Polyethylene Glycol-phosphatidylethanolamine Research Articles

Coumarin derivative dye sensitized NaYGdF4:Yb,Er nanoparticles with enhanced NIR II luminescence for bio-vascular imaging

Lanthanide-doped biocompatible nanoparticles have promising applications in near-infrared second region imaging due to their high chemical stability, enhanced photostability and sharp emission bandwidth. However, the weak light absorption capacity limits the application of rare-earth nanoparticles (RENPs) for bioimaging. We prepared a coumarin-derived dye sensitized NaYGdF4:Yb,Er nanoparticle probe, in which the organic dye enhances photon absorption through the sensitization process, improving the luminescence efficiency of the rare earth particles near 1000 and 1500 nm. In addition, good water solubility and stability of the probe are imparted by coating the particles with amphiphilic polymers distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) and polyacrylic acid. This composite probe with good biocompatibility and NIR II luminescence properties can be used for vascular imaging, providing a tool for the detection of hematologic-related diseases.

Imidazole-Based pH-Sensitive Convertible Liposomes for Anticancer Drug Delivery.

In efforts to enhance the activity of liposomal drugs against solid tumors, three novel lipids that carry imidazole-based headgroups of incremental basicity were prepared and incorporated into the membrane of PEGylated liposomes containing doxorubicin (DOX) to render pH-sensitive convertible liposomes (ICL). The imidazole lipids were designed to protonate and cluster with negatively charged phosphatidylethanolamine-polyethylene glycol when pH drops from 7.4 to 6.0, thereby triggering ICL in acidic tumor interstitium. Upon the drop of pH, ICL gained more positive surface charges, displayed lipid phase separation in TEM and DSC, and aggregated with cell membrane-mimetic model liposomes. The drop of pH also enhanced DOX release from ICL consisting of one of the imidazole lipids, sn-2-((2,3-dihexadecyloxypropyl)thio)-5-methyl-1H-imidazole. ICL demonstrated superior activities against monolayer cells and several 3D MCS than the analogous PEGylated, pH-insensitive liposomes containing DOX, which serves as a control and clinical benchmark. The presence of cholesterol in ICL enhanced their colloidal stability but diminished their pH-sensitivity. ICL with the most basic imidazole lipid showed the highest activity in monolayer Hela cells; ICL with the imidazole lipid of medium basicity showed the highest anticancer activity in 3D MCS. ICL that balances the needs of tissue penetration, cell-binding, and drug release would yield optimal activity against solid tumors.

Mn-dox metal-organic nanoparticles for cancer therapy and magnetic resonance imaging

The high toxicity and side effects of drugs as well as the difficulty of tracking their trends and metabolism have always been the core difficulties of anticancer drugs. In this paper, doxorubicin (DOX) was used as therapeutic drug to coordinate with Mn2+ to obtain the hydrophobic core of nanomedicine. The outer layer was self-assembled and coated with amphiphilic block copolymer-distearyl phosphatidylethanolamine-polyethylene glycol (DSPE-mPEG2000) to form Mn-DOX@DSPE-mPEG2000 micellar nanoparticles (MDDM NPs) with good dispersion and stability. Cell experiments showed that MDDM micellar nanoparticles could be effectively uptaked by cells in a short time, and had good biocompatibility and tumor inhibition. In vivo experiments have shown that nanoparticles not only have excellent therapeutic effects, but also have magnetic resonance imaging contrast as contrast agents due to Mn2+ coordination, which can assist in tracking drug trends and metabolism in vivo. The above work provides a certain reference significance for the study of combining organic drugs with metals to realize the reduction of drug toxicity and provide multimodal function of metals.

