Dual-targeting Drug Research Articles

Cell-activatable CdSe fluorescence probe for dual-targeted imaging and drug application

A novel doxorubicin-quantum dots-folate nanoconjugate with activatable fluorescence and cytotoxicity was prepared and used as a fluorescence probe for the targeted imaging of cancer cells. After the targeted folate receptor induced the intracellular uptake of the nanoconjugate and glutathione-mediated dissociation, the nanoconjugate became activated, showing enhanced fluorescence and cellular toxicity within the cell.

Quantitative control of active targeting of nanocarriers to tumor cells through optimization of folate ligand density

The active targeting delivery system has been widely studied in cancer therapy by utilizing folate (FA) ligands to generate specific interaction between nanocarriers and folate receptors (FRs) on tumor cell. However, there is little work that has been published to investigate the influence of the definite density of the FA ligands on the active targeting of nanocarriers. In this study, we have combined magnetic-guided iron oxide nanoparticles with FA ligands, adjusted the FA ligand density and then studied the resulting effects on the active targeting ability of this dual-targeting drug delivery system to tumor cells. We have also optimized the FA ligand density of the drug delivery system for their active targeting to FR-overexpressing tumor cells in vitro. Prussian blue staining, semi-thin section of cells observed with transmission electron microscopy (TEM) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) have shown that the optimal FA density is from 2.3 × 1018 to 2.5 × 1018 per gram nanoparticles ((g·NPs)−1). We have further tried to qualitatively and quantitatively control the active targeting and delivering of drugs to tumors on 4T1-bearing BALB/c mice. As expected, the in vivo experimental results have also demonstrated that the FA density of the magnetic nanoparticles (MNPs) could be optimized for a more easily binding to tumor cells via the multivalent linkages and more readily internalization through the FR-mediated endocytosis. Our study can provide a strategy to quantitatively control the active targeting of nanocarriers to tumor cells for cancer therapy.

Magnetic Fe3O4 nanoparticles grafted with single-chain antibody (scFv) and docetaxel loaded β-cyclodextrin potential for ovarian cancer dual-targeting therapy

In order to improve the therapeutic efficiency and reduce the side effects on nonpathological cells and tissues, targeting drug delivery systems have gained more and more attraction. Here, we report a novel dual-targeting drug delivery system for ovarian cancer therapy. The inner core was made of iron oxide (Fe3O4) nanoparticles, synthesized by co-precipitation method. It was further surface-functionalized with amine groups to link single-chain antibody (scFv) and β-cyclodextrin (β-CD). Docetaxel (TXT) was finally included in the grafted β-CD. FTIR and XPS confirmed the reactions. SEM found that the diameters of these Fe3O4 nanoparticles before and after functionalization were around 40nm. Magnetization test showed that these particles were superparamagnetic. The in vitro release of TXT was concentration-driven and sustained, depending on the renewal rate of release medium. The in vitro flow chamber experiment revealed its magnetic targeting property; modified ELISA and static binding experiments displayed its good affinity to Endoglin, indicating that our drug delivery system has the potential to be dual-targeted to ovarian cancer tissue by externally applied magnetic field and native active binding of grafted scFv to Endoglin, overexpressed by ovarian cancer tissue. MTT assays showed that the TXT released from this drug delivery system continuously inhibited the growth of Skov3 ovarian cancer cells in 72h, better than the control raw TXT. All these results demonstrated a promising dual-targeting drug delivery system with great potential for ovarian cancer therapy.

Procognitive properties of drugs with single and multitargeting H3 receptor antagonist activities.

The histamine H3 receptor (H3 R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3 R antagonists/inverse agonists involved studies of structure-activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoreceptors reinforces histaminergic transmission, while antagonism of H3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3 R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3 R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3 R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3 R antagonists/inverse agonists and dual H3 R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.

