the BBB and targeted to glial cells, and PAMAM-PEG-Angiopep/DNA NPs can be a potential non-viral delivery system for gene therapy of glial tumor.
[Show abstract][Hide abstract] ABSTRACT: A tumor-targeting carrier, peptide HAIYPRH (T7)-conjugated polyethylene glycol-modified polyamidoamine dendrimer (PAMAM-PEG-T7) was explored to deliver magnetic resonance imaging (MRI) contrast agents targeting to the tumor cells specifically. Two different types of tumors, liver cancer and early brain glioma model (involved with the blood-brain barrier), were chosen to evaluate the imaging capacity of this contrast agent. PAMAM-PEG-T7 was synthesized, conjugated with diethylene triamine pentaacetic acid (DTPA) and further chelated gadolinium (Gd), yielding GdDTPA-PAMAM-PEG-T7. The result of ICP-AES showed that about 92 Gd ions could be loaded per PAMAM molecule. The calculated longitudinal relaxivity R1 of the GdDTPA-PAMAM-PEG-T7 was 10.7 mm(-1) S(-1) per Gd (984.4 mm(-1) S(-1) per PAMAM), while that of GdDTPA was only 4.8 mm(-1) S(-1). PAMAM-PEG-T7 had better targeting capacity to the liver cancer cells in vitro and in vivo, compared with PAMAM-PEG. The accumulation of PAMAM-PEG-T7 was 162.5% times that of PAMAM-PEG. But for glioma cells, PAMAM-PEG-T7 did not show its specificity. Furthermore, GdDTPA-PAMAM-PEG-T7 could improve the diagnostic efficiency of liver cancer with the enhanced signal (187%), compared to 130% for PAMAM-PEG and 121% for GdDTPA. GdDTPA-PAMAM-PEG-T7 could selectively identify liver cancer but not early glioma. This nanoscaled MRI contrast agent GdDTPA-PAMAM-PEG-T7 might allow for selective and efficient diagnosis of tumors without the natural barrier including liver cancer.
[Show abstract][Hide abstract] ABSTRACT: Gene therapy offers great potential for brain glioma. However, therapeutic genes could not reach glioma spontaneously. A glioma-targeting gene delivery system is highly desired to transfer exogenous genes throughout the tumor focus. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the main vector. Chlorotoxin (CTX), which has been demonstrated to bind specifically to receptor expressed in glioma, was exploited as the targeting ligand to conjugate PAMAM via bifunctional polyethyleneglycol (PEG), yielding PAMAM-PEG-CTX. The cellular uptake of CTX itself was observed apparently in C6 glioma cells, almost not in 293 cells. The modification of CTX could significantly increase the cellular uptake of vectors and the DNA-loaded nanoparticles (NPs) in C6 cells. The in vivo distribution of PAMAM-PEG-CTX/DNA NPs in the brain was higher than that of PAMAM/DNA NPs and PAMAM-PEG/DNA NPs. Furthermore, the gene expression of PAMAM-PEG-CTX/DNA NPs was higher and broader in glioma than that of unmodified and PEG-modified counterparts. The TUNEL analysis showed a more wide-extended apoptosis in the CTX-modified group, compared to other groups including commercial temozolomide group. The median survival time of CTX-modified group and temozolomide group was 59.5 and 49 days, respectively, significantly longer than that of other groups. The results suggested that CTX could be exploited as a special glioma-targeting ligand, and PAMAM-PEG-CTX/DNA NPs is a potential non-viral delivery system for gene therapy of glioma via intravenous administration.
[Show abstract][Hide abstract] ABSTRACT: The blood-brain barrier (BBB) exerts its central nervous system (CNS) protective function as it hinders the delivery of diagnostic and therapeutic agents to the brain. Gene therapy could be applied in conquering brain diseases such as neurodegenerative diseases and brain tumors by up- or down-regulating expression of diseased proteins. With the development of nanotechnology during the last thirty years, the nanocarriers for delivering drugs including gene medicines make it possible to transport drugs across the BBB. The nonviral nano-scaled gene delivery systems hold great promise for treating brain diseases due to their safety and convenience. Several brain targeting strategies, such as adsorptive- and receptor-mediated pathways have been developed to improve the brain targeting efficiency of non-viral gene delivery systems. In this review, the non-viral nanocarriers are focused for gene delivery and several possible strategies are discussed to achieve brain targeting effects. Finally, the applications of gene therapy in several brain diseases will be introduced.
No preview · Article · Jan 2011 · Current Nanoscience
[Show abstract][Hide abstract] ABSTRACT: The purpose of this work was to evaluate the potential of HAIYPRH (T7) peptide as a ligand for constructing tumor-targeting drug delivery systems. T7 could target to transferrin-receptor (TfR) through a cavity on the surface of TfR and then transport into cells via endocytosis with the help of transferrin (Tf). In this study, T7-conjugated poly(ethylene glycol) (PEG)-modified polyamidoamine dendrimer (PAMAM) (PAMAM-PEG-T7) was successfully synthesized and further loaded with doxorubicin (DOX), formulating PAMAM-PEG-T7/DOX nanoparticles (NPs). In vitro, almost 100% of DOX was released during 2 h in pH 5.5, while only 55% of DOX was released over 48 h in pH 7.4. The cellular uptake of DOX could be significantly enhanced when treated with T7-modified NPs in the presence of Tf. Also, the in vitro antitumor effect was enhanced markedly. The IC(50) of PAMAM-PEG-T7/DOX NPs with Tf was 231.5 nM, while that of NPs without Tf was 676.7 nM. T7-modified NPs could significantly enhance DOX accumulation in the tumor by approximately 1.7-fold compared to that of unmodified ones and by approximately 5.3-fold compared to that of free DOX. For in vivo antitumor studies, tumor growth of mice treated with PAMAM-PEG-T7/DOX NPs was significantly inhibited compared to that of mice treated with PAMAM-PEG/DOX NPs and saline. The study provides evidence that PAMAM-PEG-T7 can be applied as a potential tumor-targeting drug delivery system. T7 may be a promising ligand for targeted drug delivery to the tumor.
Full-text · Article · Dec 2010 · Molecular Pharmaceutics