Long-circulating doxorubicin and schizandrin A liposome with drug-resistant liver cancer activity: preparation, characterization, and pharmacokinetic

The selectivity of chemotherapeutic agents for liver cancer is poor. When they kill tumour cells, they produce serious adverse reactions in the whole body and multidrug resistance (MDR) is also a major hurdle in liver cancer chemotherapy. Combination therapy is a useful method for overcoming MDR and reducing toxic and side effects. In this study, we developed a long-circulating codelivery system, in which doxorubicin (DOX) and schizandrin A (SchA) are combined against MCF-7/ADR cells. The DOX-SchA long-circulating liposome (DOX-SchA-Lip) was prepared using ammonium sulphate gradient method. The two drugs were co-encapsulated into the distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-mPEG2000) liposome and the liposome had an average particle size of (100 ± 3.5) nm and zeta electrical potential of (–31.3 ± 0.5) mV. The average encapsulation rate of DOX was 97.98% and that of SchA was 86.94%. DOX in liposome had good sustained-release effect. The results showed that DOX-SchA-Lip could significantly prolong the half-life (t 1/2z) of the DOX and SchA, increase their circulation time in vivo, improve its bioavailability and reduce their side effects. Liposome can effectively induce early apoptosis of HepG2/ADR cells and the cell cycle was blocked in S-phase by DOX-SchA-Lip in a dose-dependent manner. The IC50 of compound liposome to HepG2 and HepG2/ADR were 0.55 μmol/L and 1.38 μmol/L, respectively, which could significantly reverse the resistance of HepG2/ADR and the reversion multiple was 30.28. It was verified that DOX-SchA-Lip can effectively kill tumour cells and reverse MDR.

Surface PEGylated Cancer Cell Membrane-Coated Nanoparticles for Codelivery of Curcumin and Doxorubicin for the Treatment of Multidrug Resistant Esophageal Carcinoma

ObjectiveThe emergence of multi-drug resistance (MDR) in esophageal carcinoma has severely affected the effect of chemotherapy and shortened the survival of patients. To this end, we intend to develop a biomimetic nano-targeting drug modified by cancer cell membrane, and investigate its therapeutic effect.MethodsThe degradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) co-loaded with doxorubicin (DOX) and curcumin (Cur) were prepared by solvent evaporation method. TE10 cell membrane and Distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) were then coated on the PLGA NPs by membrane extrusion to prepare the PEG-TE10@PLGA@DOX-Cur NPs (PMPNs). Size and zeta potential of the PMPNs were analyzed by lazer particle analyzer, and the morphology of PMPNs was observed by transmission electron microscope. The TE10 cell membrane protein on PMPNs was analyzed by gel electrophoresis. The DOX-resistant esophageal cancer cell model TE10/DOX was established through high-dose induction. The In vitro homologous targeting ability of PMPNs was evaluated by cell uptake assay, and the in vitro anti-tumor effect of PMPNs was assessed through CCK-8, clone formation and flow cytometry. A Balb/c mouse model of TE10/DOX xenograft was constructed to evaluate the anti-tumor effect in vivo and the bio-safety of PMPNs.ResultsThe prepared cell membrane coated PMPNs had a regular spherical structure with an average diameter of 177 nm. PMPNs could directly target TE10 and TE10/DOX cells or TE10/DOX xenografted tumor and effectively inhibit the growth of DOX-resistant esophageal carcinoma. Besides, the PMPNs was confirmed to have high biosafety.ConclusionIn this study, a targeted biomimetic nano-drug delivery system PMPNs was successfully prepared, which overcome the MDR of esophageal carcinoma by co-delivering DOX and sensitizer curcumin.