Lactoferrin-Modified Poly(ethylene glycol)-Grafted BSA Nanoparticles as a Dual-Targeting Carrier for Treating Brain Gliomas

In this study, a dual-targeting drug delivery system based on bovine serum albumin nanoparticles (BSA-NPs) modified with both lactoferrin (Lf) and mPEG2000 loading doxorubicin (DOX) was designed, and its blood-brain barrier (BBB) penetration and brain glioma cells targeting properties were explored. BSA-NPs were prepared by a desolvation technique, and mPEG2000 was incorporated onto the surface of BSA-NPs by reacting with the free amino-group of BSA to form mPEG2000-modified BSA-NPs (P2000-NPs). Finally, Lf-modified P2000-NPs (Lf-NPs) was obtained by absorbing Lf onto the surface of P2000-NPs via the positive and negative charges interaction at physiological pH. Three levels of mPEG2000 and Lf-modified NPs were prepared and characterized, respectively. The uptake and potential cytotoxicity of different DOX preparations in vitro by the primary brain capillary endothelial cells (BCECs) and glioma cells (C6) were investigated. The dual-targeting effects were studied on the BBB model in vitro, BCECs/C6 glioma coculture model in vitro, and C6 glioma-bearing rats in vivo, respectively. The results exhibited that, with the increase of the amount of both mPEG2000 and Lf, the particle size of NPs increased and its zeta potential decreased. The in vivo pharmacokinetics study in healthy rats exhibited that P2000-NPs with a high level of mPEG2000 (P2000H-NPs) had longer circulation time in vivo. Compared to other NPs, Lf-NPs with high level of both Lf and mPEG2000 (LfH-NPs) showed the strongest cytotoxicity and the highest effectiveness in the uptake both in BCECs and C6 as well as improved the dual-targeting effects. Body distribution of DOX in different formulations revealed that LfH-NPs could significantly increase the accumulation of DOX in the brain, especially at 2 h postinjection (P < 0.05). In conclusion, Lf-NPs were a prospective dual-targeting drug delivery system for effective targeting therapy of brain gliomas.

In silico polypharmacology: retrospective recognition vs. rational design.

The „one drug – one target – one disease“ paradigm in drug discovery has been reconsidered during the last decade. This paradigm change was mainly caused by high attrition rates in drug approvals due to toxicity and lack of efficacy. Computational techniques play an important role in prediction and recognition of novel targets for approved drugs. We will discuss two machine learning approaches – self organizing maps and inverse distance weighting – for polypharmacological profiling of bioactive compounds, exemplified by two prospective studies [1,2]. While the recognition of occasional polypharmacological behavior is an established task, the rational design of multitarget ligands remains challenging. Dual or multi-target ligands have several advantages compared with selective compounds, including improved efficacy and more simple pharmacokinetic and pharmacodynamic properties in comparison to the combination of several drugs. In this context we present two in silico approaches to design dual inhibitors of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH). The first study contains the discovery of a benzimidazole-based dual 5-LO/sEH inhibitor by means of in silico screening [3]. The strategy of the virtual screening protocol was an exhaustive pairwise evaluation of pharmacophore models for both targets to obtain a dual-target pharmacophore model. Our second study deals with the development of a fragment based strategy for dual-target drug discovery. Here, we applied a modified self-organizing map algorithm for in silico recognition of molecular fragments binding both targets. The predicted properties were confirmed by complementary screening techniques: STD-NMR and enzyme assay. The enlargement of the fragment hit led to submicromolar dual target inhibitor of sEH and 5-LO.[4]

115: Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation and doxorubicin treatment: a new concept of dual targeting drugs

115: Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation and doxorubicin treatment: a new concept of dual targeting drugs

Study and evaluation of mechanisms of dual targeting drug delivery system with tumor microenvironment assays compared with normal assays

A dual targeting delivery system was developed to completely conquer the two barriers that glioma treatment faces: the blood–brain barrier (BBB) and the brain–glioma barrier. Recently, a system comprising AS1411 aptamer (for glioma targeting) and TGN peptide (for BBB targeting) modified nanoparticles (AsTNPs) was developed, which can effectively target brain glioma and improve the survival of glioma-bearing mice. However, the in vitro models currently used are far too different from the in vivo tumor microenvironment that the glioma targeting delivery system actually faces. In this study, the pharmacology mechanisms of AsTNPs were explored in several models that imitated the tumor microenvironment. AsTNPs can be selectively taken up by endothelial and glioma cells, effectively penetrating the BBB and brain–glioma barriers to reach glioma cells and display their anti-glioma effect. The cell monolayers, tumor spheroids and coculture systems were more suitable in vitro models for the pharmacology evaluation of targeted drug delivery systems.

