Dual-targeting Delivery System Research Articles

A novel digitonin/graphene oxide/iron oxide nanocomposite: synthesis, physiochemical characterization and antioxidant activity.

In this work, iron oxide (Fe3O4) magnetic nanoparticles (MNPs) and graphene oxide (GO) nanosheets were prepared via the co-precipitation technique and the Modified Hummer method. Fe3O4 MNPs and GO nanosheets were combined to prepare Fe3O4/GO nanocomposite and subsequently conjugated with Digitonin (DIG) in order to obtain a dual-targeted delivery system based on DIG/Fe3O4/GO nanocomposite. SEM images reveal the presence of Fe3O4 MNPs at a scale of 100nm, exhibiting dispersion between the GO nanosheets. Aggregation of the DIG/Fe3O4/GO nanocomposite was observed at various size scales. The XRD structural analysis confirms the crystal structure of the prepared samples. The Fe3O4 MNPs demonstrated the main XRD-diffracted peaks. Also, GO nanosheets exhibit crystalline characteristics on the (001) and (002) planes. The predominant peaks observed in the DIG/GO/Fe3O4 nanocomposite are attributed to the crystal phases of Fe3O4 MNPs. The FT-IR vibrational modes observed in the GO/DIG/Fe3O4 nanocomposite indicate the presence of crosslinking between GO nanosheet layers and the Fe3O4 MNPs. The antioxidant activity of the prepared samples was measured and the DIG/GO/Fe3O4 nanocomposite demonstrated a significantly high antioxidant activity in both 2-diphenyl-1-picrylhydrazyl (DPPH·) and 2,2-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS·+) tests.

Chitosan-coated magnetic graphene oxide for targeted delivery of doxorubicin as a nanomedicine approach to treat glioblastoma

In this study, magnetic graphene oxide (mGO) was first prepared and modified with chitosan to prepare chitosan-coated mGO (mGOC). Gastrin-releasing peptide (GRP)-conjugated mGOC (mGOCG) was then prepared from mGOC. The chemo drug doxorubicin (DOX) was adsorbed to mGOCG surface for dual active/magnetic targeted drug delivery. The DOX loading to mGOCG is 1.71 mg/mg, and drug release is pH-sensitive to facilitate drug delivery in endosomes. In vitro studies confirmed enhanced mGOCG endocytosis by U87 glioblastoma cells, with which enhanced cytotoxicity towards cancer cells could be achieved. This could be revealed from the drastically reduced half-maximal inhibitory concentration of mGOCG/DOX compared with DOX and mGOC/DOX. Furthermore, mGOCG/DOX can be localized under the influence of a magnetic field (MF) to exert this cytotoxic effect. An orthotopic brain tumor model by implanting U87 cells in the intracranial area of BALB/c nude mice was used to study the in vivo anti-tumor efficacy by intravenous injection of different samples and followed with bioluminescence imaging. The tumor size in the mGOCG/DOX + MF group demonstrated the best potency to suppress tumor growth and prolong animal survival time compared with mGOCG/DOX, mGOC/DOX, or DOX groups, indicating this new dual-targeting delivery system for DOX can effectively treat glioblastoma.

Efficacy and Mechanism of a Biomimetic Nanosystem Carrying Doxorubicin and an IDO Inhibitor for Treatment of Advanced Triple-Negative Breast Cancer.

Chemotherapy is still the treatment of choice for advanced triple-negative breast cancer. Chemotherapy combined with immunotherapy is being tried in patients with triple-negative breast cancer. As a kind of "cold tumor", triple-negative breast cancer has a bottleneck in immunotherapy. Indoleamine 2, 3-dioxygenase-1 inhibitors can reverse the immunosuppressive state and enhance the immune response. In this study, mesoporous silica nanoparticles were coated with the chemotherapeutic drug doxorubicin and indoleamine 2, 3-dioxygenase 1 inhibitor 1-Methyl-DL-tryptophan (1-MT), and then encapsulate the surfaces of a triple-negative breast cancer cell membrane to construct the tumor dual-targeted delivery system CDIMSN for chemotherapy and immunotherapy, and to investigate the immunogenic death effect of CDIMSN. The CDIMSN could target the tumor microenvironment. Doxorubicin induced tumor immunogenic death, while 1-MT reversed immunosuppression. In vivo findings showed that the tumor size in the CDIMSN group was 2.66-fold and 1.56-fold smaller than that in DOX and DIMSN groups, respectively. CDIMSN group was better than naked DIMSN in stimulating CD8+T cells, CD4+T cells and promoting DendriticCells(DC) maturation. In addition, blood analysis, biochemical analysis and Hematoxylin staining analysis of mice showed that the bionic nanoparticles had good biological safety.