Enhanced lymphatic delivery of nanomicelles encapsulating CXCR4-recognizing peptide and doxorubicin for the treatment of breast cancer

Lymph node metastases in cancer patients are associated with high aggressiveness, poor prognosis, and short survival time. The chemokine receptor 4 (CXCR4)/stroma derived factor 1α (CXCL12) biological axis plays a critical role in the spread of cancer cells. Designing effective delivery systems that can successfully deliver CXCR4 antagonists to lymph nodes, which are rich in CXCR4-overexpressing cancer cells, for controlling cancer metastasis remain challenging. In this study, we demonstrated that such a challenge may be alleviated by developing nanometer-sized polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles for the co-delivery of the CXCR4 antagonistic peptide E5 and doxorubicin (M-E5-Dox). This nanomicelle platform enables the preferential accumulation of cargos into lymph nodes and thus can better inhibit cancer metastasis and enhance antitumor efficacy than either free drugs or single drug-loaded micelles in breast cancer-bearing mouse models. Hence, M-E5-Dox is expected to be a potential therapeutic agent that would improve the clinical benefits of breast cancer therapy and treatment of various CXCR4-overexpressing malignancies.

Characterization of DMXAA‐Loaded Reconstituted High‐Density Lipoprotein Nanoparticles

DMXAA is a drug agonist of the stimulator of interferon genes (STING) receptor. As such, it is capable of modulating the functional phenotype of tumor‐associated macrophages (TAMs) that originate from infiltrating monocytes and tissue‐resident macrophages. TAMs can account for up to 50% of the tumor mass and are recognized as major contributors to tumorigenesis. The pro‐tumoral activity of TAMs is linked to the ability of cancer cells and other components of the tumor microenvironment (TME) to educate TAMs, inducing them to take on a tumor‐promoting (M2) phenotype. The classical phenotype of macrophages (M1) is pro‐inflammatory and can facilitate anti‐tumoral effects. The M2 phenotype, on the other hand, sustains tumor growth, immunosuppression, matrix remodeling and metastasis. Amongst the several immunotherapy strategies used to target TAMs, DMXAA has been used to reverse the phenotype of TAMs back to the anti‐tumoral M1 phenotype in murine models of cancer. In order to avoid off‐target effects, there is a need to develop delivery strategies to direct such macrophage phenotype‐modulating drugs specifically to the tumor site since macrophages are present in all vertebrate tissues, contribute to homeostasis and act as central mediators of immune response. Biocompatible nanoparticles offer a way to achieve the selective delivery of DMXAA to TAMs, and reconstituted high‐density lipoprotein type nanoparticles (rHDL Nps) are particularly suitable for such task. Previous studies have shown that rHDL Nps readily penetrate the TME and scavenger receptors mediate the intracellular delivery of the rHDL payload. Protein expression analysis showed that M2 macrophages express these scavenger receptors. For the purpose of delivering DMXAA to TAMs and achieving a phenotype reversal, rHDL Nps transporting DMXAA (rHDL‐DMXAA) were prepared via a microfluidics process and characterized via dynamic light scattering (33.9 ± 14.28 nm particle diameter size). The fast protein liquid chromatography profile of this formulation suggested a homogeneous preparation with an estimated molecular weight of particles of about 132.3 kDa. The DMXAA encapsulation efficiency which was initially about 30.4 ± 12.4 % doubled when polyethylene glycol–phosphatidylethanolamine was included in the formulation. The rHDL‐DMXAA particles displayed increased fluorescence anisotropy over the free drug, indicating that the majority of DMXAA molecules were trapped in the core of the rHDL carrier. The characteristics of the rHDL‐DMXAA such as the small size of the particle and the receptor‐mediated uptake by the target cells suggest that DMXAA will be efficiently delivered to TAMs in the TME via the rHDL Nps. Thus, the rHDL‐DMXAA formulation is likely to impact tumor progression with potential therapeutic implications.Support or Funding Information2019 UNTHSC intramural seed grant

Delivered antigen peptides to resident CD8α+ DCs in lymph node by micelle-based vaccine augment antigen-specific CD8+ effector T cell response