Nanoparticles of 2-deoxy-d-glucose functionalized poly(ethylene glycol)-co-poly(trimethylene carbonate) for dual-targeted drug delivery in glioma treatment

Based on the facilitative glucose transporter (GLUT) over-expression on both blood–brain barrier (BBB) and glioma cells, 2-deoxy-d-glucose modified poly(ethylene glycol)-co-poly(trimethylene carbonate) nanoparticles (dGlu–NP) were developed as a potential dual-targeted drug delivery system for enhancing the BBB penetration via GLUT-mediated transcytosis and improving the drug accumulation in the glioma via GLUT-mediated endocytosis. In vitro physicochemical characterization of the dual-targeted nanoparticulate system presented satisfactory size of 71 nm with uniform distribution, high encapsulation efficiency and adequate loading capacity of paclitaxel (PTX). Compared with non-glucosylated nanoparticles (NP), a significantly higher amount of dGlu–NP was internalized by RG-2 glioma cells through caveolae-mediated and clathrin-mediated endocytosis. Both of the transport ratios across the in vitro BBB model and the cytotoxicity of RG-2 cells after crossing the BBB were significantly greater of dGlu–NP/PTX than that of NP/PTX. In vivo fluorescent image indicated that dGlu–NP had high specificity and efficiency in intracranial tumor accumulation. The anti-glioblastoma efficacy of dGlu–NP/PTX was significantly enhanced in comparison with that of Taxol and NP/PTX. Preliminary safety tests showed no acute toxicity to hematological system, liver, kidney, heart, lung and spleen in mice after intravenous administration at a dose of 100 mg/kg blank dGlu–NP per day for a week. Therefore, these results indicated that dGlu–NP developed in this study could be a potential dual-targeted vehicle for brain glioma therapy.

CGKRK-modified nanoparticles for dual-targeting drug delivery to tumor cells and angiogenic blood vessels

Antiangiogenic therapy shows great advantages in clinical cancer treatment while no overall survival has been achieved. The compromised results were mainly contributed by intrinsic/acquired antiangiogenic drug resistance and increased local invasion or distant metastasis after antiangiogenic therapy. Here we constructed a CGKRK peptide-modified PEG-co-PCL nanoparticulate drug delivery system (DDS), aiming at targeting both tumor angiogenic blood vessels and tumor cells to achieve enhanced anti-tumor activity as well as holding a great potential to overcome the drawbacks of antiangiogenic therapy alone. The obtained CGKRK-functionalized PEG-co-PCL nanoparticles (CGKRK-NP) with a particle size of 117.28 ± 10.42 nm and zeta potential of −15.7 ± 3.32 mV, exhibited an enhanced accumulation via an energy-dependent, lipid raft/caveolae-mediated endocytosis with the involvement of microtubules in human umbilical vein endothelial cells (HUVEC) and an energy-dependent, lipid raft/caveolae-mediated endocytosis with the participation of Golgi apparatus in human U87MG cells. Using coumarin-6 as the fluorescence probe, in vitro U87MG tumor spheroids assays showed that CGKRK-NP effectively penetrated into the tumor spheroids. Selective accumulation and extensive bio-distribution of CGKRK-NP at tumor site was confirmed by in vivo imaging and tumor section analysis. After drug loading, CGKRK-NP enhanced cytotoxicity and apoptosis induction activity of the loaded PTX on both HUVEC cells and U87MG cells and improved its inhibition effect on the growth of U87MG tumor spheroids. The smallest tumor volume was achieved by those mice bearing subcutaneous U87MG tumor following the treatment of PTX-loaded CGKRK-NP. The findings here indicated that CGKRK peptide-functionalized nanoparticulate DDS could be used as an effective tumor angiogenic blood vessels and tumor cells dual-targeting DDS and might provide a great promising approach for reducing the disadvantages of antiangiogenic therapy alone.

Src Family Kinases as Novel Therapeutic Targets to Treat Breast Cancer Brain Metastases

Despite better control of early-stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens can treat HER2(+) brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients' brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood-brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, an Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells through the induction of cell-cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat patients with breast cancer suffering from brain metastasis.

LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma

Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetrate the blood–brain barrier (BBB) and non-selective drug accumulation in the entire brain. To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP–PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP–PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&E staining showed that PNP–PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. Taken together, these promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.

