Dual-targeting Drug Delivery System Research Articles

Dual-targeting CD44 and mucin by hyaluronic acid and 5TR1 aptamer for epirubicin delivery into cancer cells: Synthesis, characterization, in vitro and in vivo evaluation

One of the revolutionized cancer treatment is active targeting nanomedicines. This study aims to create a dual-targeted drug delivery system for Epirubicin (EPI) to cancer cells. Hyaluronic acid (HA) is the first targeting ligand, and 5TR1 aptamer (5TR1) is the second targeting ligand to guide the dual-targeted drug delivery system to the cancer cells. HA is bound to highly expressed receptors like CD44 on cancer cells. 5TR1, DNA aptamer, is capable of recognizing MUC1 glycoprotein, which is overexpressed in cancer cells.The process involved binding EPI and 5TR1 to HA using adipic acid dihydrazide (AA) as a linker. The bond between the components was confirmed using 1H NMR. The binding of 5TR1 to HA-AA-EPI was confirmed using gel electrophoresis. The particle size (132.6 ± 9 nm) and Zeta Potential (−29 ± 4.4 mV) were measured for the final nanoformulation (HA-AA-EPI-5TR1). The release of EPI from the HA-AA-EPI-5TR1 nanoformulation was also studied at different pH levels. In the acidic pH (5.4 and 6.5) release pattern of EPI from the HA-AA-EPI-5TR1 nanoformulation was higher than physiological pH (7.4). The cytotoxicity and cellular uptake of the synthetic nanoformula were evaluated using MTT and flow cytometry analysis. Flow cytometry and cellular cytotoxicity studies were exhibited in a negative MUC1−cell line (CHO) and two positive MUC1+cell lines (MCF-7 and C26). Results confirmed that there is a notable contrast between the dual-targeted (HA-AA-EPI-5TR1) and single-targeted (HA-AA-EPI) nanoformulation in MCF-7 and C26 cell lines (MUC1+). In vivo studies showed that HA-AA-EPI-5TR1 nanoformulation has improved efficiency with limited side effect in C26 tumor-bearing mice. Also, Fluorescence imaging and pathological evaluation showed reduced side effects in the heart tissue of mice receiving HA-AA-EPI-5TR1 than free EPI.So, this targeted approach effectively delivers EPI to cancer cells with reduced side effects.

Facile construction of dual-drug loaded nanoparticles for improvement synergistic chemotherapy in prostate cancer

Recently, functionalized materials have been extensively investigated and reported as drug delivery carriers. Furthermore, many groups have concentrated their efforts on establishing unique and effective therapeutic modalities, such as photothermal and photodynamic therapy, which have displayed promising anticancer ability. In the suggested techniques, the described treatments demonstrated better cooperative behavior and the capacity to substitute for the negative effects of traditional monotherapy. Herein, we developed a thermosensitive dual-targeting drug delivery system traction to improve the administration of capecitabine and two photosensitizers (indocyanine green (ICG) and methylene blue (MB). Capecitabine and photosensitizers were incorporated into nanoparticles using the thin film hydration process. Meanwhile, the dynamic identification of tumor cells may be achieved by modifying the targeted peptide cRGD and the folate targeting molecule coated on the surface of the nanoparticles. According to DLS experiments, the fabricated nanoparticles possessed an excellent dispersive index and a homogeneous size of ∼103.12 nm. Compared to free nanoparticles, the nanoparticles demonstrated dose-dependent in vitro cytotoxic properties in DU145 and PC3 cells. Based on the results examined from a confocal laser scanning microscope, the modified nanoparticles were more efficiently endocytosed by DU145 cancer cells compared to PC3 cells. On DU145 cells, the photothermal conversion-triggered release of drug and phototherapies resulted in an apoptotic rate of ∼80%. Additionally, the apoptosis cell death mechanism was displayed that the nanoparticles significantly induce apoptosis in the DU145 and PC3 cancer cells. The impressive findings concluded that the developed delivery system had put in a lot of work and established many changes to achieve precise interaction and provide a potential prostate cancer treatment strategy.

Sequentially targeting and intervening mutual Polo-like Kinase 1 on CAFs and tumor cells by dual targeting nano-platform for cholangiocarcinoma treatment.

Rationale: Synergistic treatment strategies for two or more drugs have gradually developed as the main options in clinics for cholangiocarcinoma (CCA) owing to the complicated crosstalk between the tumor and stroma. However, the different synergetic mechanisms pose great challenges to the dosages and order of administration of drugs. Thus, a strategy for exploring and intervening in mutual targets derived from stromal cells and cholangiocarcinoma cells was proposed.Methods: Genes with overexpression patterns in tumors and displaying a significant association with overall survival were identified from RNA-seq data of human CCA patients and CCA mouse models. Western blotting, qRT-PCR, immunofluorescence (IF), colony formation and flow cytometry assays were conducted to determine the biological roles of the key oncogene in cholangiocarcinoma and stromal cells respectively. Additionally, a dual-targeting drug delivery system (AA-HA-ODA) for cancer-associated fibroblasts (CAFs) and tumor cells was constructed to verify the effectiveness of intervening the screened genes in vivo.Results: Polo-like kinase 1 (PLK1) was verified to play vital role in the malignant proliferation of CCA by regulating the cell cycle pathway. PLK1 also decreased stromal production by regulating the CAF phenotype. In addition, a PLK1 inhibitor (Ro3280) loaded dual-targeting drug delivery system (AA-HA-ODA) was prepared and exhibited high affinity for CAFs and cholangiocarcinoma cells. The in vivo distribution pattern and antitumor efficacy of AA-HA-ODA/Ro also verify the effectiveness of inhibiting PLK1 in CCA in vivo.Conclusion: In summary, PLK1 is a mutual target derived from tumor cells and stroma due to its crucial role in the proliferation of tumor cells and stroma regulation in CAFs, which might provide enlightenment for multitarget treatment strategies and guidance for clinical cholangiocarcinoma treatment.

MMP2-responsive dual-targeting drug delivery system for valence-controlled arsenic trioxide prodrug delivery against hepatic carcinoma

Arsenic trioxide (ATO) is the active ingredient in traditional Chinese medicine, i.e., Arsenic, which has shown excellent therapeutic effects on hepatocellular carcinoma. However, due to its poor tumor distribution and high toxicity, the mass adoption of ATO in clinical applications has been severely impeded. In this study, matrix metalloproteinase 2 (MMP2)-responsive cleaved cell-penetrating peptide (PF) and folate (FA) co-modified liposome coated calcium arsenate nanoparticles (FA/PF-LP-CaAs) were fabricated based on these two considerations: (1) The tumor microenvironment characterized by overexpressed MMP2 in extracellular matrix and folate receptor on the cell membrane can enhance drug accumulation and accelerate endocytosis; (2) leveraging different toxicity of arsenic in different valence states, i.e., AsV can be reduced to more toxic AsIII by glutathione in tumor cells. Furthermore, FA/PF-LP-CaAs could be responsively degraded by the mild acidic tumor environment, and the degraded product could escape from lysosomes after endocytosis. More importantly, in light of the in vivo biodistribution and pharmacodynamic studies, the vehicle was able to accumulate in the tumor efficiently. Also, it was able to exhibit excellent anti-tumor efficacy with minimized side effects when compared to single-modified counterparts. Thus, the novel strategy based on the tumor microenvironment proposed in this work can enhance the tumor-targeting efficiency and intratumor toxicity.

Dual-Targeting Polymeric Nanocarriers to Deliver ROS-Responsive Prodrugs and Combat Multidrug Resistance of Cancer Cells.

Targeting delivery of anticancer drugs that can interact with DNA into mitochondria of cancer cells has been demonstrated to be an effective method to combat drug resistance. In this report, a cancer cell and mitochondria dual-targeting drug delivery system (DT-NP) is presented based on nanoparticles self-assembled from amphiphilic block copolymers with pH-responsive release of cinnamaldehyde (CA), which is used to encapsulate reactive oxygen species (ROS)-activable prodrug, phenylboronic pinacol ester-caged doxorubicin (BDOX). The surfaces of nanoparticles are conjugated by cancer cell-targeting folic acid (FA) and mitochondria-targeting triphenyl phosphonium (TPP) for dual targeting delivery. After incubation of DT-NP with multidrug-resistant breast cancer cells MCF-7/ADR, CA release under acidic conditions in endosomes from DT-NP can effectively induce intracellular oxidative stress improvement, especially in mitochondria. After targeting drug delivery into mitochondria, high level of ROS in mitochondria can in situ activate BDOX to interact with mitochondrial DNA and induce cell apoptosis. DT-NP displays a remarkably higher cancer cell killing effect on MCF-7/ADR as compared with DOX. Accordingly, DT-NP shows great potentials toward multidrug-resistant cancers as dual-targeting drug delivery systems with intracellular oxidative stress improvement and ROS-responsive prodrug activation in mitochondria.

