Dual-targeting Drug Delivery Research Articles

Dual-Targeted Drug Delivery to Myeloid Leukemia Cells via Complement- and Transferrin-Based Protein Corona.

Although traditionally regarded as an impediment, the protein corona can facilitate the advancement of targeted drug delivery systems. This study presents an innovative approach for targeting acute myeloid leukemia (AML) using nanoparticles with agglutinated protein (NAPs). Agglutinated transferrin and C3b in NAPs selectively bind to CD71 and CD11b, receptors that are overexpressed on myeloid leukemic cells compared to nonmalignant cells. In vitro, NAPs achieved a 73.9% doxorubicin (DOX) uptake in leukemic cells, compared to 6.19% for the free drug, while significantly reducing off-target accumulation in normal cells from 42.9% to 5.76%. In vivo, the distribution of NAPs correlated to the organ infiltration pattern of leukemic cells. NAPs demonstrated antileukemic activity in both in vitro and in vivo NSG mouse models, inducing cell death via apoptosis and ferroptosis. In conclusion, NAP-mediated targeted drug delivery represents a promising therapeutic strategy for AML, enhancing treatment efficacy and minimizing off-target effects.

Cancer cell-derived exosome based dual-targeted drug delivery system for non-small cell lung cancer therapy

Lung cancer is among most prevalent cancers in the world, in which non-small cell lung cancer (NSCLC) accounts for more than 85 % of all subtypes of lung cancers. NSCLC is often diagnosed at an advanced stage with a high mortality rate. Despite the demonstrated efficacy of chemotherapy in the treatment of NSCLC, the main drawback of current therapy is the lack of an effective drug-targeted delivery system, which may result in undesirable side effects during the clinical treatment. In this study, we construct a "dual-targeting" anti-cancer drug delivery platform by combining superparamagnetic iron oxide nanoparticles (SPIONs) with exosomes derived from NSCLC cells. We successfully promoted the targeted delivery of anti-drug doxorubicin (DOX) at the cellular levels by combining the homing targeted ability of exosomes with the magnetic targeted ability of SPIONs. Moreover, non-small cell lung cancer cell (NCI-h1299) tumor models were established. It was found that exosome-SPIONs (Exo-SPIONs) loaded with DOX exhibited optimal tumor tissue delivery and tumor suppression in the presence of an external magnetic field, and reduced the toxicity of the DOX to normal tissues. The constructed "dual-targeting" anti-cancer drug delivery platform holds promise for targeted chemotherapy for NSCLC.

Incorporating mannose-functionalized hydroxyapatite/metal-organic framework into the hyaluronic acid hydrogel film: A potential dual-targeted oral anticancer delivery system

The recent challenge in enhancing the targeted delivery of anticancer drugs to cancer cells is improving the bioavailability and therapeutic efficacy of drug delivery systems while minimizing their systemic side effects. In this study, the MIL-88(Fe) metal-organic framework was synthesized using the in situ method in the presence of hydroxyapatite nanoparticles (HAP) toward the HAP/MIL-88(Fe) (HM) nanocomposite preparation. It was then functionalized with mannose (M) as an anticancer receptor through the Steglich esterification method. Various analyses confirmed the successful synthesis of MHM. For drug release investigation, 5-Fu was loaded into the MHM, which was then coated with a hyaluronic acid (HA) hydrogel film. Characterization analyses verified the structure of the resulting HA/5-Fu-MHM hydrogel film. In vitro drug release experiments showed that the release of 5-Fu drug from HA/5-Fu-MHM could be controlled with pH, reducing its release rate in the acidic environment of the stomach while increasing it in the intestinal environment. Cytotoxicity results of the HA/5-Fu-MHM hydrogel film against HT29 cancer cells showed enhanced cytotoxicity due to the mannose and hyaluronic acid in its structure, which triggers a dual-targeted drug delivery system. The obtained results indicate that the prepared hydrogel films can be a promising bio-platform for colon cancer treatment.

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.

Macrophage membrane-coated nanovesicles for dual-targeted drug delivery to inhibit tumor and induce macrophage polarization.

Immunosuppressive M2 macrophages in the tumor microenvironment (TME) can mediate the therapeutic resistance of tumors, and seriously affect the clinical efficacy and prognosis of tumor patients. This study aims to develop a novel drug delivery system for dual-targeting tumor and macrophages to inhibit tumor and induce macrophage polarization. The anti-tumor effects of methyltransferase like 14 (METTL14) were investigated both in vitro and in vivo. The underlying mechanisms of METTL14 regulating macrophages were also explored in this study. We further constructed the cyclic (Arg-Gly-Asp) (cRGD) peptide modified macrophage membrane-coated nanovesicles to co-deliver METTL14 and the TLR4 agonist. We found that METTL14 significantly inhibits the growth of tumor in vitro. METTL14 might downregulate TICAM2 and inhibit the Toll-like receptor 4 (TLR4) pathway of macrophages, meanwhile, the combination of METTL14 and the TLR4 agonist could induce M1 polarization of macrophages. Macrophage membrane-coated nanovesicles are characterized by easy modification, drug loading, and dual-targeting tumor and macrophages, and cRGD modification can further enhance its targeting ability. It showed that the nanovesicles could improve the in vivo stability of METTL14, and dual-target tumor and macrophages to inhibit tumor and induce M1 polarization of macrophages. This study anticipates achieving the dual purposes of tumor inhibition and macrophage polarization, and providing a new therapeutic strategy for tumors.

Specific anti-glioma targeted-delivery strategy of engineered small extracellular vesicles dual-functionalised by Angiopep-2 and TAT peptides.

Glioma is one of the primary malignant brain tumours in adults, with a poor prognosis. Pharmacological reagents targeting glioma are limited to achieve the desired therapeutic effect due to the presence of blood‐brain barrier (BBB). Effectively crossing the BBB and specifically targeting to the brain tumour are the major challenge for the glioma treatments. Here, we demonstrate that the well‐defined small extracellular vesicles (sEVs) with dual‐targeting drug delivery and cell‐penetrating functions, modified by Angiopep‐2 and trans‐activator of transcription peptides, enable efficient and specific chemotherapy for glioma. The high efficiency of engineered sEVs in targeting BBB and glioma was assessed in both monolayer culture cells and BBB model in vitro, respectively. The observed high targeting efficiency was re‐validated in subcutaneous tumour and orthotopic glioma mice models. After loading the doxorubicin into dual‐modified functional sEVs, this specific dual‐targeting delivery system could cross the BBB, reach the glioma, and penetrate the tumour. Such a mode of drug delivery significantly improved more than 2‐fold survival time of glioma mice with very few side effects. In conclusion, utilization of the dual‐modified sEVs represents a unique and efficient strategy for drug delivery, holding great promise for the treatments of central nervous system diseases.

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.

A dual-targeting peptide facilitates targeting anti-inflammation to attenuate atherosclerosis in ApoE-/- mice.

We report a peptidic dual-targeting drug delivery platform (integrins targeting and self-assembly instructed by matrix metalloproteinases) towards inflamed endothelial cells, which improved the anti-inflammatory ability of the loaded drug (i.e., puerarin) in vitro and thus improved the antiatherogenic effect of the loaded drug (i.e., puerarin) in vivo.

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.

Bone-targeted erythrocyte-cancer hybrid membrane-camouflaged nanoparticles for enhancing photothermal and hypoxia-activated chemotherapy of bone invasion by OSCC

BackgroundJaw bones are the most common organs to be invaded by oral malignancies, such as oral squamous cell carcinoma (OSCC), because of their special anatomical relationship. Various serious complications, such as pathological fractures and bone pain can significantly decrease the quality of life or even survival outcomes for a patient. Although chemotherapy is a promising strategy for bone invasion treatment, its clinical applications are limited by the lack of tumor-specific targeting and poor permeability in bone tissue. Therefore, it is necessary to develop a smart bone and cancer dual targeting drug delivery platform.ResultsWe designed a dual targeting nano-biomimetic drug delivery vehicle Asp8[H40-TPZ/IR780@(RBC-H)] that has excellent bone and cancer targeting as well as immune escape abilities to treat malignancies in jaw bones. These nanoparticles were camouflaged with a head and neck squamous cell carcinoma WSU-HN6 cell (H) and red blood cell (RBC) hybrid membrane, which were modified by an oligopeptide of eight aspartate acid (Asp8). The spherical morphology and typical core-shell structure of biomimetic nanoparticles were observed by transmission electron microscopy. These nanoparticles exhibited the same surface proteins as those of WSU-HN6 and RBC. Flow cytometry and confocal microscopy showed a greater uptake of the biomimetic nanoparticles when compared to bare H40-PEG nanoparticles. Biodistribution of the nanoparticles in vivo revealed that they were mainly localized in the area of bone invasion by WSU-HN6 cells. Moreover, the Asp8[H40-TPZ/IR780@(RBC-H)] nanoparticles exhibited effective cancer growth inhibition properties when compared to other TPZ or IR780 formulations.ConclusionsAsp8[H40-TPZ/IR780@(RBC-H)] has bone targeting, tumor-homing and immune escape abilities, therefore, it is an efficient multi-targeting drug delivery platform for achieving precise anti-cancer therapy during bone invasion.Graphical

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.