Dual-targeted delivery system using hollow silica nanoparticles with H+-triggered bubble generating characteristic coated with hyaluronic acid and AS1411 for cancer therapy

Objective Herein, a dual-targeting delivery system using mesoporous silica nanoparticles with hollow structures (HMSNs) was developed for the specific delivery of epirubicin (EPI) to cancer cells and introducing a H+-triggered bubble generating nanosystem (BGNS). HMSNs containing EPI are covered by hyaluronic acid (HA) shell and AS1411 aptamer to create the BGNS-EPI-HA-Apt complex, which is highly selective against CD44 marker and nucleolin overexpressed on the surface of tumor cells. Methods MTT assay compared the cytotoxicity of different treatments in CHO (Chinese hamster ovary) cells as well as 4T1 (murine mammary carcinoma) and MCF-7 (human breast adenocarcinoma) cells. The internalization of Epi was assessed by flow cytometry along with fluorescence imaging. In vivo studies were conducted on BALB/c mice bearing a tumor from 4T1 cell line where monitoring included measuring tumor volume, mouse weight changes over time alongside mortality rate; accumulation levels for Epi within organs were also measured during this process. Results The collected data illustrated that BGNS-EPI-HA-Apt complex controlled the release of EPI in a sustained method. Afterward, receptor-mediated internalization via nucleolin and CD44 was verified in 4T1 and MCF-7 cells using fluorescence microscopy assay and flow cytometry analysis. The results of tumor inhibitory effect study exhibited that BGNS-EPI-HA-Apt complex decreased off-target effect and improved on-target effects because of its targeting ability. Conclusion The data acquired substantiates that HA-surface modified HMSNs functionalized with aptamers possess significant potential as a focused platform for efficient transportation of anticancer agents to neoplastic tissues.

Dual-Targeted Nanoparticle-In-Microparticle System for Ulcerative Colitis Therapy.

Conventional oral therapy for ulcerative colitis (UC) is associated with premature release or degradation of drugs in the harsh gastrointestinal environment, resulting in reduced therapeutic effectiveness. Consequently, we aimed to develop a dual-targeted delivery system with a nanoparticle-in-microparticle (nano-in-micro) structure. The prepared Asiatic Acid-loaded delivery system (AA/CDM-BT-ALG) had pH-sensitive properties. Cellular uptake evaluation confirmed that nanoparticles exhibited targeted absorption by macrophages and Caco-2 cells through mannose (Man) receptor and biotin-mediated endocytosis, respectively. Therefore, this mechanism effectively enhances intracellular drug concentration. Additionally, the biodistribution study conducted on the gastrointestinal tract of mice indicated that the colon of the microspheres group showed higher fluorescence intensity with longer duration than the other groups. This finding indicated that the microspheres exhibited selective accumulation in areas of colon inflammation. In vivo experiments in colitis mice showed that AA/CDM-BT-ALG significantly alleviated the histopathological characteristics of the colon, reduced neutrophil and macrophage infiltration, and decreased pro-inflammatory cytokine expression. Furthermore, the effect of AA/CDM-BT-ALG on colitis was validated to be closely related to the TLR4/MyD88/NF-κB signaling pathway. The present findings suggest that the development of a dual-targeted delivery system has been accomplished effectively, with the potential to serve as a drug-controlled release system for treatingUC. This article is protected by copyright. All rights reserved.

