Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting

Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.     

Paclitaxel-loaded PLGA nanoparticles surface modified with transferrin and Pluronic®P85, an in vitro cell line and in vivo biodistribution studies on rat model

The development of multidrug resistance (due to drug efflux by P-glycoproteins) is a major drawback with the use of paclitaxel (PTX) in the treatment of cancer. The rationale behind this study is to prepare PTX nanoparticles (NPs) for the reversal of multidrug resistance based on the fact that PTX loaded into NPs is not recognized by P-glycoproteins and hence is not effluxed out of the cell. Also, the intracellular penetration of the NPs could be enhanced by anchoring transferrin (Tf) on the PTX-PLGA-NPs. PTX-loaded PLGA NPs (PTX-PLGA-NPs), Pluronic^®P85-coated PLGA NPs (P85-PTX-PLGA-NPs), and Tf-anchored PLGA NPs (Tf-PTX-PLGA-NPs) were prepared and evaluted for cytotoxicity and intracellular uptake using C6 rat glioma cell line. A significant increase in cytotoxicity was observed in the order of Tf-PTX-PLGA-NPs > P85-PTX-PLGA-NPs > PTX-PLGA-NPs in comparison to drug solution. In vivo biodistribution on male Sprague–Dawley rats bearing C6 glioma (subcutaneous) showed higher tumor PTX concentrations in animals administered with PTX-NPs compared to drug solution.     

Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue

Surface-modified poly(d,l-lactic-co-glycolic acid) PLGA nanoparticles (NPs) were fabricated via nanoprecipitation for obtaining therapeutic concentration of paclitaxel (PTX) in brain tumor. The cellular uptake and cytotoxicity of NPs were evaluated on C6 glioma cells in vitro, and BALB/c mice were used to study the brain penetration and biodistribution upon intravenous administration. Results showed that by finely tuning nanoprecipitation parameters, PLGA NPs coated with surfactants with a size around 150 nm could provide a sustained release of PTX for >2 weeks. Surface coatings could increase cellular uptake efficiency when compared with noncoated NPs, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) showed the most significant enhancement. The in vivo evaluation of TPGS-PLGA NPs showed amplified accumulation (>800% after 96 h) of PTX in the brain tissue when compared with bare NPs and Taxol^®. Therefore, PLGA-NPs with PLGA-TPGS coating demonstrate a promising approach to efficiently transport PTX across blood-brain barrier in a safer manner, with the advantages of easy formulation, lower production cost, and higher encapsulation efficiency.     

Dextran microspheres could enhance immune responses against PLGA nanospheres encapsulated with tetanus toxoid and Quillaja saponins after nasal immunization in rabbit

Potent immunoadjuvants are needed to elicit responses following mucosal delivery. PLGA (poly[D,L-lactic-co-glycolic acid]) nanospheres, Quillaja saponin (QS) and cross-linked dextran microspheres (CDM) as drug delivery and absorption enhancer adjuvants were evaluated. PLGA nanospheres were prepared by solvent evaporation method. Particulate characteristics of nanospheres were studied by optical and scanning electron microscopes and dynamic light scattering technique. The mean diameter of nanospheres encapsulated with TT and TT?+?QS determined as 425 and 390?nm. Loadings of TT and QS were 30?±?1.9% and 23?±?2.8%. Nanospheres encapsulated with TT or QS were intranasally administered to rabbits, three times in two-week intervals and the serum IgG and nasal lavage IgA titers were determined by ELISA. The serum IgG titer induced with (TT)_PLGA nanospheres was higher than TT solution (P?<?0.001). IgG titers induced with (TT?+?QS)_PLGA was higher than (TT)_PLGA (P?<?0.0001). When (TT)_PLGA and (TT?+?QS)_PLGA nanospheres were mixed with CDM, higher IgG titers were induced (P?<?0.001). The highest mucosal sIgA titers were seen in animals immunized with (TT?+?QS)_PLGA?+?CDM. Co-encapsulation of QS and TT in PLGA nanospheres increased sIgA titers. In conclusion, the highest immune responses were observed by concomitant use of three adjuvants.     