Dual-targeting Janus Dendrimer Based Peptides for Bone Cancer: Synthesis and Preliminary Biological Evaluation

The development of dual-targeting drug delivery system is helpful to overcome the poor physiochemical properties of chemotherapeutic agents. The RGD sequence has a potential dual-targeting property, with which the chemotherapeutic agents can be delivered to bone tissue and tumor. And the Janus dendrimer which consists of two dendrons with different tasks is useful for improving the effect of polymer on pharmacokinetic properties. In this paper, a Janustype peptide dendrimer which consisted of RGD dimer and 5-FU dimer was synthesized and well characterized by 1H NMR and MS techniques, as well as the other three compounds for contrast. The hydroxyapatite binding assay and drug release study were evaluated. The Janus-type dendrimer with both enhanced targeting property and optimized release property, may reduce the side effects in normal tissues and have potential sustained-release effect. Thus, it may represent a novel opportunity to apply the versatile Janus-type dual-targeting delivery system to applications in bone tumor treatment. Keywords: Bone cancer, dual-targeting, hydroxyapatite, in vitro, Janus dendrimer, peptide, RGD.

Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: A new concept of dual targeting drugs

Background and purposeCarbonic anhydrase IX (CAIX) plays an important role in pH regulation processes critical for tumor cell growth and metastasis. We hypothesize that a dual targeting bioreductive nitroimidazole based anti-CAIX sulfamide drug (DH348) will reduce tumor growth and sensitize tumors to irradiation in a CAIX dependent manner. Material and methodsThe effect of the dual targeting anti-CAIX (DH348) and its single targeting control drugs on extracellular acidification and radiosensitivity was examined in HT-29 colorectal carcinoma cells. Tumor growth and time to reach 4× start volume (T4×SV) was monitored for animals receiving DH348 (10mg/kg) combined with tumor single dose irradiation (10Gy). ResultsIn vitro, DH348 reduced hypoxia-induced extracellular acidosis, but did not change hypoxic radiosensitivity. In vivo, DH348 monotherapy decreased tumor growth rate and sensitized tumors to radiation (enhancement ratio 1.50) without systemic toxicity only for CAIX expressing tumors. ConclusionsA newly designed nitroimidazole and sulfamide dual targeting drug reduces hypoxic extracellular acidification, slows down tumor growth at nontoxic doses and sensitizes tumors to irradiation all in a CAIX dependent manner, suggesting no “off-target” effects. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting.

An innovative strategy for dual inhibitor design and its application in dual inhibition of human thymidylate synthase and dihydrofolate reductase enzymes.

Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases. Nevertheless, to design multitarget inhibitors is concurrently a great challenge for medicinal chemists. We have developed a novel computational approach by integrating the affinity predictions from structure-based virtual screening with dual ligand-based pharmacophore to discover potential dual inhibitors of human Thymidylate synthase (hTS) and human dihydrofolate reductase (hDHFR). These are the key enzymes in folate metabolic pathway that is necessary for the biosynthesis of RNA, DNA, and protein. Their inhibition has found clinical utility as antitumor, antimicrobial, and antiprotozoal agents. A druglike database was utilized to perform dual-target docking studies. Hits identified through docking experiments were mapped over a dual pharmacophore which was developed from experimentally known dual inhibitors of hTS and hDHFR. Pharmacophore mapping procedure helped us in eliminating the compounds which do not possess basic chemical features necessary for dual inhibition. Finally, three structurally diverse hit compounds that showed key interactions at both active sites, mapped well upon the dual pharmacophore, and exhibited lowest binding energies were regarded as possible dual inhibitors of hTS and hDHFR. Furthermore, optimization studies were performed for final dual hit compound and eight optimized dual hits demonstrating excellent binding features at target systems were also regarded as possible dual inhibitors of hTS and hDHFR. In general, the strategy used in the current study could be a promising computational approach and may be generally applicable to other dual target drug designs.

Fabrication and characterization of a triple functionalization of graphene oxide with Fe3O4, folic acid and doxorubicin as dual-targeted drug nanocarrier

A novel triple functionalized drug delivery system was synthesized by encapsulation of superparamagnetic graphene oxide (GO) and doxorubicin (DOX) with folic acid (FA) conjugated chitosan (CHI). The carrier exhibited a high loading efficiency (0.98mg/mg), a high saturation magnetization (10.5emu/g) and a prolonged release rate. A real-time monitoring method on the drug release from graphene oxide (GO) was reported using DOX as the model drug. The release mechanism of DOX at different pH was investigated via monitoring the time dependency of the accumulative drug release. Results show that the drug release of DOX was pH sensitive as observed at pH 5.3 and pH 7.4 PBS solutions, the lower pH values lead to weaker hydrogen bonds and degradation of CHI, and thus result in a higher release rate of DOX. Especially, this system could be applied as a dual-targeted drug nanocarrier by combined biological (active) and magnetical (passive) targeting capabilities. Our research suggests that a novel triple functionalized, pH-responsive nanocarrier for anticancer drug has been synthesized.