Magnetic liposome as a dual-targeting delivery system for idiopathic pulmonary fibrosis treatment

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, where M2 macrophages play an irreplaceable role in the anti-inflammatory progress. Targeting M2 macrophages and regulating their polarization may be a potential treatment strategy for IPF. Herein, we designed a magnetic liposome based dual-targeting delivery system for the IPF treatment, constructed by mannose-modified magnetic nanoparticles (MAN-MNPs) loaded on the surface of the liposome (MAN-MNPs@LP). The delivery system is capable of responding to a static magnetic field (SMF) and then recognizing in situ of M2 macrophages through the mannose receptor-dependent internalization. Firstly, a series of physical and chemical assays were used to characterize these nanoparticles. Subsequently, magnetic liposomes accumulation in the damaged lung with/without mannose modification and SMF were compared by in vivo imaging system. Finally, the reduction of M2 macrophages and inhibition of their polarization confirmed that the development of IPF was retarded due to the in situ release of encapsulated dexamethasone (Dex) in lungs under the SMF. Further investigation demonstrated that the expression of α-SMA and collagen deposition was reduced. Altogether, this dual-targeting delivery system can effectively deliver Dex into M2 macrophages in the lung, making it a novel and promising therapeutic system for the IPF treatment.

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.

A novel dual-targeting delivery system for specific delivery of CRISPR/Cas9 using hyaluronic acid, chitosan and AS1411

A facile method was designed that can specifically deliver CRISPR/Cas9 into target cells nuclei and reduce the off-target effects. A multifunctional delivery vector for FOXM1 knockout was composed by integration of cell targeting polymer (hyaluronic acid) and cell and nuclear targeting group (AS1411 aptamer) on the surface of nanoparticles formed by genome editing plasmid and chitosan (CS) as the core (Apt-HA-CS-CRISPR/Cas9). The data of cytotoxicity experiment and western blot confirmed this issue. The results of flow cytometry analysis and fluorescence imaging demonstrated that Apt-HA-CS-CRISPR/Cas9 was significantly internalized into target cells (MCF-7, SK-MES-1, HeLa) but not into nontarget cells (HEK293). Furthermore, the in vivo studies displayed that the Apt-HA-CS-CRISPR/Cas9 was strongly rendered tumor inhibitory effect and delivered efficiently CRISPR/Cas9 into the tumor with no detectable distribution in other organs compared with naked plasmid. This approach provides an avenue for specific in vivo gene editing therapeutics with the lowest side effect.

Dual-targeted delivery of doxorubicin by mesoporous silica nanoparticle coated with AS1411 aptamer and RGDK-R peptide to breast cancer in vitro and in vivo

Statistics show that breast cancer is the first cause of cancer-related deaths in women worldwide. Doxorubicin (DOX) is one of the chemotherapeutics with high efficacy in breast cancer. Nevertheless, due to its lack of specificity, it causes severe adverse effects and that is how the targeting delivery to cancer cells with high precision and efficiency becomes crucial. Combining nanoparticles and active targeting agents in forming a drug delivery system (DDS) for cytotoxic drugs is a promising strategy to circumvent the drawbacks of chemotherapy. Herein, a new dual-targeting delivery system for DOX was fabricated by loading DOX into mesoporous silica nanoparticles (MSN) which were then covalently attached to AS1411 aptamer and electrostatically conjugated to RGDK-octa-arginine peptide sequence (RGDK-R). The in vitro data elucidated a significant safety effect of the encapsulated DOX in MSN.COOH decorated with AS1411 and RGDK-R for non-cancerous cells, while the same toxicity as DOX towards breast cancer cells. In vivo results indicated that the designed system could effectively improve the inhibitory effect of DOX on tumor growth with single-dose administration.

Cascade targeting codelivery of ingenol-3-angelate and doxorubicin for enhancing cancer chemoimmunotherapy through synergistic effects in prostate cancer.

Immunotherapy has led to an expansion of the treatment of malignancies, but its effect in prostate cancer (PCa) patients is modest. Chemoimmunotherapy is a promising approach that has attracted substantial attention. Although the widely used clinical chemotherapeutic drug doxorubicin (DOX) elicits immunogenic cell death (ICD), its weak ICD effect and the abnormal vasculature of tumors severely limit its efficacy in chemoimmunotherapy. Ingenol-3-angelate (I3A), an emerging antitumor drug with dual chemotherapeutic and immune response-eliciting effects, is expected to exert synergistic effects when administered in combination with DOX. I3A induces the ICD of PCa cells by triggering mitophagy and apoptosis and promotes the normalization of tumor vessels, resulting in sufficient infiltration of immune cells into tumors. A synergistic effect of I3A and DOX was observed in vitro at a molar ratio of 1:4. To codeliver this ratio of I3A and DOX to tumor and ensure their uptake, we designed a dual-targeting delivery system, polylactide-poly(ethylene) glycol-2-(3-((S)-5-amino-1-carboxypentyl)-ureido) pentanedioate/triphenylphosphonium (PLA-PEG-ACUPA/TPP), which targets prostate-specific membrane antigen (PSMA) and mitochondria. Delivery of these nanomedicines led to inhibited tumor growth and a strong antitumor immune response. This study sheds light on the mitophagic and antiangiogenic mechanisms underlying I3A treatment of PCa and provides a strategy for combining vascular normalization and chemoimmunotherapy for PCa treatment.