Paclitaxel-loaded polyester nanoparticles prepared by spray-drying technology: in vitro bioactivity evaluation

Paclitaxel (PTX), an antimicrotubular agent used in the treatment of ovarian and breast cancer, was encapsulated in nanoparticles (NPs) of poly(lactide-co-glycolide) (PLGA) and poly(ε-caprolactone) (PCL) polymers using the spray-drying technique. Morphology, size distribution, drug encapsulation efficiency, thermal degradation and drug release were characterized. MCF7 cells were employed to evaluate the efficacy of the systems on cell cycle and cytotoxicity. The particle size was in the range 0.8–1?µm. The incorporation efficiency of PTX was more than 80% in all NPs obtained. In vitro drug release took place during 35 days, and drug release rates were in the order PCL?>?PLGA 50:50?>?PLGA 75:25. Unloaded NPs showed to be cytocompatible at MCF7 cells. PTX-loaded NPs demonstrated the release of the drug block cells in the G2/M phase. All PTX-loaded formulations showed their efficacy in killing MCF7 cells, mainly PTX-loaded PLGA 50:50 and PLGA 75:25 that cause a decrease in cell viability lower than 20%.     

New approach to treating spinal cord injury using PEG-TAT-modified,cyclosporine-A-loaded PLGA/polymeric liposomes

Cyclosporine-A (CsA) is an immunosuppressant agent that has shown effectiveness as a neuroprotective drug; however, it does not readily cross the blood-spinal cord barrier (BSCB), which constrains the clinical applications of CsA for the treatment of spinal cord injury (SCI). Our group recently tested the ability of novel polyethylene glycol (PEG)-transactivating-transduction protein (TAT)-modified CsA-loaded cationic multifunctional polymeric liposome-poly(lactic-co-glycolic acid) (PLGA) core/shell nanoparticles (PLGA/CsA NPs) to transport and deliver CsA across the BSCB to treat SCI. The PLGA/CsA NPs were successfully constructed. In vitro drug release studies have demonstrated that the sustained release of CsA from PLGA/CsA NPs occurs over ～25?h. The in vivo study presented here showed that injured animals that received PLGA/CsA NPs through the tail vein, exhibited a significant up-regulation of growth-associated protein-43 (GAP-43) expression and an increased number of GAP-43-stained neurons compared with animals that received CsA or the vehicle alone. The improvement in neurological function was also evaluated by the Basso–Beattie–Bresnahan (BBB) open-field test. Moreover, fluorescein isothiocyanate (FITC)-attached PLGA/CsA NPs were successfully aggregated in the intact spinal cord 4?h after injection. Our data suggest that PLGA/CsA NPs have the potential for use as a new treatment method for SCI.     

Does ligand–receptor mediated competitive effect or penetrating effect of iRGD peptide when co-administration with iRGD-modified SSL?

Ligand-mediated targeting of anticancer therapeutic agents is a useful strategy for improving anti-tumor efficacy. It has been reported that co-administration of a tumor-penetrating peptide iRGD (CRGDK/RGPD/EC) enhances the efficacy of anticancer drugs. Here, we designed an experiment involving co-administration of iRGD-SSL-DOX with free iRGD to B16-F10 tumor bearing mice to examine the action of free iRGD. We also designed an experiment to investigate the location of iRGD-modified SSL when co-administered with free iRGD or free RGD to B16-F10 tumor bearing nude mice. Considering the sequence of iRGD, we selected the GPDC, RGD and CRGDK as targeting ligands to investigate the targeting effect of these peptides compared with iRGD on B16-F10 and MCF-7 cells, with or without enzymatic degradation. Finally, we selected free RGD, free CRGDK and free iRGD as ligand to investigate the inhibitory effect on RGD-, CRGDK- or iRGD-modified SSL on B16-F10 or MCF-7 cells. Our results indicated that iRGD targeting to tumor cells was ligand–receptor mediated involving RGD to αv-integrin receptor and CRGDK to NRP-1 receptor. Being competitive effect, the administration of free iRGD would not be able to further enhance the anti-tumor activity of iRGD-modified SSL. There is no need to co-administrate of free iRGD with the iRGD-modified nanoparticles for further therapeutic benefit.     

GSH-responsive SN38 dimer-loaded shape-transformable nanoparticles with iRGD for enhancing chemo-photodynamic therapy

Accurate tumor targeting, deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine. To achieve these requirements, a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer (d-SN38)-loaded nanoparticles (d-SN38@NPs/iRGD). Upon intravenous injection, d-SN38@NPs with high drug loading efficiency (33.92 ± 1.33%) could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD. The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy. The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm, which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor. In vitro, co-administering iRGD with d-SN38@NPs+laser showed higher cellular uptake, apoptosis ratio and multicellular spheroid penetration. In vivo, d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor, leading to 60.89% of tumor suppression in 4T1 tumor-bearing mouse model with a favorable toxicity profile. Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting, penetrating and retention, and empowers anticancer efficacy.     

Brain-targeted delivery of Tempol-loaded nanoparticles for neurological disorders

Brain-targeted Tempol-loaded poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) conjugated with a transferrin antibody (OX 26) were developed using the nanoprecipitation method. These NPs may have utility in treating neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Central to these diseases is an increased production of reactive oxygen and nitrogen species which may take part in the development of these conditions. As proof of principle, the NPs were loaded with Tempol, a free radical scavenger that has been shown to be protective against oxidative insults. To enhance the delivery of NPs to the central nervous system (CNS), we conjugated the transferrin receptor antibody covalently to PLGA NPs using the NHS-PEG3500-Maleimide crosslinker. The NPs showed a particle size suitable for blood brain barrier (BBB) permeation (particle size 80–110?nm) and demonstrated a sustained drug release behavior. A high cellular uptake of antibody-conjugated NPs was demonstrated in RG2 rat glioma cells. The ability of the Tempol-loaded NPs to prevent cell death by resveratrol in RG2 cells was determined using the MTT assay. The conjugated NPs containing Tempol were more effective in preventing cell viability by resveratrol when compared with unconjugated NPs or free Tempol in solution. Our findings suggest that transferrin-conjugated NPs containing antioxidants may be useful in the treatment of neurodegenerative diseases.     

Intracellular drug delivery in Leishmania-infected macrophages: Evaluation of saponin-loaded PLGA nanoparticles

Drug delivery systems present an opportunity to potentiate the therapeutic effect of antileishmanial drugs. Colloidal carriers are rapidly cleared by the phagocytic cells of the reticuloendothelial system (RES), rendering them ideal vehicles for passive targeting of antileishmanials. This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the antileishmanial saponin β-aescin. NPs were prepared using the combined emulsification solvent evaporation/salting-out technique. Confocal microscopy was used to visualise the internalisation and intracellular trafficking of fluorescein- and nile red-labelled PLGA NPs in J774A.1 macrophages infected with GFP-transfected Leishmania donovani. The in vitro activity of aescin and aescin-loaded NPs on L. infantum was determined in the axenic model as well as in the ex vivo model. The developed PLGA NPs were monodispersed with Z_ave<300?nm, exhibited negative zeta potentials and had relatively high drug loadings ranging from 5.80 to 8.68% w/w PLGA. The fluorescent NPs were internalised by the macrophages and trafficked towards the lysosomes after 2?h in vitro incubation. Co-localisation of the NPs and the parasite was not shown. A two-fold increase in activity was observed in the ex vivo macrophage model by encapsulating β-aescin in PLGA NPs (IC₅₀, 0.48–0.76 µg/mL vs. 1.55?±?0.32 µg/mL for the free drug).     

Compared in vivo toxicity in mice of lung delivered biodegradable and non-biodegradable nanoparticles

To design nanoparticle (NP)-based drug delivery systems for pulmonary administration, biodegradable materials are considered safe, but their potential toxicity is poorly explored. We here explore the lung toxicity in mice of biodegradable nanoparticles (NPs) and compare it to the toxicity of non-biodegradable ones. NP formulations of poly(d,l-lactide-co-glycolide) (PLGA) coated with chitosan (CS), poloxamer 188 (PF68) or poly(vinyl alcohol) (PVA), which renders 200?nm NPs of positive, negative or neutral surface charge respectively, were analyzed for their biodistribution by in vivo fluorescence imaging and their inflammatory potential after single lung nebulization in mice. After exposure, analysis of bronchoalveolar lavage (BAL) cell population, protein secretion and cytokine release as well as lung histology were carried out. The inflammatory response was compared to the one induced by non-biodegradable counterparts, namely, TiO₂ of rutile and anatase crystal form and polystyrene (PS). PLGA NPs were mostly present in mice lungs, with little passage to other organs. An increase in neutrophil recruitment was observed in mice exposed to PS NPs 24?h after nebulization, which declined at 48?h. This result was supported by an increase in interleukin (IL)-6 and tumor necrosis factor α (TNFα) in BAL supernatant at 24?h. TiO₂ anatase NPs were still present in lung cells 48?h after nebulization and induced the expression of pro-inflammatory cytokines and the recruitment of polymorphonuclear cells to BAL. In contrast, regardless of their surface charge, PLGA NPs did not induce significant changes in the inflammation markers analyzed. In conclusion, these results point out to a safe use of PLGA NPs regardless of their surface coating compared to non-biodegradable ones.     

Polydopamine-Based Surface Modification for the Development of Peritumorally Activatable Nanoparticles

Purpose

To create poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), where a drug-encapsulating NP core is covered with polyethylene glycol (PEG) in a normal condition but exposes a cell-interactive TAT-modified surface in an environment rich in matrix metalloproteinases (MMPs).

Methods

PLGA NPs were modified with TAT peptide (PLGA-pDA-TAT NPs) or dual-modified with TAT peptide and a conjugate of PEG and MMP-substrate peptide (peritumorally activatable NPs, PANPs) via dopamine polymerization. Cellular uptake of fluorescently labeled NPs was observed with or without a pre-treatment of MMP-2 by confocal microscopy and flow cytometry. NPs loaded with paclitaxel (PTX) were tested against SKOV-3 ovarian cancer cells to evaluate the contribution of surface modification to cellular delivery of PTX.

Results

While the size and morphology did not significantly change due to the modification, NPs modified with dopamine polymerization were recognized by their dark color. TAT-containing NPs (PLGA-pDA-TAT NPs and PANPs) showed changes in surface charge, indicative of effective conjugation of TAT peptide on the surface. PLGA-pDA-TAT NPs and MMP-2-pre-treated PANPs showed relatively good cellular uptake compared to PLGA NPs, MMP-2-non-treated PANPs, and NPs with non-cleavable PEG. After 3 h treatment with cells, PTX loaded in cell-interactive NPs showed greater toxicity than non-interactive ones as the former could enter cells during the incubation period. However, due to the initial burst drug release, the difference was not as clear as microscopic observation.

Conclusions

PEGylated polymeric NPs that could expose cell-interactive surface in response to MMP-2 were successfully created by dual modification of PLGA NPs using dopamine polymerization.     

Transferrin Adsorption onto PLGA Nanoparticles Governs Their Interaction with Biological Systems from Blood Circulation to Brain Cancer Cells

Purpose

Nanomedicines represent an alternative for the treatment of aggressive glioblastoma tumors. Behaviour of PLGA-nanoparticles (NPs) was here investigated as a function of their protein adsorption characteristics at the different biological interfaces they are expected to face in order to reach brain cancer cells.

Methods

NPs were studied for size, zeta potential, blood half-life, in vitro endocytic behavior and in vivo accumulation within healthy rat brain and brain tumors.

Results

While slightly modifying size (80 to 90?nm) and zeta potential (?44 to ?32?mV) protein coating of PLGA-NPs by bovine serum albumin (BSA) or transferrin (Tf) greatly prolonged their blood half-life when intravenously injected in rats and mice. In contrast with THP-1 monocytes, differentiated THP-1 macrophages, F98 glioma cells and astrocytes internalized BSA- and Tf-NPs in vitro. Increase of Tf-NP uptake by F98 cells through caveolae- and clathrin-mediated pathways supports specific interaction between Tf and overexpressed Tf-receptor. Finally, in vivo targeting of healthy brain was found higher with Tf-NPs than with BSA-NPs while both NPs entered massively within brain-developed tumors.

Conclusion

Taken together, those data evidence that Tf-NPs represent an interesting nanomedicine to deliver anticancer drugs to glioma cells through systemic or locoregional strategies at early and late tumor stages.     

Folic acid-modified and functionalized CuS nanocrystal-based nanoparticles for combined tumor chemo- and photothermal therapy

Recent studies have identified that CuS nanocrystal (CuS NCs) could be used as a new class of promising photo-thermal agents due to their excellent plasmonic absorption abilities in a wide near-infrared (NIR) region. However, most of nanocarriers lack target capacity for combining chemotherapy and photothermal therapy effects. Herein, we reported chitosan (CS)-encapsulated and folic acid (FA)-modified nanoparticles (NPs) simultaneously loading with functionalized CuS NCs and docetaxel (DTX) (FA-DTX-PVP/CuS-NPs). Compared with free DTX, the photothermal agent CuS NCs and DTX not only could be specially targeted to deliver into MCF-7 cancer cells via a receptor-mediated endocytosis pathway, but also could be effectively transferred into tumor tissues of S₁₈₀ tumor-bearing mice in vivo. More important, when combination with NIR laser irradiation, FA-DTX-PVP/CuS-NPs showed a higher antitumor efficacy than the individual therapies. Thus, as a remote and noninvasive tumor therapy strategy, these active targeting NPs may provide a great potential for tumor synergistic therapy.     