Quantum Dots Conjugated with Fe3O4-Filled Carbon Nanotubes for Cancer-Targeted Imaging and Magnetically Guided Drug Delivery

A novel and specific nanoplatform for in vitro simultaneous cancer-targeted optical imaging and magnetically guided drug delivery is developed by conjugating CdTe quantum dots with Fe(3)O(4)-filled carbon nanotubes (CNTs) for the first time. Fe(3)O(4) is filled into the interior of the CNTs, which facilitates magnetically guided delivery and improves the synergetic targeting efficiency. In comparison with that immobilized on the external surface of CNTs, the magnetite nanocrystals inside the CNTs protect it from agglomeration, enhance its chemical stability, and improve the drug loading capacity. It also avoids magnetic nanocrystals-induced quenching of fluorescence of the quantum dots. The SiO(2)-coated quantum dots (HQDs) attached on the surface of CNTs exhibit favorable fluorescence as the hybrid SiO(2) shells on the QDs surface prevent its fluorescence quenching caused by the CNTs. In addition, the hybrid SiO(2) shells also mitigate the toxicity of the CdTe QDs. By coating transferrin on the surface of the herein modified CNTs, it provides a dual-targeted drug delivery system to transport the doxorubicin hydrochloride (DOX) into Hela cells by means of an external magnetic field. The nanocarrier based on the multifunctional nanoplatform exhibits an excellent drug loading capability of ca. 110%, in addition to cancer-targeted optical imaging as well as magnetically guided drug delivery.

Dual-targeting delivery system for bone cancer: synthesis and preliminary biological evaluation

Chemotherapy in treatment of malignant tumors has many side effects due to the poor physiochemical properties and the toxicity to normal tissues. The dual-targeting drug delivery system combining two high-affinity ligands can target anticancer drug primary to the diseased tissue, then to the tumor, which provides both greater efficacy of treatment and less harm to normal tissues. In this paper, a novel dual-targeting moiety RGD7 (R-G-D-D-D-D-D-D-D; Nonapeptide for bone cancer combining D6 peptide as bone target moiety and RGD peptide as tumors target moiety was contracted. A series of bone and/or tumor targeting conjugates have been synthesized in a convergent approach and well characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. The hydroxyapatite (HAP) binding, water solubility, the drug release and the distribution in vivo were evaluated. All the conjugates were water-soluble and able to release the parent drugs in vitro. The bone-targeting property of the dual-targeting delivery system was enhanced from the results of the HAP binding and the distribution in vivo. The experiment for verifying tumor targeting property was underway. These results provided an effective entry to the development of a new dual-targeting delivery system for bone cancer.

Anti-glioblastoma efficacy and safety of paclitaxel-loading Angiopep-conjugated dual targeting PEG-PCL nanoparticles

Therapeutic effect of glioma is often limited due to low permeability of delivery systems across the Blood-Brain Barrier (BBB) and poor penetration into the tumor tissue. In order to overcome the two barriers, we proposed Angiopep-conjugated PEG-PCL nanoparticles (ANG-PEG-NP) as a dual targeting drug delivery system for glioma treatment basing on low density lipoprotein receptor related protein (LRP) receptor not only over-expressed on BBB but also on glioma cells. This system could transport across BBB through LRP-mediated transcytosis and then targeted glioma via LRP-mediated endocytosis. In this study, we evaluated the preliminary availability and safety of ANG-PEG-NP for glioma treatment. The penetration, distribution, and accumulation into 3D glioma spheroid and in vivo glioma region of ANG-PEG-NP were obviously higher than that of plain PEG-PCL nanoparticles (PEG-NP). The anti-glioblastoma efficacy of paclitaxel (PTX) loading ANG-PEG-NP was significantly enhanced as compared to that of Taxol and PEG-NP. Preliminary safety results showed that no acute toxicity to hematological system, liver, kidney and brain tissue was observed after intravenous administration with a dose of 100 mg/kg blank ANG-PEG-NP per day for a week. Results indicate that Angiopep-conjugated dual targeting PEG-PCL nanoparticle is a potential brain targeting drug delivery system for glioma treatment.

A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas

A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood–brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG1000 and PEG2000 chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced.