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Abstract: Enhanced in vivo gene expression using non-viral vectors is a critical issue in gene therapy in general. Among the many potential utilities of non-viral vector-mediated gene delivery, its application in DNA-based vaccination is an attractive approach with several practical advantages over conventional vaccination. We have previously shown that the endosomolytic bacterial protein listeriolysin O (LLO) is capable of facilitating transfection in vitro using the LPDII (anionic liposome–polycation–DNA complexes) delivery system. In the present study we have extended and investigated the DNA delivery of LLO-containing LPDII to in vivo and evaluated its utility in DNA vaccination in mice. We further investigated the ability of this non-viral gene delivery system to elicit an immune response to a model antigen ovalbumin (OVA), particularly focusing on the OVA-specific CD8+ cytotoxic T lymphocyte (CTL) response, after delivery of a plasmid containing the OVA cDNA. A DNA prime and protein boost protocol was employed to generate cytotoxic T cell responses. Our results show that increased in vitro and in vivo transfection efficiencies were observed when LLO was incorporated into LPDII. This LLO-LPDII formulation produced an enhanced functional antigen-specific CD8+ T cell response in vivo compared to the heat-inactivated LLO-containing LPDII (HI-LLO-LPDII) formulation. Furthermore, a significantly higher CTL frequency was observed in the splenocytes isolated from the mice primed with LLO-LPDII by an enzyme-linked immunosorbent spot assay. Interferon-γ production upon specific stimulation by OVA-specific CD8+ peptide was also significantly stronger with the inclusion of LLO into LPDII. These findings suggest that the LLO-containing LPDII system possesses noteworthy potential as a candidate carrier for DNA vaccine delivery. [ABSTRACT FROM AUTHOR]

Selective targeting of drugs to kidneys may improve renal effectiveness and reduce extrarenal toxicity. Using fluorescence imaging, we found for the first time that randomly 50% N-acetylated low molecular weight chitosan (LMWC) selectively accumulated in the kidneys, especially in the renal tubules after i.v. injection in mice. To develop and evaluate the novel renal drug carrier, prednisolone, used as a model drug, was covalently coupled with various molecular weight LMWCs via a succinic acid spacer. The mean residence time (MRT) in plasma of prednisolone conjugates increased as the molecular weight increased. The conjugate with molecular weight 19 kD (conjugate-19k) displayed the highest accumulation rate in the kidneys, which was 14.06 ± 2.81% of the administered dose 15 min after i.v. injection. The total amount of the conjugate-19k in the kidneys was 13-fold higher than that of controlled prednisolone group. Both conjugate-19k and conjugate-31k had higher retention and about 10% of injected dose was still retained in the kidneys after 120 min. Additionally, MTT assay showed LMWCs were noncytotoxic towards L929 and NRK-52E cells. Conclusion can be drawn that the coupling of prednisolone to the proper molecular weight LMWC results in increased prednisolone concentration in the kidneys. Therefore, LMWC with a proper molecular weight can be applied as a promising carrier for renal targeting. [ABSTRACT FROM AUTHOR]

Abstract: Drug–phospholipid lipid nanoparticles (DPLNs) are prepared by incorporating drug–phospholipid complexes (DPCs) with a liquid lipid. DPLNs demonstrated interesting properties including increased encapsulation capacity, improved stability and controlled drug release profile. A comprehensive characterization of DPLNs was presented and then a schematic model was suggested according to the characterization results. Transmission electron microscopy and scanning electron microscope measurements showed the morphology of DPLNs. X-ray diffraction exhibited a predominantly amorphous structure for DPCs and totally amorphous for DPLNs. Laser confocal scanning microscopy revealed the relative position of DPCs and liquid lipid, showing that DPLNs formed a homogeneous system. Fluorescence spectra and electron spin resonance further confirmed the chemical environment inside the DPLNs in a non-invasive way. [Copyright &y& Elsevier]

Transdermal drug delivery systems for rheumatoid arthritis (RA) have been receiving increasing attention as they can potentially overcome drawbacks which exist in traditional oral or injection strategies, including low patient compliance and serious gastrointestinal side effects. However, transdermal delivery of RA drugs especially biological drugs suffers from low drug delivery efficiency due to the robust skin barrier. Herein, we fabricated melittin-loaded hyaluronic acid (HA) microneedles and investigated their capacity for inhibiting RA. We showed that melittin-loaded HA microneedles possessed high mechanical strength for successful delivery of melittin into the skin and effectively inhibited RA progression in adjuvant induced both rodent and murine models, as shown by results in histological, paw swelling and arthritis score. Furthermore, after modifying HA with cross-linkable groups, the fabricated microneedles with sustained release properties could further improve the therapeutic potency. Cytokine and T cell analysis in the paws and lymphatic organs indicated that the application of microneedles suppressed the levels of pro-inflammation cytokines including IL-17 and TNF-α, and increased the percentage of regulatory CD4 T cells. Our study revealed that polymeric microneedle-mediated transdermal delivery of melittin could serve as a new therapy with high compliance and good therapeutic efficacy for RA and other autoimmune diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain-specific delivery strategy targeting to pyrilamine-sensitive H + /OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H + /OC antiporter in a pH-dependent, Na + -independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC 0 − t and C max in the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo . Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H + /OC antiporter. [ABSTRACT FROM AUTHOR]

Glucocorticoid (GC) is the cornerstone therapy of rheumatoid arthritis, but high doses are associated with serious adverse effects. In an effort to improve the efficacy of low-dose GC therapy, we developed a micelle system for targeted delivery to inflamed joints and validated the approach in a rat model of arthritis. Micelles loaded with dexamethasone (Dex) self-assembled from the amphipathic poly (ethylene glycol)-block–poly (ε­caprolactone) (PCL–PEG) polymer via film dispersion, and they were injected intravenously at a dose of only 0.8 mg/kg into rats with adjuvant-induced arthritis. The micelles persisted for a relatively long time in the circulation, and they accumulated preferentially in inflamed joints. Micelle-delivered Dex potently reduced joint swelling, bone erosion, and inflammatory cytokine expression in both joint tissue and serum. PCL–PEG micelles caused only moderate adverse effects on body weight, lymphocyte count and blood glucose concentration, and they weakly activated the host complement system. These results suggest that encapsulating Dex in PCL–PEG micelles may allow for safe and effective low-dose GC therapy targeting inflammatory disorders. [ABSTRACT FROM AUTHOR]

To inhibit both the local and systemic complications with acute pancreatitis, an effective therapy requires a drug delivery system that can efficiently overcome the blood–pancreas barrier while achieving lung-specific accumulation. Here, we report the first dual pancreas- and lung-targeting therapeutic strategy mediated by a phenolic propanediamine moiety for the treatment of acute pancreatitis. Using the proposed dual-targeting ligand, an anti-inflammatory compound Rhein has been tailored to preferentially accumulate in the pancreas and lungs with rapid distribution kinetics, excellent tissue-penetrating properties and minimum toxicity. Accordingly, the drug–ligand conjugate remarkably downregulated the proinflammatory cytokines in the target organs thus effectively inhibiting local pancreatic and systemic inflammation in rats. The dual-specific targeting therapeutic strategy may help pave the way for targeted drug delivery to treat complicated inflammatory diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] The clinical application of bacteria-mediated immune therapy dates back over a century ago. In recent years, these strategies have advanced greatly with the rapid development of synthetic biology and nanotechnology. Several bacterial therapies have been developed allowing for more effective treatments for cancers, and Salmonella is one of the most studied bacterial species. Here, we review the advances in the bioengineered and functionalized Salmonella Typhimurium strains as drug delivery carries, including the various genetic circuits for programing these bacteria, the surface modification strategies using nanoparticles or other therapeutic agents for richer and broader features, and the bacterial component-based vehicles for cancer immunotherapy. This review will include the promises and challenges of these optimized Salmonella -based delivery systems and their related clinical trials. Ultimately, we hope to provide a spark of thought in the field of drug delivery and find important crosstalk between bacteria-mediated therapy and other different forms of treatments. [ABSTRACT FROM AUTHOR]

Purpose: In this study, cationic mannosylated nanostructured lipid carriers (Man-NLCs) were developed for the targeted delivery of rifampicin to alveolar macrophages. Methods: Rifampicin loaded Man-NLCs (RFP-Man-NLCs) and rifampicin loaded unmodified nanostructured lipid carriers (REP-NLCs) were prepared using thin film homogenization method and characterized by particle size, polydispersity index, zeta potential, transmission electron microscopy, encapsulation efficiency, pharmacokinetics, biodistribution, cell specific targeting, cytotoxicity and inflammatory response. Results: RFP-Man-NLCs and REP-NLCs obtained displayed a size distribution around 160 nm (PDI <0.30) with positive charges of approximately 30 mV. The encapsulation efficiency of RFP was above 90%. In the biodistribution study, both RFP-Man-NLCs and RFP-NLCs, compared with the commercially available rifampicin solution, displayed superior lung-targeting ability. Compared to REP-NLCs, RFP-Man-NLCs exhibited significantly higher uptake efficiency in NR8383 cells and alveolar macrophages, which achieved cell-specific targeting. In addition, RFP-Man-NLCs were demonstrated to be a safe formulation with minimum toxicity and no inflammatory response. Conclusions: RFP-Man-NLCs provided an alternative strategy for selectively delivering rifampicin to alveolar macrophages. [ABSTRACT FROM AUTHOR]

Neutral particles 20–45 nm in diameter showed potential as tumor antigen vectors because they targeted the draining lymph nodes after subcutaneous injection. However, they were weakly immune-stimulatory and could also spread throughout the body, raising the risk of systemic toxicity. Here we explored whether incorporating positively charged amphiphilic polymers into micelles improves their site specificity and immunogenicity. Cationic polyethylenimine (2k)-stearic acid (PSA) micelles were loaded with the melanoma antigen peptide Trp2; they showed an average size of 28.7 ± 8.2 nm and an encapsulation efficiency of 99.21 ± 5.38%. Empty PSA micelles acted as a robust adjuvant in vitro, promoting maturation, proliferation and migration of bone marrow-derived dendritic cells in a dose-dependent manner. After subcutaneous injection into mice, Trp2-loaded PSA micelles accumulated preferentially in the medulla and paracortex of the draining lymph nodes and were present at negligible levels in the systemic circulation. Mice immunized with Trp2-loaded PSA micelles showed significantly higher Trp2-specific cytotoxic T lymphocyte activity than mice immunized with free Trp2 or a mixture of Trp2 and empty PSA micelles. In a B16-F10 murine melanoma model, Trp2-loaded PSA micelles inhibited tumor growth significantly more than did free Trp2 and PSA micelles caused less systemic toxicity. These findings suggest that cationic PSA micelles loaded with Trp2 may be a potential approach for melanoma immunotherapy. [ABSTRACT FROM AUTHOR]

A co-delivery system that can transport cancer related microRNAs and chemotherapeutics to their distinct targets in the tumors is an attractive strategy to eliminate tumor relapse in lung cancer therapy. In this study, we developed a dual-drug delivery system for an endogenous microRNA (miR-34a) and paclitaxel (PTX) for synergistic cancer therapy. PTX (a meiotic inhibitor) and miR-34a were loaded into cationic solid lipid nanoparticles (miSLNs-34a/PTX) which were used to treat murine B16F10-CD44 + melanoma metastasized to the lungs of mice. This nanoparticle system demonstrated good protection for miR-34a and PTX from degradation in the serum, and had an average size of approximately 220 nm by photon correlation spectroscopy (PCS). In vitro , the parallel activity of PTX and miR-34a show synergistic anticancer efficacy. In vivo , miSLNs-34a/PTX showed passive targetability to the tumor-bearing lung tissues, and was demonstrated to be much more potent in inhibition of B16F10-bearing tumor growth and elimination of cancer cell populations in the lung than single drug-loaded solid lipid nanoparticles. It has been shown that such co-delivery of miR-34a and PTX is promising for enhanced cancer therapy to reduce tumor relapse. [ABSTRACT FROM AUTHOR]

The ability to control the size and quality of nanoparticles ( NPs) during production is critical for their success as a commercial product for clinical applications. Here, we employed a statistical design of experiment approach to identify the key process variables affecting the size of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) ( PHBHHx) NPs during production via the solvent evaporation method. The number of sonication cycles had a standardzed effect on NP size of 55, with sonication power at 25, and PHBHHx concentration at 27 with a combination of these variables having a lower yet significant effect on NP size ( p < 0.05). The PHBHHx NPs were stable for at least 7 days with an average polydispersity index of 0.18, a zeta potential of −10 to −40 mV, and an encapsulation efficiency of 63.5 ± 2%. These data were utilized to produce a prediction graph whereby particles could be produced with sizes ranging from 90 to 205 nm with a low mean curve prediction error of 1.96% for Haperzine-A-loaded NPs. Furthermore, a range of drug encapsulates NPs were produced and showed a sustained release of the encapsulated drug. This study demonstrates the ability to control the size of drug-loaded particles by manipulation of the production variables, which will allow targeted and controlled drug release to fit a variety of applications. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2498-2508, 2014 [ABSTRACT FROM AUTHOR]

Purpose: To develop a tumor-targeted drug delivery system based on solid lipid nanoparticles (SLNs) conjugated with the enzymatically cleavable polyethylene glycol (PEG). Methods: SLNs loaded with paclitaxel (PTX) were prepared using the film ultrasonication method, followed by conjugation with a PEGylated peptide (Pp) that can specifically interact with matrix metalloproteinases (MMPs) that is over-expressed by tumor cells. The physicochemical characteristics of the Pp-PTX-SLNs were studied and the in vitro drug release, cytotoxicity and cell uptake of the formulations were investigated. Furthermore, using an animal model, the pharmacokinetic properties, biodistribution and anti-tumor activity of this system were evaluated. Results: The resulting Pp-PTX-SLNs penetrated through tumor cells via facilitated uptake mediated by MMPs. The uncleavable Pp'-PTX-SLNs showed a lower cell uptake efficiency, compared with the Pp-PTX-SLNs. In a tumor-bearing mice model, Pp-PTX-SLNs accumulated to a greater extent at the tumor location, persisted longer in blood circulation, and showed lower toxicity than did PTX-SLNs or Taxol®. Most importantly, the mice treated with Pp-PTX-SLNs survived longer than the groups treated with Pp'-PTX-SLNs, PTX-SLNs or Taxol®. Conclusions: These results suggest that Pp-PTX-SLNs hold promise as a new strategy for paclitaxel chemotherapy, and that Pp-SLNs can be a useful nanocarrier for other chemotherapeutic drugs. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Highlights: [•] The entrapment efficiency of peptide loaded nanostructured lipid carriers (NLCs) could reach to 95%. [•] The porous nanoparticle-aggregate particles (PNAPs) powders could remain in lungs for a longer time than octreotide acetate (OA) solution and reach a sustained release. [•] The bioavailability was markedly enhanced by pulmonary deliver PNAPs compared with pulmonary deliver OA solutions and subcutaneous inject OA solution. [•] As far as we know, this is the first report on the anti-hepatic ischemia–reperfusion injury (HIRI) effects through intrapulmonary administration. [Copyright &y& Elsevier]

The present study aimed at developing a drug delivery system targeting the densest site of tuberculosis infection, the alveolar macrophages (AMs). Rifampicin (RFP)-loaded solid lipid nanoparticles (RFP-SLNs) with an average size of 829.6 ± 16.1 nm were prepared by a modified lipid film hydration method. The cytotoxicity of RFP-SLNs to AMs and alveolar epithelial type II cells (AECs) was examined using MTT assays. The viability of AMs and AECs was above 80 % after treatment with RFP-SLNs, which showed low toxicity to both AMs and AECs. Confocal Laser Scanning Microscopy was employed to observe the interaction between RFP-SLNs and both AMs and AECs. After incubating the cells with RFP-SLNs for 2 h, the fluorescent intensity in AMs was more and remained longer (from 0.5 to 12 h) when compared with that in AECs (from 0.5 to 8 h). In vitro uptake characteristics of RFP-SLNs in AMs and AECs were also investigated by detection of intracellular RFP by High performance liquid chromatography. Results showed that RFP-SLNs delivered markedly higher RFP into AMs (691.7 ng/mg in cultured AMs, 662.6 ng/mg in primary AMs) than that into AECs (319.2 ng/mg in cultured AECs, 287.2 ng/mg in primary AECs). Subsequently, in vivo delivery efficiency and the selectivity of RFP-SLNs were further verified in Sprague-Dawley rats. Under pulmonary administration of RFP-SLNs, the amount of RFP in AMs was significantly higher than that in AECs at each time point. Our results demonstrated that solid lipid nanoparticles are a promising strategy for the delivery of rifampicin to alveolar macrophages selectively. [ABSTRACT FROM AUTHOR]

Abstract: In order to develop a novel kidney-targeted drug delivery system, we synthesized prednisolone carbamate–glucosamine conjugate (PCG) using 2-glucosamine as a ligand, and investigated its potential targeting efficacy. In vitro studies demonstrated that PCG could remarkably improve the uptake of drug by kidney cells. And the specific uptake of PCG could be largely reduced by the inhibitors of megalin receptor. More importantly, PCG showed an excellent kidney targeting property in vivo, and the concentration of the conjugate in the kidney was 8.1-fold higher than that of prednisolone group at 60min after intravenous injection. Besides, PCG could significantly reverse the disease progression in renal ischemia–reperfusion (I/R) injury animal models. Furthermore, PCG presented no adverse effect on bone density while prednisolone resulted in severe osteoporosis. Thus, it indicated that 2-glucosamine could be a potential ligand for kidney-targeted delivery of prednisolone. [Copyright &y& Elsevier]

Purpose: PHBHHx (poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)) is an excellent biomaterial for tissue repair. Here, we aim to develop a PHBHHx-based three-dimensional (3D) scaffold system for sustained delivery of proteins (insulin serves as a model protein). Methods: The insulin-phospholipid complex (INS-PLC) was prepared to enhance the insulin lipophilicity. INS-PLC loaded PHBHHx 3D scaffolds (INS-PLC-SCAs) containing PEG-2000 were fabricated by lyophilization. In vitro release was performed in the medium with or without lipase. The bioactivity of INS-PLC-SCAs was measured in diabetic rats. Results: In vitro release shows that the release rate of INS-PLC-SCAs was very slow (~6% of total insulin was released within 120 days), and PEG-2000 or lipase had no effect on its release pattern. The bioactivity test shows that the hypoglycaemic effect of insulin was maintained after formulated into scaffolds. After subcutaneous (s.c.) implantation, its therapeutic effect lasted for over 130 h, and its bioavailability was enhanced by 4-fold. Conclusions: PHBHHx based 3D scaffold has a great potential for sustained delivery of proteins, especially growth factors. When growth factors are incorporated, it can serve as a bifunctional system that provides a porous skeleton for cells attachment and proliferation, as well as a matrix for long term release of the loaded growth factors. [ABSTRACT FROM AUTHOR]

Purpose: To improve gene transducibility mediated by adenovirus (Ad) in cancer cells and further enhance anti-tumor effects by co-delivery. Methods: Calcium-induced phase change method was used to prepare the complex of anionic liposomes and adenovirus (AL/Ad5). Gene expression was qualitatively detected by X-gal staining and quantitatively detected by ELISA. Taking adenovirus-mediated stromal cell-derived factor-1α (Ad5-SDF1α) as therapeutic gene and carmustine (BCNU) as chemotherapeutic agent, a co-delivering system of AL/Ad5-SDF1α/BCNU was prepared and administered to tumor-bearing mice by intratumor injection. Results: Enhanced LacZ gene transduction was obtained in B16 and Lewis lung carcinoma cells in vitro and in vivo. Complexes of AL/Ad5-SDF1α improved SDF1α gene expression and led to accumulation of dendritic cells among the murine B16 melanoma cells in vivo. This co-delivery system of AL/Ad5-SDF1α/BCNU could significantly suppress tumor growth and prolong survival of tumor-bearing mice. Conclusions: Through the co-delivering system, AL/Ad5-SDF1α could synergize with BCNU to improve the antitumor effect. It may be a promising strategy for solid tumor therapy. [ABSTRACT FROM AUTHOR]

Abstract: We have synthesized a renal-specific drug carrier, 14-succinyl triptolide-lysozyme (TPS-LZM) conjugate for targeted delivery of TP to the PTECs. TPS-LZM could be taken up by HK-2 cells, free TP would be degraded and released, mainly from basolateral side of the cells. Compared with TP, the overall targeting efficiency (TE) of TPS-LZM was significantly enhanced from 11.74% to 95.54% and its MRT was moderately prolonged from 3.08h to 4.10h. At very low concentration, TPS-LZM could significantly reverse the disease progression in renal ischemia-reperfusion (I/R) injury animal models, while the mixture of free TP and LZM was ineffective. Further, TPS-LZM conjugate presented much lower hepatotoxicity (0.78 folds lower than TP) and no adverse effect on the immune (1.13 folds higher than TP) and genital system. Thus, TPS-LZM represents a very effective drug candidate for specific treatment of immunological renal diseases with low adverse side effect. [Copyright &y& Elsevier]

In article number 1802250 Qing Lin, Ling Zhang, and co‐workers report an artificial "closed‐loop" structure for intravenous glucose‐responsive insulin delivery. An acid‐sensitive matrix forms the "inner core" and RBCm‐derived coating the "outer shell". Under hyperglycemic condition, the glucose internalized by the anchored glucose transporters is enzymatically converted into gluconic acid and subsequently triggers acid degradation of the "inner core" to secrete insulin. [ABSTRACT FROM AUTHOR]

An artificial "closed‐loop" system that mimics the glucose‐responsive insulin secretion of pancreas β‐cells can potentially improve the treatment efficacy for diabetes. Herein, a lipid bilayer‐coated polymeric nanoparticle (NP) with "core–shell" structure is designed. As far as it is known, it is the first and only intravenous nanoplatform utilizing enzymatic‐oxidation scheme to achieve glucose‐responsive insulin delivery so far. Ethoxy acetal–derivatized dextran nanoparticles (Ace‐DEX NPs) are constructed as "inner core" loaded with insulin, and coloading glucose oxidase (GOx) and catalase (CAT) endow the "inner core" excellent glucose‐sensitive ability. Red blood cell membrane (RBCm)‐derived coating is adopted as "outer shell." It collectively provides a closed microenvironment for GOx‐based enzymatic‐oxidation scheme and camouflages it from elimination. Above all, the anchored glucose transporters (GLUTs) on the "outer shell" are able to sense blood glucose levels and facilitate the transport of outer blood glucose getting inside. Under a hyperglycemic condition, the internalized glucose is catalytically converted into gluconic acid with the aid of the GOx and subsequently triggers acid degradation of the "inner core" to secrete insulin. By governing the blood glucose levels on an automatic and continuous basis, the RBCm‐Ace‐DEX NPs can effectively respond to hyperglycemia and turn to resting conditions under normoglycemia. Ethoxy acetal derivatized dextran nanoparticles (Ace‐DEX NPs) are constructed as "inner core" and red blood cell membrane (RBCm)‐derived coating is adopted as "outer shell". This glucose‐responsive nanoplatform can steadily circulate in the blood at normalglycemia. While under hyperglycemic condition, the glucose internalized by the anchored GLUTs is catalytically converted into gluconic acid with the aid of GOx and CAT and subsequently triggers acid degradation of RBCm‐Ace‐DEX NPs to secrete insulin. [ABSTRACT FROM AUTHOR]

Although monomethoxy(polyethyleneglycol)-poly (D,L-lactic-co-glycolic acid)-monomethoxy (PELGE) nanoparticles have been widely studied as a drug delivery system, little is known about their toxicity in vivo. Here we examined the subchronic toxicity and immunotoxicity of different doses of PELGE nanoparticles with diameters of 50 and 200 nm (PELGE50 and PELGE200) in rats. Neither size of PELGE nanoparticles showed obvious subchronic toxic effects during 28 d of continuous intravenous administration based on clinical observation, body weight, hematology parameters and histopathology analysis. PELGE200 nanoparticles showed no overt signs of immunotoxicity based on organ coefficients, histopathology analysis, immunoglobulin levels, blood lymphocyte subpopulations and splenocyte cytokines. Conversely, PELGE50 nanoparticles were associated with an increased organ coefficient and histopathological changes in the spleen, increased serum IgM and IgG levels, alterations in blood lymphocyte subpopulations and enhanced expression of spleen interferon-γ. Taken together, these results suggest that PELGE nanoparticles show low subchronic toxicity but substantial immunotoxicity, which depends strongly on particle size. These findings will be useful for safe application of PELGE nanoparticles in drug delivery systems. [ABSTRACT FROM AUTHOR]