Combination therapy of surgical tumor resection with implantation of a hydrogel containing camptothecin-loaded poly(lactic-co-glycolic acid) microspheres in a C6 rat glioma model

We have developed a drug-loaded poly(lactic-co-glycolic acid) (PLGA) microsphere-containing thermoreversible gelation polymer (TGP) (drug/PLGA/TGP) formulation as a novel device for implantation after surgical glioma resection. TGP is a thermosensitive polymer that is a gel at body temperature and a sol at room temperature. When a drug/PLGA/TGP formulation is injected into a target site, PLGA microspheres in TGP gel localize at the injection site and do not diffuse across the entire brain tissue, and thus, sustained drug release from the PLGA microspheres at the target site is expected. Using in vivo imaging, we confirmed that the implantation of indocyanine green (ICG)/PLGA/TGP formulation exhibited a stronger localization of ICG at the injection site 28 d after injection compared with that of ICG/PLGA formulation. The therapeutic effect (mean survival) was evaluated in a C6 rat glioma model. Surgical tumor resection alone showed almost no effect on survival (controls, 18 d; surgical resection; 18.5 d). Survival was prolonged after the treatment with a camptothecin (CPT; 10 μg)/PLGA/TGP formulation (24 d). The combination treatment of surgical tumor resection and CPT/PLGA/TGP showed almost the same therapeutic effect (24 d) compared with CPT/PLGA/TGP alone, while the combination treatment produced long term survivors (>60 d). Therefore, the CPT/PLGA/TGP formulation can be an effective candidate for localized and sustained long-term glioma therapy.     

Doxorubicin-loaded galactose-conjugated poly(d,l-lactide-co-glycolide) nanoparticles as hepatocyte-targeting drug carrier

The objective of this work is to produce doxorubicin-loaded galactose-conjugated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) to be specifically recognised by human hepatoma cellular carcinoma (Hep G2) cells and assess NPs cytotoxicity. Doxorubicin-unloaded and doxorubicin-loaded galactose-conjugated PLGA NPs were prepared using an emulsion method and characterised for morphology, size, drug release behaviour, Hep G2 recognition and cell cytotoxicity. The produced doxorubicin-loaded PLGA-galactose-conjugate nanoparticles (PLGA-GAL NPs) are spherical in shape with a size of 365?±?74?nm, a drug encapsulation efficiency of 69% and released in a biphasic pattern with higher release rates at pH 5. In vitro cell studies confirmed the specific interaction between the receptors of Hep G2 and the PLGA-GAL NPs. Cell cytotoxicity tests showed that unloaded NPs are non-toxic and that doxorubicin-loaded NPs caused a cellular viability decrease of around 80%, therefore representing a promising approach to improve liver-specific drug delivery.     

Toxicity of surface-modified PLGA nanoparticles toward lung alveolar epithelial cells

In vitro cytotoxicity and inflammatory response following exposure to nanoparticles (NPs) made of poly(lactide-co-glycolide) (PLGA) have been investigated on A549 human lung epithelial cells. Three different PLGA NPs (230 nm) were obtained using different stabilizers (polyvinyl alcohol, chitosan, or Pluronic^® F68) to form respectively neutral, positively or negatively charged NPs. Polystyrene NPs were used as polymeric but non-biodegradable NPs, and titanium dioxide (anatase and rutile) as inorganic NPs, for comparison. Cytotoxicity was evaluated through mitochondrial activity as well as membrane integrity (lactate dehydrogenase release, trypan blue exclusion, propidium iodide staining). The cytotoxicity of PLGA-based and polystyrene NPs was lower or equivalent to the one observed after exposure to titanium dioxide NPs. The inflammatory response, evaluated through the release of the IL-6, IL-8, MCP-1, TNF-α cytokines, was low for all NPs. However, some differences were observed, especially for negative PLGA NPs that led to a higher inflammatory response, which can be correlated to a higher uptake of these NPs. Taken together, these results show that both coating of PLGA NPs and the nature of the core play a key role in cell response.     