Although nanoparticle vaccine is one of the promising therapeutic vaccines against cancers and many chronic infections, induction of strong and long-lasting antigen specific T cell response has still remained many challenges. A major challenge in achieving a robust CD8+ T cell response is the requirement of spatio-temporal orchestration of antigen cross-presentation in dendritic cells with innate stimulation. CD8α+ DCs are specialized for cross presentation and critical for cytotoxic T cell responses, which locate in the deeper paracortex of lymph nodes (LNs) in mice. However, due to size exclusion of compartmentalized network in LNs, nanoparticles with a radius of larger than 5 nm are difficult to access to the CD8α+ DCs. Here, we showed that polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles had an extensive contact with the resident CD8α+ DCs in LNs and delivered more OVA peptides than their free form to these DCs. Meanwhile, successfully delivering antigens into the CD8α+ DCs resulted in the increased cross presentation of antigens and the enhanced generation of effector CD8+ T cell. Our findings further demonstrated the critical role of CD8α+ DCs in cytotoxic T cell immunity in response to PEG-PE micelle-based vaccine, and also provided a valuable approach to generate T cell-mediated immune response.

Targeted delivery of DOX by transferrin conjugated DSPE-PEG nanoparticles in leukemia therapy

In this study, transferrin (Tf) conjugated distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) nanoparticles (DPT) was successfully prepared to deliver doxorubicin (DOX) to improve the chemotherapy efficacy of K562 leukemia cells. The results show that DPT were nanosized and presented spherical shaped particles, and the average particle size is about 80 nm. The DOX encapsulation efficiency of DPT was >70%. These nanoparticles could release DOX in the acid nucleus and facilitate the delivery of DOX after endocytosis. In addition, DPT is more targeted to K562 cancer cells than DSPE-PEG nanoparticles (DP). To be specific, the cytotoxic effect of DPT on cancer cells was significantly higher than that of DP, indicating that the tf modified nanoparticle system has better targeting efficiency. In summary, the results clearly show that the targeting of leukemia cells by the Tf -coupled nanoparticle system may pave the way for successful treatment of leukemia.

CRYPTOSOMES: A REVOLUTIONARY BREAKTHROUGH IN NOVEL DRUG DELIVERY

The vesicular drug delivery systems are promising approaches to overthrown the problems of drugs having lesser bioavailability and rapid elimination from the body. The four type of lipid based drug delivery systems are: solid-lipid particulate system, emulsion based system, solid lipid tablet and vesicular system. Cryptosomes, a novel emerging vesicular drug delivery system which can overcome the disadvantages associated with conventional drug delivery systems like high stability, increased bioavailability, sustained release, decreased elimination of rapidly metabolizable drugs etc. The word Cryptosome was orginated from Greek word ‘’Crypto’’ means hidden and ‘’Soma’’ means body. It is formed from the mixture of phospholipids like distearoyl phosphatidyl ethanolamine-polyethylene glycol (DSPE-PEG) with distearoylphosphatidylcholine. These entire information regarding its origin and formation is explained in Dinesh Kumar et al. Vesicular systems symbolizes the use of vesicles in the different fields as carrier system or additives. This review disclose various vesicular drug delivery system and point out the advancement of cryptosome in the world of drug delivery.This review would help researchers involved in the field of vesicular drug delivery.

αvβ3 integrin receptor specific peptide modified, salvianolic acid B and panax notoginsenoside loaded nanomedicine for the combination therapy of acute myocardial ischemia