Surface-modified engineered exosomes attenuated cerebral ischemia/reperfusion injury by targeting the delivery of quercetin towards impaired neurons

BackgroundThe incidence of ischemic stroke in the context of vascular disease is high, and the expression of growth-associated protein-43 (GAP43) increases when neurons are damaged or stimulated, especially in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R).ExperimentaldesignWe bioengineered neuron-targeting exosomes (Exo) conjugated to a monoclonal antibody against GAP43 (mAb GAP43) to promote the targeted delivery of quercetin (Que) to ischemic neurons with high GAP43 expression and investigated the ability of Exo to treat cerebral ischemia by scavenging reactive oxygen species (ROS).ResultsOur results suggested that Que loaded mAb GAP43 conjugated exosomes (Que/mAb GAP43-Exo) can specifically target damaged neurons through the interaction between Exo-delivered mAb GAP43 and GAP43 expressed in damaged neurons and improve survival of neurons by inhibiting ROS production through the activation of the Nrf2/HO-1 pathway. The brain infarct volume is smaller, and neurological recovery is more markedly improved following Que/mAb GAP43-Exo treatment than following free Que or Que-carrying exosome (Que-Exo) treatment in a rat induced by MCAO/R.ConclusionsQue/mAb GAP43-Exo may serve a promising dual targeting and therapeutic drug delivery system for alleviating cerebral ischemia/reperfusion injury.

Dual-targeted drug delivery system based on dopamine functionalized human serum albumin nanoparticles as a carrier for methyltestosterone drug

Objective(s): This study aims to enhance 17 a-methyltestosterone loaded human serum albumin nanoparticles (MT-HSA NPs) bioavailability through a desolvation technique. Dopamine (DA) molecules were conjugated on the surface of MT-HSA NPs and have the potential to act as tiny proper ligands in a unique treatment system to cope with cancer in which drug will be transmitted to the cancer area. Herein, we used HSA as an adaptable carrier of anticancer agents for methyltestosterone transport to the tumor site via DA D1-D5 receptors. In the present study, sonication of MT-HSA solution was carried out before the desolvation procedure to increase the drug loading and entrapment efficiency. Materials and Methods: Various parameters were optimized to characterize NPs including morphology, size, zeta potential, polydispersity index, drug release profile, and entrapment efficiency. Results: Under the optimum conditions of HSA and drug (1:41), at pH 9, results demonstrate sizes of 69 nm and 82 nm for MT-HSA and MT-HSA-DA NPs respectively. For MT-HSA NPs, the polydispersity index was found to be 0.3 and the average drug loading and encapsulation efficiency were 14% and 91% respectively. Anticancer activity and the release of drug was investigated through MCF-7 breast cancer cell line. Results show that targeted NPs are more effective than non-targeted NPs. Conclusion: According to these studies, the therapeutic effects against various diseases such as cancers increase through cellular targeting property of a biocompatible drug delivery system. This is the first report for methyltestosterone delivery to breast cancer cells based on HSA NPs.

Nanoparticles Dual Targeting Both Myeloma Cells and Cancer-Associated Fibroblasts Simultaneously to Improve Multiple Myeloma Treatment.

Cancer-associated fibroblasts (CAFs) and myeloma cells could mutually drive myeloma progression, indicating that drug delivery to kill both CAFs and myeloma cells simultaneously could achieve better therapeutic benefits than to kill each cell type alone. Here, we designed a dual-targeting drug delivery system by conjugating paclitaxel (PTX)-loaded poly(ethylene glycol)-poly(lactic acid) nanoparticles (NPs) with a cyclic peptide (CNPs-PTX) with a special affinity with platelet-derived growth factor/platelet-derived growth factor receptor (PDGFR-β) overexpressed on both CAFs and myeloma cells. Cellular uptake experiments revealed that the cyclic peptide modification on CNPs could significantly enhance CNPs uptake by both CAFs and myeloma cells compared with unmodified NPs. Cytotoxicity tests showed that CNPs-PTX was more toxic to both CAFs and myeloma cells compared with its counterpart PTX-loaded conventional NPs (NPs-PTX). In vivo imaging and biodistribution experiments showed that CNPs could abundantly accumulate in tumors and were highly co-localized with CAFs and myeloma cells. The in vivo anti-tumor experiments confirmed that the anti-myeloma efficacy of CNPs-PTX was significantly stronger than that of NPs-PTX and free drugs. In summary, it is the first time that a dual-targeting strategy was utilized in the field of myeloma treatment through targeting both CAFs and myeloma cells simultaneously, which harbors a high potential of clinical translation for myeloma treatment.

Dual-targeting tumor cells and tumor associated macrophages with lipid coated calcium zoledronate for enhanced lung cancer chemoimmunotherapy

Lung cancer is the leading cause of cancer death among both men and women, and non-small cell lung cancer (NSCLC) accounts for almost 80% of such death. Tumor associated macrophage (TAMs) are abundant components in NSCLC. TAMs play critical roles in angiogenesis, immune escape and chemoresistance. Here we developed a dual-targeting drug delivery system (CaZOL@BMNPs) of zoledronate, which could bind to both tumor cells with overexpressed biotin receptors and macrophage mannose receptor (MMR) positive TAMs. The biotin- and mannose-modified lipid coated calcium zoledronate nanoparticles were preferentially internalized in both tumor cells and TAMs, and thereby inhibited their survivals. Our studies demonstrated that CaZOl@BMNPs treatment obviously reduced angiogenesis, reprogrammed immunosuppressive tumor microenvironment and eventually restrained tumor progression with negligible systemic toxicity. Collectively, CaZOL@BMNPs could be a promising approach by dual-targeting tumor cells and TAMs for NSCLS chemoimmunotherapy.

Folate Receptor Targeting and Cathepsin B-Sensitive Drug Delivery System for Selective Cancer Cell Death and Imaging.

In this work, a folate receptor (FR)-mediated dual-targeting drug delivery system was synthesized to improve the tumor-killing efficiency and inhibit the side effects of anticancer drugs. We designed and synthesized an FR-mediated fluorescence probe (FA-Rho) and FR-mediated cathepsin B-sensitive drug delivery system (FA-GFLG-SN38). FA-GFLG-SN38 is composed of the FR ligand (folic acid, FA), the tetrapeptide substrate for cathepsin B (GFLG), and an anticancer drug (SN38). The rhodamine B (Rho)-labeled probe FA-Rho is suitable for specific fluorescence imaging of SK-Hep-1 cells overexpressing FR and inactive in FR-negative A549 and 16-HBE cells. FA-GFLG-SN38 exhibited strong cytotoxicity against FR-overexpressing SK-Hep-1, HeLa, and Siha cells, with IC50 values of 2-3 μM, but had no effect on FR-negative A549 and 16-HBE cells. The experimental results show that the FA-CFLG-SN38 drug delivery system proposed by us can effectively inhibit tumor proliferation in vitro, and it can be adopted for the diagnostics of tumor tissues and provide a basis for effective tumor therapy.

Design and fabrication of dual-targeted delivery system based on gemcitabine-conjugated human serum albumin nanoparticles.

Dual-targeted drug delivery system has established their reputation as potent vehicles for cancer chemotherapies. Herein, gemcitabine (Gem) was conjugated to human serum albumin (HSA) via dithiodipropionic anhydride to fabricate Gem-HSA nanoparticles. It was hypothesized that this system can enhance the low stability of Gem and can improve its intracellular delivery. Furthermore, folate was applied as targeting agent on HSA nanoparticles for increasing the tumor selectivity of Gem. To evaluate the structural properties of synthesized products, 1 H NMR and FT-IR were performed. Moreover, HPLC was implemented for confirming the conjugation between HSA and Gem. Nanoparticles have shown spherical shape with negative charge. The release rate of Gem was dependent to the concentration of glutathione and pH. Folate-targeted HSA nanoparticles have shown higher cytotoxicity, cellular uptake, and apoptosis induction on folate receptor overexpressing MDA-MB-231 cells in comparison to non-targeted nanoparticles. Finally, it is considered that the developed dual-targeted nanoparticles would be potent in improving the stability and efficacy of intracellular delivery of Gem and its selective delivery to cancer cells.