Constructing of pH and reduction dual-responsive folic acid-modified hyaluronic acid-based microcapsules for dual-targeted drug delivery via sonochemical method

In this study, an eco-friendly, biodegradable, biocompatible, non-immunogenic, non-toxic polysaccharide hyaluronic acid (HA) was used to design and fabrication folic acid (FA)-modified pH and reduction-responsive HA-base microcapsules (FA-PRMCs). The microcapsules loaded with curcumin (CUR) are fabricated by a fast, economical and environmentally friendly sonochemical method. Ethyl acetate as the core solvent phase loaded with curcumin can be recycled and reused repeatedly. The obtained microcapsules showed good biocompatibility and targeting in anti-tumor evaluation and endocytosis evaluation in vitro. The responsive release characteristics of microcapsules could avoid side effects on normal tissues. As a low-cost intelligent targeted delivery vector, FA-PRMCs have great clinical application potential in the future.

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.

Brain-Targeted Delivery of Pre-miR-29b Using Lactoferrin-Stearic Acid-Modified-Chitosan/Polyethyleneimine Polyplexes.

The efficacy of brain therapeutics is largely hampered by the presence of the blood–brain barrier (BBB), mainly due to the failure of most (bio) pharmaceuticals to cross it. Accordingly, this study aims to develop nanocarriers for targeted delivery of recombinant precursor microRNA (pre-miR-29b), foreseeing a decrease in the expression of the BACE1 protein, with potential implications in Alzheimer’s disease (AD) treatment. Stearic acid (SA) and lactoferrin (Lf) were successfully exploited as brain-targeting ligands to modify cationic polymers (chitosan (CS) or polyethyleneimine (PEI)), and its BBB penetration behavior was evaluated. The intracellular uptake of the dual-targeting drug delivery systems by neuronal cell models, as well as the gene silencing efficiency of recombinant pre-miR-29b, was analyzed in vitro. Labeled pre-miR-29b-CS/PEI-SA-Lf systems showed very strong fluorescence in the cytoplasm and nucleus of RBE4 cells, being verified the delivery of pre-miR-29b to neuronal cells after 1 h transfection. The experiment of transport across the BBB showed that CS-SA-Lf delivered 65% of recombinant pre-miR-29b in a period of 4 h, a significantly higher transport ratio than the 42% found for PEI-SA-Lf in the same time frame. Overall, a novel procedure for the dual targeting of DDS is disclosed, opening new perspectives in nanomedicines delivery, whereby a novel drug delivery system harvests the merits and properties of the different immobilized ligands.

Facile Synthesis of Poly(DMAEMA-co-MPS)-coated Porous Silica Nanocarriers as Dual-targeting Drug Delivery Platform: Experimental and Biological Investigations

Inorganic structures with functionalized polymers play essential roles in diverse biological trends. Herein, thermal and CO2 dual-stimuli nanomaterials composed of mesoporous silica nanoparticles (MSN) anchored with two grafted copolymers: poly(3-methacryloxypropyltrimethoxysilane) "PMPS" & poly(N,N-dimethylaminoethyl methacrylate) "PDMAEMA" were synthesized via one-step reaction and characterized by BET as well as BJH methods to estimate pore sizes, pore volumes, and surface areas. The smart PDMAEMA acted as an active gatekeeper to adjust the loading or in vitro release processes of a fungicidal drug-loaded inside the mesopores by altering temperature or CO2 of the tested environment. Furthermore, treating the nanomaterials by CO2 for a few minutes was found to have a bactericidal effect with promising results as indicated by the disk diffusion technique. In general, the positive biological activity against selected strains of bacteria and fungi indicates that these particles may be helpful for engineering more efficient antifungal or antibacterial agents for pharmaceutical applications.

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.