PurposeTo achieve the combination therapy of acute myocardial ischemia, arginyl-glycyl-aspartic acid (RGD) conjugated lipid was synthesized and RGD modified, salvianolic acid B (Sal B) and panax notoginsenoside (PNS) co-loaded lipid-polymer hybrid nanoparticles (RGD-S/P-LPNs) was fabricated an evaluated. MethodsRGD was conjugated to distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG-NH2) through amide linkage. Lipid-polymer hybrid nanoparticles (LPNs) were fabricated by nanoprecipitation method. RGD-S/P-LPNs was characterized in terms of morphology, size, charge, drug loading, entrapment, stability, drug release and cytotoxicity in vitro. Cardiac distribution, pharmacokinetics study and infarct therapy effect were evaluated in vivo. ResultsThe LPNs are generally spherical in shape with uniform size distribution, have sizes of 100–200nm and zeta potentials range from −30.7∼ −39.8. In vitro release behaviors of drugs loaded LPNs are in a sustained release manner, which does not exhibit obviously cytotoxicity against H9c2 cardiomyocytes. RGD-S/P-LPNs group shows the most significant cardiac distribution and infarct therapy effect in vivo. ConclusionThe results illustrated that RGD modified dual drugs co-loaded LPNs are stable, sustained release carriers. Cardiac distribution, pharmacokinetics, and infarct therapy effect results suggested that the RGD-S/P-LPNs could improve the in vivo therapeutic efficacy of the double drugs.

PEG-PE/clay composite carriers for doxorubicin: Effect of composite structure on release, cell interaction and cytotoxicity.

DOX PEG-PE/clay formulations were design as an efficient drug delivery system. The main aim was to develop PEG-PE/clay formulations of different structures based on various PEG-PE/clay ratios in order to achieve tunable release rates, to control the external surface characteristics and formulation stability. The formulations showed significantly higher toxicity in comparison to "free" DOX, explained by formulation internalization. For each cell line tested, sensitive and ADR resistant, a different formulation structure was found most efficient. The potential of PEG-PE/clay-DOX formulations to improve DOX administration efficacy was demonstrated and should be further explored and implemented for other cancer drugs and cells.

Coordinating antigen cytosolic delivery and danger signaling to program potent cross-priming by micelle-based nanovaccine

Although re-activating cytotoxic T-cell (CTLs) response inside tumor tissues by checkpoint blockade has demonstrated great success in tumor immunotherapy, active induction of efficient endogenous CTL response by therapeutic vaccines has been largely hampered by inefficient cytosolic delivery of antigens and coordinated activation of dendritic cells (DCs) in lymph nodes. Here we show that polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles transform soluble peptides into α-helix to enable their efficient cytosolic delivery. The same PEG-PE micelles also serve as chaperon of TLR4 signaling to coordinate its adjuvant effect on the same DCs. Furthermore, these nanovaccines effectively target lymph node DCs. Thus, PEG-PE micelle vaccines program at multiple key aspects for inducing strong CTL responses and build up a foundation for combinational tumor therapy.

The reversal of multidrug resistance in ovarian carcinoma cells by co-application of tariquidar and paclitaxel in transferrin-targeted polymeric micelles

In this study, a transferrin (Tf)-modified polyethylene glycol-phosphatidyl ethanolamine (PEG-PE)-based micellar delivery system containing paclitaxel (PTX) and tariquidar (TRQ), a potent third generation P-gp inhibitor, was prepared. The nanoformulation was evaluated by targeting efficiency, cellular association, cellular internalization pathway and cytotoxicity for reversal of PTX resistance on two multidrug resistant (MDR) ovarian carcinoma cell lines, SKOV-3TR and A2780-Adr. PTX and TRQ are both hydrophobic compounds. They were successfully encapsulated into the micellar structure containing vitamin E as the encapsulation enhancer. The Tf-targeted micelles were internalized mainly via clathrin-dependent endocytosis by both cell lines. For SKOV-3TR, additional mechanisms including caveolin-dependent endocytosis and macropinocytosis were found to play a significant role. The PTX cytotoxicity against the SKOV-3TR and A2780-Adr MDR cells was increased significantly in the presence of micellar encapsulation. However, unlike the A2780-Adr cell line, the Tf-targeting effect was significant on SKOV-3TR cells when co-administrated with TRQ. Penetration of the Tf-targeted micelles in a cancer cell spheroid culture was also investigated.

Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance.

In this study, a type of multifunctional mixed micelles were prepared by a novel biodegradable amphiphilic polymer (MPEG-SS-2SA) and a multidrug resistance (MDR) reversal agent (d-α-tocopheryl polyethylene glycol succinate, TPGS). The mixed micelles could achieve rapid intracellular drug release and reversal of MDR. First, the amphiphilic polymer, MPEG-SS-2SA, was synthesized through disulfide bonds between poly (ethylene glycol) monomethyl ether (MPEG) and stearic acid (SA). The structure of the obtained polymer was similar to poly (ethylene glycol)-phosphatidylethanolamine (PEG-PE). Then the mixed micelles, MPEG-SS-2SA/TPGS, were prepared by MPEG-SS-2SA and TPGS through the thin film hydration method and loaded paclitaxel (PTX) as the model drug. The in vitro release study revealed that the mixed micelles could rapidly release PTX within 24 h under a reductive environment because of the breaking of disulfide bonds. In cell experiments, the mixed micelles significantly inhibited the activity of mitochondrial respiratory complex II, also reduced the mitochondrial membrane potential, and the content of adenosine triphosphate, thus effectively inhibiting the efflux of PTX from cells. Moreover, in the confocal laser scanning microscopy, cellular uptake and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assays, the MPEG-SS-2SA/TPGS micelles achieved faster release and more uptake of PTX in Michigan Cancer Foundation-7/PTX cells and showed better antitumor effects as compared with the insensitive control. In conclusion, the biodegradable mixed micelles, MPEG-SS-2SA/TPGS, could be potential vehicles for delivering hydrophobic chemotherapeutic drugs in MDR cancer therapy.

Paclitaxel-loaded PEG-PE-based micellar nanopreparations targeted with tumor-specific landscape phage fusion protein enhance apoptosis and efficiently reduce tumors.

In an effort to improve the therapeutic index of cancer chemotherapy, we developed an advanced nanopreparation based on the combination of landscape phage display to obtain new targeting ligands with micellar nanoparticles for tumor targeting of water-insoluble neoplastic agents. With paclitaxel as a drug, this self-assembled nanopreparation composed of MCF-7-specific phage protein and polyethylene glycol-phosphatidylethanolamine (PEG-PE) micelles showed selective toxicity to target cancer cells rather than nontarget, non cancer cells in vitro. In vivo, the targeted phage micelles triggered a dramatic tumor reduction and extensive necrosis as a result of improved tumor delivery of paclitaxel. The enhanced anticancer effect was also verified by an enhanced apoptosis and reduced tumor cell proliferation following the treatment with the targeted micellar paclitaxel both in vitro and in vivo. The absence of hepatotoxicity and pathologic changes in tissue sections of vital organs, together with maintenance of overall health of mice following the treatment, further support its translational potential as an effective and safe chemotherapy for improved breast cancer treatment.

The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors

Multicellular 3D cancer cell culture (spheroids) resemble to in vivo tumors in terms of shape, cell morphology, growth kinetics, gene expression and drug response. However, these characteristics cause very limited drug penetration into deeper parts of the spheroids. In this study, we used multi drug resistant (MDR) ovarian cancer cell spheroid and in vivo tumor models to evaluate the co-delivery of paclitaxel (PCL) and a potent NF-κB inhibitor curcumin (CUR). PCL and CUR were co-loaded into the polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) based polymeric micelles modified with transferrin (TF) as the targeting ligand. Cytotoxicity, cellular association and accumulation into the deeper layers were investigated in the spheroids and compared with the monolayer cell culture. Comparing to non-targeted micelles, flow cytometry and confocal imaging proved significantly deeper and higher micelle penetration into the spheroids with TF-targeting. Both in monolayers and in spheroids, PCL cytotoxicity was significantly increased when co-delivered with CUR in non-targeted micelles or as single agent in TF-targeted micelles, whereas TF-modification of co-loaded micelles did not further enhance the cytotoxicity. In vivo tumor inhibition studies showed good correlation with the 3D cell culture experiments, which suggests the current spheroid model can be used as an intermediate model for the evaluation of co-delivery of anticancer compounds in targeted micelles.