In Vitro Cytotoxicity and Antitumor Activity of Dual-Targeting Drug Delivery System Based on Modified Magnetic Carbon by Folate

A dual-targeting drug delivery system (DTDDS) with magnetic targeting and active targeting was obtained to improve the targeting and drug-loading capacity of magnetic drug nanocarriers. An ultraviolet-visible spectrophotometer and flow cytometry were used to investigate the drug-loading and release capacity, cytotoxicity, and inhibition of tumor cell proliferation, separately. Results show that DTDDS has obvious magnetic characteristics, on which the modification amount of folic acid is 64.82 mg g-1. Doxorubicin was taken as a template drug to evaluate its drug-loading capacity, which was as high as 577.12 mg g-1. Good biocompatibility and low cytotoxicity of DTDDS were further confirmed. Moreover, DTDDS can target the folate receptor on the surface of HeLa cells and deliver doxorubicin into HeLa cells, thereby increasing the proliferation inhibition for cancer cells. Therefore, this new dual-targeting drug delivery system shows potential in significantly reducing the toxic side effects of chemotherapy and improving chemotherapy efficiency.

Muscone/RI7217 co-modified upward messenger DTX liposomes enhanced permeability of blood-brain barrier and targeting glioma.

Rationale: The dual-targeted drug delivery system was designed for enhancing permeation of the blood-brain barrier (BBB) and providing an anti-glioma effect. As transferrin receptor (TfR) is over-expressed by the brain capillary endothelial (hCMEC/D3) and glioma cells, a mouse monoclonal antibody, RI7217, with high affinity and selectivity for TfR, was used to study the brain targeted drug delivery system. Muscone, an ingredient of traditional Chinese medicine (TCM) musk, was used as the "guide" drug to probe the permeability of the BBB for drug delivery into the cerebrospinal fluid. This study investigated the combined effects of TCM aromatic resuscitation and modern receptor-targeted technology by the use of muscone/RI7217 co-modified docetaxel (DTX) liposomes for enhanced drug delivery to the brain for anti-glioma effect.Methods: Cellular drug uptake from the formulations was determined using fluorescence microscopy and flow cytometry. The drug penetrating ability into tumor spheroids were visualized using confocal laser scanning microscopy (CLSM). In vivo glioma-targeting ability of formulations was evaluated using whole-body fluorescent imaging system. The survival curve study was performed to evaluate the anti-glioma effect of the formulations.Results: The results showed that muscone and RI7217 co-modified DTX liposomes enhanced uptake into both hCMEC/D3 and U87-MG cells, increased penetration to the deep region of U87-MG tumor spheroids, improved brain targeting in vivo and prolonged survival time of nude mice bearing tumor.Conclusion: Muscone and RI7217 co-modified DTX liposomes were found to show improved brain targeting and enhanced the efficacy of anti-glioma drug treatment in vivo.

Dopamine-conjugated apoferritin protein nanocage for the dual-targeting delivery of epirubicin