Modified Paclitaxel-loaded Nanoparticles for Inhibition of Hyperplasia in a Rabbit Arterial Balloon Injury Model

Purpose This study tested the possibility of localized intravascular infusion of positive charged paclitaxel-loaded nanoparticles (NPs) to better prevent neointimal formation in a rabbit carotid artery injury model. Materials and Methods NPs were prepared by oil–water emulsion/solvent evaporation technique using biodegradable poly (lactide-co-glycolide) (PLGA). A cationic surfactant, didodecyldimethylammonium bromide (DMAB), was absorbed on the NP surface by electrostatic attraction between positive and negative charges. NPs were characterized in such aspects as size, surface morphology, surface charges as well as in vitro drug release profile. Balloon injured rabbit carotid arteries were treated with single infusion of paclitaxel-loaded NP suspension and observed for 28 days. The inhibitory effects of NPs on neointima formation were evaluated as end-point. Results NPs showed spherical shape with a diameter ranging from 200 to 500 nm. Negatively charged PLGA NPs shifted to positive after the DMAB modification. The in vitro drug release profile showed a biphasic release pattern. Morphometric analyses on the retrieved artery samples revealed that the inhibitory effect of intima proliferation was dose-dependent. At a concentration of 30 mg ml⁻¹, NP infusion completely inhibited intima proliferation in a rabbit vascular injury model. Conclusions Paclitaxel-loaded NPs with DMAB modification were proven an effective means of inhibiting proliferative response to vascular injury in a rabbit model.     

Long circulating PEGylated poly(d,l-lactide-co-glycolide) nanoparticulate delivery of Docetaxel to solid tumors

Purpose: The aim of this study was to investigate the ability of PEGylated poly(d,l-lactide-co-glycolide) nanoparticles (NPs) to deliver Docetaxel (DTX) (an anticancer agent) to solid tumors.

Methods: PLGA–mPEG diblock copolymers were synthesized by ring opening polymerization reaction and characterized by ¹H NMR, FT-IR and gel permeation chromatography. NPs, with a smooth spherical shape and near 100 nm size were prepared using the emulsion solvent evaporation technique and characterized. The drug release rate was investigated in acidic and physiological media (phosphate buffer saline, pH 5.0 and 7.4). The therapeutic efficacy and biocompatibility of NP formulations were evaluated for in vitro cytotoxicity by MTT assay using MCF-7 and C26 cell lines. The pharmacokinetic and biodistribution studies were performed on C26 tumor bearing mice. The antitumor efficacy of DTX NP formulations on C26 tumor bearing mice was investigated.

Results: DTX-loaded PEGylated NPs increased the drug's biological half-life while providing substantial accumulation at the solid tumors. PEGylated NPs appear to be a promising alternate carrier for DTX having greater efficacy in inhibiting tumor growth.     

Self-Assembled Biodegradable Nanoparticles Developed by Direct Dialysis for the Delivery of Paclitaxel

Purpose The main objective of this study was to obtain self-assembled biodegradable nanoparticles by a direct dialysis method for the delivery of anticancer drug. The in vitro cellular particle uptake and cytotoxicity to C6 glioma cell line were investigated. Methods Self-assembled anticancer drugs—paclitaxel-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) and poly(l-lactic acid) (PLA) nanoparticles—were achieved by direct dialysis. The physical and chemical properties of nanoparticles were characterized by various state-of-the-art techniques. The encapsulation efficiency and in vitro release profile were measured by high-performance liquid chromatography. Particle cellular uptake was studied using confocal microscopy, microplate reader, and flow cytometry. In addition, the cytotoxicity of this drug delivery system was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on C6 glioma cell line to predict the possible dose response of paclitaxel-loaded PLGA and PLA nanoparticles. Results PLGA and PLA nanoparticles with or without vitamin E tocopherol polyethylene glycol succinate (TPGS) as an additive were obtained, in which the sustained release of paclitaxel of more than 20 days was achieved. The coumarin6-loaded PLGA and PLA nanoparticles could penetrate the C6 glioma cell membrane and be internalized. The cytotoxicity of paclitaxel-loaded nanoparticles seemed to be higher than that of commercial Taxol? after 3 days incubation when paclitaxel concentrations were 10 and 20 μg/ml. Conclusions Direct dialysis could be employed to achieve paclitaxel-loaded PLGA and PLA nanoparticles, which could be internalized by C6 glioma cells and enhance the cytotoxicity of paclitaxel because of its penetration to the cytoplasm and sustained release property.