Peptide-Targeted High-Density Lipoprotein Nanoparticles for Combinatorial Treatment against Metastatic Breast Cancer.

The sonic hedgehog (SHH) signaling pathway exhibits aberrant activation in triple-negative breast cancer (TNBC), wherein it regulates several malignant phenotypes related to tumor metastasis. GANT61, an inhibitor of the SHH signaling pathway, may offer promise when administered in combination with conventional chemotherapy to treat metastatic TNBC. However, poor bioavailability and substantial off-target toxicity limit its clinical application. To address these limitations, we designed a peptide-functionalized dual-targeting delivery system encapsulating paclitaxel and GANT61 in tLyP-1 peptide-modified reconstituted high-density lipoprotein nanoparticle (tLyP-1-rHDL-PTX/GANT61 NP) for metastatic TNBC treatment. The apolipoprotein A-1 and tLyP-1 peptide modified on the surface of nanoparticles enable the delivery system to target tumor cells by binding to the overexpressed scavenger receptor B type I and neuropilin-1 receptor. Moreover, the tLyP-1 peptide also enables the deep tumor penetration of nanoparticles further facilitating paclitaxel and GANT61 delivery. Increased cellular uptake of the nanoparticles was observed in both MDA-MB-231, BT-549 tumor cells, and their 3D tumor spheroids. A series of in vitro experiments reveal that GANT61 was able to suppress key metastasis-related tumor cell activities including angiogenesis, migration, invasion, and stemness. Owing to more effective drug administration, the metastasis suppression efficiency of GANT61 was significantly enhanced by the dual-targeting tLyP-1-rHDL delivery system. Meanwhile, the codelivery of paclitaxel and GANT61 by dual-targeting tLyP-1-rHDL nanoparticles demonstrated superior efficiency of disrupting proliferation and inducing apoptosis in tumor cells compared with drug solutions. In a spontaneous metastasis breast cancer NCG mice model, the tLyP-1-rHDL-PTX/GANT61 nanoparticles exhibited highly tumor-specific distribution and result in significant inhibition of the primary tumor growth and dramatic reduction of lung metastasis without obvious side effects. The present work suggests that a combination of the SHH signaling pathway suppression and chemotherapy assisted by peptide-functionalized targeting tLyP-1-rHDL nanoparticles may provide a promising strategy for metastatic TNBC treatment.

Nanoparticle-based co-delivery of siRNA and paclitaxel for dual-targeting of glioblastoma.

Aim: To explore the therapeutic effect of nanoparticle-based dual-targeting delivery of antitumor agents for glioblastoma treatment. Materials & methods: A hepatitis B core protein-virus-like particle (VLP)-based dual-targeting delivery system was designed with the primary brain targeting peptide TGN for blood-brain barrier penetration and tumor vascular preferred ligand RGD (arginine-glycine-aspartic acid) for glioblastoma targeting. Chemo- and gene-therapeutic agents of paclitaxel and siRNA were co-packaged inside the vehicle. Results: The results demonstrated efficient delivery of the packaged agents to invasive tumor sites. The combination of chemo- and gene-therapies demonstrated synergistic antitumor effects through enhancing necrosis and apoptosis, as well as being able to inhibit tumor invasion with minimal cytotoxicity. Conclusion: Our hepatitis B core-VLP-based dual-targeting delivery of chemo- and gene-therapeutic agents possesses a synergistic antitumor effect for glioblastoma therapy.