Objective(s): Nanocarriers are drug delivery vehicles, which have attracted the attention of researchers in recent years, particularly in cancer treatment. The encapsulation of anticancer drugs using protein nanocages is considered to be an optimal approach to reducing drug side-effects and increasing the bioavailability of anticancer drugs. Epirubicin (EPR) is an active chemotherapeutic medication used in the treatment of breast cancer. However, the toxicity of this drug against normal cells is a considerable limitation in therapy. EPR toxicity could be reduced using nanocarriers and dual-targeted drug delivery. Dual-targeted drug delivery system was developed by the conjugation of dopamine (DA) with horse spleen apoferritin (HsAFr)-encapsulated EPR to overcome the limitations of chemotherapeutic EPR in breast cancer treatment. HsAFr-EPR-DA complexes could target the scavenger receptors, transferrin receptors 1, and DA receptors, which are overexpressed on breast cancer cells. Materials and Methods: UV-Visible, fluorescence, and circular dichroism (CD) spectroscopic techniques and transmission electronic microscope (TEM) have been applied to characterize HsAFr-EPR-DA complexes. In the present study, we utilized human breast cancer cell line (MCF-7), aiming to compare the cytotoxicity of HsAFr-EPR-DA complexes to free EPR. Results: The toxicity was measured using the MTT assay, which demonstrated that the dual-targeted nanocarrier (HsAFr-EPR-DA) enhanced cytotoxicity against MCF-7 more significantly compared to non-targeted nanocarriers.Conclusion: The findings of the current research indicated that the synthesized HsAFr-DA complex was an optimal nanocarrier for the dual-targeted delivery of anticancer drugs.

In vivo Evaluation and Alzheimer's Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System.

To deliver drugs to treat Alzheimer's Disease (AD), nanoparticles should firstly penetrate through blood brain barrier, and then target neurons. Recently, we developed an Apo A-I and NL4 dual modified nanoparticle (ANNP) to deliver beta-amyloid converting enzyme 1 (BACE1) siRNA. Although promising in vitro results were obtained, the in vivo performance was not clear. Therefore, in this study, we further evaluated the in vivo neuroprotective effect and toxicity of the ANNP/siRNA. The ANNP/siRNA was 80.6 nm with good stability when incubated with serum. In vivo, the treatment with ANNP/siRNA significantly improves the spatial learning and memory of APP/PS1 double transgenic mice, as determined by mean escape latency, times of crossing the platform area during the 60 s swimming and the percentage of the distance in the target quadrant. After the treatment, BACE1 RNA level of ANNP/siRNA group was greatly reduced, which contributed a good AD treatment outcome. Finally, after repeated administration, the ANNP/siRNA did not lead to significant change as observed by HE staining of main organs, suggesting the good biocompatibility of ANNP/siRNA. These results demonstrated that the ANNP was a good candidate for AD targeting siRNA delivery.

A dual fluorescent reverse targeting drug delivery system based on curcumin-loaded ovalbumin nanoparticles for allergy treatment

A reverse targeting drug delivery based on antigen-modified nanoparticles provided an innovative strategy for effectively alleviating or inhibiting immune response. In this study, a dual fluorescent reverse targeting drug delivery system based on curcumin-loaded ovalbumin nanoparticles is developed for allergy treatment. The self-crosslinked ovalbumin nanoparticles achieved the double function of reverse targeting and sustained delivery carriers to maximize the anti-allergy of curcumin. Using a murine model of ovalbumin-induced allergy, this drug delivery system suppressed antigen-specific IgG1 and IgE production, inhibited CD4+ T activity, and decreased the level of ovalbumin-sensitized memory B cells. The curcumin-loaded ovalbumin nanoparticles exert stronger and more effective treatment on the immunomodulatory role. Furthermore, fluorescence imaging in vivo can reveal the precise delivery process for the effective allergy immunotherapy. The dual fluorescent reverse targeting delivery system provided a significant potential for the visible treatment of allergy with the merged functions of targeting, vehicles and fluorescence.

Peptide-functionalized and high drug loaded novel nanoparticles as dual-targeting drug delivery system for modulated and controlled release of paclitaxel to brain glioma

A dual-targeting drug delivery system for paclitaxel (PTX) was developed by functionalizing novel polyester-based nanoparticles (NPs) with peptides possessing special affinity for low-density lipoprotein receptor (LDLR), overcoming the limitations of the current chemotherapeutics, to transport drug from blood to brain, and then target glioma cells. Employing novel biodegradable block co-polymers (P and 2P), PTX loaded and peptide-functionalized nanoparticles were prepared by a modified nano-co-precipitation method, carried out in one step only without emulsifier, allowing to obtain spherical nanometric (<200 nm), monodisperse (PDI ∼ 0.1), Poly (Ethylene Glycol) (PEG)-coated and high PTX loaded NPs with a slow and controlled release rate for a prolonged period of time. Peptide functionalization, confirmed by fluorimetric assay and HPLC amino acids analysis, enhanced the cellular uptake of functionalized-PTX-NPs by human primary glioblastoma cell line (U-87 MG) and Bovine Brain Endothelial Cells (BBMVECs), compared with non-functionalized-PTX-NPs. To confirm dual-targeting effect, transendothelial transport experiments in an in vitro BBB model and in vitro anti-tumoral activity against U-87 MG revealed that peptide-functionalized-PTX-NPs significantly increased the transport ratio of PTX across the BBB along with an improved anti-proliferative efficiency. Pharmacokinetics and biodistribution studies in rats, carried out by in vivo experiments with 125I radiolabelled dual-targeting PTX-NPs, confirmed the stealthy behavior of NPs and indicated slightly lower levels of penetration into brain tissue in comparison with peptides known to be able to cross the BBB. These promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.