Polyethylene glycol-phosphatidylethanolamine (PEG-PE)/vitamin E micelles for co-delivery of paclitaxel and curcumin to overcome multi-drug resistance in ovarian cancer

The therapeutic potential of mixed micelles, made of PEG-PE and vitamin E co-loaded with curcumin and paclitaxel, was investigated against SK-OV-3 human ovarian adenocarcinoma along with its multi-drug resistant version SK-OV-3-paclitaxel-resistant (TR) cells in vitro and in vivo. The addition of curcumin at various concentrations did not significantly enhance the cytotoxicity of paclitaxel against SK-OV-3 in vitro. However, a clear synergistic effect was observed with the combination treatment against SK-OV-3TR in vitro. In vivo, this combination treatment produced a three-fold tumor inhibition with each of these cell lines. Our results indicate that such co-loaded mixed micelles could have significant clinical advantages for the treatment of resistant ovarian cancer.

Transferrin- and folate-modified, double-targeted nanocarriers for gene delivery

Context: Surface modification of nanocarriers with specific ligands defines a new biological identity, which assist in targeting and internalization of the nanocarriers to specific cell populations, such as cancers and disease organs.Objective: This study aimed to develop systemically administrable dual ligands modified nanocarriers, which could target the cells through receptor-mediated pathways to increase the nuclear uptake of genetic materials.Materials and methods: In the present work, transferrin (Tf) and folate (Fa) were linked onto polyethylene glycol-phosphatidylethanolamine (PEG-PE) separately to get transferrin-PEG-PE (T-PEG-PE) and folate-PEG-PE (F-PEG-PE) ligands for the surface modification of carriers. The in vivo transfection efficiency of the novel dual ligands modified (D-modified) vectors were evaluated in tumor-bearing animal models.Results: D-Modified solid lipid nanoparticles/enhanced green fluorescence protein plasmid (D-SLN/pEGFP) has a particle size of 226 nm and a gene-loading quantity of 90%. D-SLN/pEGFP displayed over 30% higher transfection efficiency than unmodified SLN/pEGFP and single ligand modified particles in HepG2 cells.Conclusion: It could be concluded that Tf and Fa could function as excellent active targeting ligands to improve the cell-targeting ability of the carriers and the resulting dual ligands modified vectors could be applied as a promising active targeting gene delivery system.

Polymeric micelles for enhanced lymphatic drug delivery to treat metastatic tumors

Polymeric micelles have been proven to be a promising nano-sized system for drug delivery. Understanding its in vivo behaviors at the whole body, tissue and cellular levels is critical for translating this drug delivery system into clinical practice. In this study, the 14.5nm micelles made of polyethylene glycol-phosphatidylethanolamine (PEG-PE) for delivery of doxorubicin and vinorelbine were investigated. Using confocal and two-photon microscopy imaging of live mice or tissue sections, we observed that after systemic administration, the fluorescently labeled PEG-PE micelles encapsulating doxorubicin migrated through blood vessels in entirety into the interstitial tissue, collected by lymphatic vessels, and accumulated in lymph nodes. Importantly, encapsulated drugs such as vinorelbine (Nanovin), preferentially accumulate in lymph nodes when compared to the free drugs. Moreover, the in vivo bioluminescent imaging showed that Nanovin significantly reduced lymph node metastasis rate (P<0.05) in 4T1-luc2 murine breast tumor bearing mice. Finally, we observed that Nanovin enhanced antitumor activity against primary tumors and lung metastases while having low toxicity in various 4 T1 tumor models. This study suggests that PEG-PE micelle is a promising drug delivery system for the treatment of lymphatic metastases, and may also have important applications in other lymphatic system-related diseases.