Folate receptor-targeted RNAi nanoparticles for silencing STAT3 in tumor-associated macrophages and tumor cells

We developed a STAT3 silencing siRNA to both tumor cells and M2 macrophages. The dual-targeting system prepared by electronic self-assembly was composed of folic acid-conjugated carboxymethyl chitosan for targeting and cationic chitosan derivatives for siRNA package. The effects of siRNA delivery was investigated in M2 macrophages and Lewis lung cancer cells (LLC). Due to the enhanced delivery efficiency, the dual-targeting delivery system exhibited a higher efficacy compared with non-targeting nanoparticles, resulting in a dramatically reduction of STAT3 expression in both cells, and a successful shift from M2 phenotypes (pro-tumor) to M1 phenotypes (anti-tumor) for macrophages. Additionally, the influence of the nanoparticles on LLC cells co-cultured with M2 macrophages was also investigated. The increased apoptosis and inhibition of proliferation of LLC cells were observed. In vivo therapeutic effect was also evaluated in s.c. tumor models, tumor growth was effectively inhibited and the level of M2 macrophages in tumor tissues was dramatically reduced.

The enhanced treatment efficacy of invasive brain glioma by dual-targeted artemether plus paclitaxel micelles

High grade-gliomas are highly invasive and prone to metastasis, leading to poor survival and prognosis. Currently, we urgently need a new treatment strategy to effectively inhibit glioma. In this study, artemether and paclitaxel were used as two agents for tumour suppression. Two functional materials were synthesised and modified on the surface of the micelle as targeting molecules. The addition of two functional materials confers the ability of the micelles to effectively cross the blood-brain barrier (BBB) and then target the glioma cells. Thus, this dual-targeted delivery system allows the drug to play a better role in inhibiting tumour invasion and vasculogenic mimicry (VM) channels. In this paper, the anticancer effects of dual-targeted artemether plus paclitaxel micelles on glioma U87 cells were studied in three aspects: (I) In vitro and in vivo targeting assessment, including the role of penetrating BBB and targeting glioma; (II) In vitro regulation of invasion-associated proteins; (III) Inhibition of VM channels formation and invasion in vitro; (IV) The study of pharmacodynamics in tumour-bearing mice. These results suggest that dual-targeted artemether plus paclitaxel micelle may provide a new strategy to treat glioma via inhibiting invasive and VM channels.

LHRH Targeted Chonderosomes of Mitomycin C in Breast Cancer: An In Vitro/ In Vivo Study.

Mitomycin C (MMC) is an anti-cancer drug used for the treatment of breast cancer with limited therapeutic index, extreme gastric adverse effects and bone marrow suppression. The purpose of the present study was the preparation of a dual-targeted delivery system of MMC for targeting CD44 and LHRH overexpressed receptors of breast cancer. MMC loaded LHRH targeted chonderosome was prepared by precipitation method and was characterized for their physicochemical properties. Cell cycle arrest and cytotoxicity tests were studied on cell lines of MCF-7, MDA-MB231 and 4T1 (as CD44 and LHRH positive cells) and BT-474 cell line (as CD44 negative receptor cells). The in vivo histopathology and antitumor activity of MMC-loaded chonderosomes were compared with free MMC in 4T1 cells inducing breast cancer in Balb-c mice. MMC loaded LHRH targeted chonderosomes caused 3.3 and 5.5 fold more cytotoxicity on MCF-7 and 4T1 cells than free MMC at concentrations of 100μM and 10μM, respectively. However, on BT-474 cells the difference was insignificant. The cell cycle test showed no change for MMC mechanism of action when it was loaded in chonderosomes compared to free MMC. The in vivo antitumor studies showed that MMC loaded LHRH targeted chonderosomes were 6.5 fold more effective in the reduction of tumor volume than free MMC with the most severe necrosis compared to non-targeted chonderosomes in pathological studies on harvested tumors. The developed MMC loaded LHRH targeted chonderosomes were more effective in tumor growth suppression and may be promising for targeted delivery of MMC in breast cancer.

Enhanced Anti-tumor of Pep-1 Modified Superparamagnetic Iron Oxide/PTX Loaded Polymer Nanoparticles.

Superparamagnetic iron-oxide nanoparticle (SPION) has gained tremendous attention for drug delivery applications due to their unique properties. In this study, we developed a dual targeted delivery system with paclitaxel (PTX) and SPION co-loaded PLGA nanoparticles, modified with Pep-1 peptide (Pep-NP-SPION/PTX), to achieve magnetic targeting and active targeting for tumor treatment. SPION was synthesized by a co-precipitation method and was then encapsulated with PTX simultaneously into PLGA nanoparticles. After that, the non-complex was conjugated with Pep-1 through chemical modification. The resulting Pep-NP-SPION/PTX showed a spherical morphology and an average size of 100 nm. The enhancement cellular uptake of Pep-NP-SPION was demonstrated in in vitro through cell experiments. The IC50 value of Pep-NP-SPION/PTX and NP-SPION/PTX was determined to be 10.2 and 19.4 μg/mL, respectively. A biodistribution study showed that obvious higher accumulations of Pep-NP-SPION was observed in tumors, compared with that of non-targeting nanocomposites. Moreover, under the condition of a magnetic field, both NP-SPION and Pep-NP-SPION exhibited much higher tumor distribution. Furthermore, Pep-NP-SPION/PTX presented desirable in vivo anti-tumor effects based on active targeting and magnetic targeting characteristics. Altogether, Pep-NP-SPION/PTX can offer magnetic targeting and receptor mediated targeting to enhance the anti-tumor outcome.

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.

Dual‐Targeted Supramolecular Vesicles Based on the Complex of Galactose Capped Pillar[5]Arene and Triphenylphosphonium Derivative for Drug Delivery

AbstractIn this study, a dual targeted supramolecular glycol‐vesicle based on the host‐guest complexation of galactose capped pillar[5]arene (GALWP5) and triphenylphosphonium derivative (D‐TPP) have been constructed (GALWP5⊃D‐TPP), which showed dual target potential (cell and mitochondria targeting) resulting from its galactose units and TPP units, respectively. The dual targeted glycol‐vesicle displays ignorable cytotoxicity and good mitochondria targeting. Our work presents a good example of rational design for an effective cell and subcellular organelles dual targeted delivery system.

Glioma Therapy: Combination Glioma Therapy Mediated by a Dual-Targeted Delivery System Constructed Using OMCN-PEG-Pep22/DOX (Small 42/2018)

Glioma Therapy: Combination Glioma Therapy Mediated by a Dual-Targeted Delivery System Constructed Using OMCN-PEG-Pep22/DOX (Small 42/2018)

A dual-targeting reconstituted high density lipoprotein leveraging the synergy of sorafenib and antimiRNA21 for enhanced hepatocellular carcinoma therapy

Sorafenib (So) is a multi-target kinase inhibitor extensively used in clinic for hepatocellular carcinoma therapy. It demonstrated strong inhibition both in tumor proliferation and tumor angiogenesis, while hampered by associated cutaneous side-effect and drug resistance. The knockdown of miR-21 with antisense oligonucleotides (antimiRNA21) was regarded as an efficient strategy for increasing tumor sensibility to chemotherapy, which could be employed to appreciate the efficacy of So. Herein, we successfully formulated a dual-targeting delivery system for enhanced hepatocellular carcinoma therapy by encapsulating So and antimiRNA21 in RGD pentapeptide-modified reconstituted high-density lipoprotein (RGD-rHDL/So/antimiRNA21). The RGD and apolipoprotein A-I (ApoA-I) on nanoparticles (NPs) could drive the system simultaneously to tumor neovascular and parenchyma by binding to the overexpressed ανβ3-integrin and SR-B1 receptors, achieving precise delivery of therapeutics to maximize the efficacy. A series in vitro and in vivo experiments revealed that co-delivery of So and antimiRNA21 by RGD-rHDL significantly strengthened the anti-tumor and anti-angiogenic effect of So with negligible toxicity towards major organs, reversed drug-resistance and was capable of remodeling tumor environments. The constructed RGD-rHDL/So/antimiRNA21 with improved efficacy and excellent tumor targeting ability provided new idea for chemo-gene combined therapy in hepatocellular carcinoma. Statement of SignificanceSorafenib (So) is a multi-target kinase inhibitor which was approved by FDA as first-line drug for hepatocellular carcinoma (HCC) therapy. However, long term application of So in clinic was hampered by serious dermal toxicity and drug resistance. Although numerous researchers were devoted to finding alternatives or therapies as combination treatments with So to reach more desired therapeutic efficacy, the therapeutic options were still limited. The present study prepares RGD pentapeptide decorated biomimic reconstituted high-density lipoprotein (rHDL) loaded with So and antimiRNA21 (RGD-rHDL/So/antimiRNA21) for enhanced HCC therapy. The RGD-rHDL/So/antimiRNA21 NPs offer an effective platform for anti-tumor and anti-angiogenesis therapy in HCC and provide new approach to reverse drug-resistance of So for feasible clinical application.