A Dual Targeting Drug Delivery System for Penetrating Blood-Brain Barrier and Selectively Delivering siRNA to Neurons for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is one of most serious threats to human beings, however, the treatment is hindered by blood-brain barrier and poor intra-brain cell selectivity. In this study, we developed a novel dual targeting drug delivery system by modification of NL4 peptide and apolipoprotein A-I (ApoA-I) onto dendrimer particles that may efficiently deliver siRNA into neuron cells to down-regulate BACE1 and inhibit Aβ formation. The constructed ANNP/ siRNA was approximately 79.26 nm with a spherical structure and a zeta potential of 3.53 mV. At N/P ratio of 10, the siRNA could be completely packaged into particles to avoid degradation by RNAase. In vitro, the modification with ApoA-I considerably increased bEnd.3 cell uptake and NL-4 considerably increased PC12 cell uptake. As a result, ANNP/siRNA showed higher uptake in both the cells. In addition, ANNP/siRNA could efficiently penetrate through bEnd.3 monolayers, which was 2.4-fold higher than unmodified complexes. In PC12 cells, the ANNP/siRNA could escape from endosomes and transport into cytoplasm after 8 h incubation, resulting in 87.5% BACE1 gene knockdown capacity, which was better than PEI. Additionally, the particles showed low cytotoxicity to both bEnd.3 and PC12 cells. In conclusion, this study preliminarily demonstrated that ApoA-I and NL4 dual modified dendrimer nanoparticles were efficient carriers for siRNA delivery to AD bearing brain.

Assessment of the antitumor activity of a cyclopalladated ferrocene compound assisted by a dual-targeting drug delivery system.

One cyclopalladated ferrocene compound CP was synthesized, which showed a good cell cytotoxicity. Assisted by a dual-targeting drug delivery system, the anticancer activity of CP to MDA-MB-468 remained unchanged, but the toxicity to non-tumorigenic cell line NIH3T3 was remarkably reduced. This provided a new path for the development of cyclopalladated ferrocene as an antitumor drug candidate.

Dual targeting mesoporous silica nanoparticles for inhibiting tumour cell invasion and metastasis

The invasion and metastasis of tumour cells are closely correlated with poor prognosis of cancer patients. In this study, a CD44 and N-cadherin dual targeting drug delivery system based on mesoporous silica nanoparticles (MSNs) has been successfully constructed for inhibiting tumour cell invasion and metastasis. Amino modified MSN (MSN/NH2) was first synthesized and then functionalized with hyaluronic acid (HA) and ADH-1, constructing the carrier ADH-1-HA-MSN. Doxorubicin hydrochloride (DOX) was selected as a model anticancer drug. The prepared vector had a spherical shape with a narrow distribution of particle size. Flow cytometry and confocal microscopy studies showed that the modification with HA significantly enhanced CD44-mediated cellular uptake of this nanocarrier. ADH-1-HA-MSN/DOX exhibited higher cytotoxicity compared to non-ADH-1 modified counterparts. Of note, a transwell chamber assay demonstrated that the migration and invasion of tumour cells were markedly inhibited by ADH-1-HA-MSN/DOX. Furthermore, Western blotting analysis revealed that ADH-1-HA-MSN/DOX inhibited tumour cell invasion and metastasis by down-regulating N-cadherin expression. Taken together, these results indicated that ADH-1-HA-MSN might be a promising targeted drug delivery system for inhibiting cancer invasion and metastasis.