PEG-PCL Nanoparticles Research Articles

PRO-DRUG NANOPARTICLES AS SYNERGISTIC DRUG COMBINATION CARRIERS FOR IDH1-WT GLIOBLASTOMA

Abstract AIMS Synergistic combinations of doxorubicin and gemcitabine have been assessed for post-surgical treatment of IDH1 wild-type glioblastoma (GBM). As a complementary drug carrier, hyperbranched and micellar nanoparticles are being investigated to enable enhanced drug loading and sustained drug release. METHOD 2D and 3D spheroid in vitro models have been generated from patient-derived glioblastoma cells resected from tumour core and invasive margin. Drug combinations were screened using synergy quantification from the Chou and Talalay method and synergy mechanisms investigated using measures of caspase 3/6-mediated apoptosis and γH2AX-mediated DNA damage. Polymeric nanoparticles (PEG-PCL) loaded with Cy5 were tested for internalisation and subsequent endocytosis pathway determination. Both single drug and drug combinations are currently being incorporated into PEG-PCL nanoparticles for in vitro assessment of biocompatibility, cellular uptake and cytotoxicity. RESULTS Data demonstrate synergism with doxorubicin and gemcitabine combinations is obtained in a molar ratio de- pendent manner. Consistent with this, enhanced apoptosis and DNA damage is observed in a synergistic manner. PEG-PCL nanoparticles demonstrate effcient cellular uptake and are internalised via dynamin-dependent caveolae and clathrin endocytotic pathways. Interestingly, nanoparticle internalisation is substantially in- creased (approx. 50%) in invasive GBM cells relative to proliferative core cells. CONCLUSIONS Doxorubicin and gemcitabine has been identified as a synergistic drug combination with the potential for sustained drug release when combined with PEG-PCL nanoparticle formulations. Together, the data has provided a platform of knowledge that will enable translation to pre-clinical in vivo models.

Comment on: "Codelivery of Gemcitabine and MUC1 Inhibitor Using PEG-PCL Nanoparticles for Breast Cancer Therapy".

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTComment on: “Codelivery of Gemcitabine and MUC1 Inhibitor Using PEG-PCL Nanoparticles for Breast Cancer Therapy”Tian Tian*Tian TianDepartment of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China*Email: [email protected]. Tel.: +86-0371-66295561.More by Tian Tianhttps://orcid.org/0000-0002-0796-4561Cite this: Mol. Pharmaceutics 2023, 20, 2, 1447–1448Publication Date (Web):December 28, 2022Publication History Received26 October 2022Accepted23 December 2022Revised22 December 2022Published online28 December 2022Published inissue 6 February 2023https://doi.org/10.1021/acs.molpharmaceut.2c00903Copyright © 2022 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views60Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (776 KB) Get e-AlertsSUBJECTS:Cancer,Chemotherapy,Drug delivery,Inhibitors,Nanoparticles Get e-Alerts

Nanoparticle-Delivered Transforming Growth Factor-β1 siRNA Induces PD-1 against Gastric Cancer by Transforming the Phenotype of the Tumor Immune Microenvironment.

Immune checkpoint blockade (ICB) is currently considered to be an important therapeutic method, which obtained FDA approval for clinical use in gastric cancer in 2017. As a new mechanism, it was found that the effect of αPDL1 could be improved by blocking the TGF-β1 signaling pathway, which converts the tumor immune microenvironment from the "immune-excluded phenotype" to the "immune-inflamed phenotype". Based on this phenomenon, this project was designed to prepare TGF-β1-siRNA-loaded PEG-PCL nanoparticles conjugated to αPDL1 (siTGF-β1-αPDL1-PEG-PCL) since we have linked similar antibodies to PEG-PCL previously. Therefore, MFC tumor-engrafted mice were established to simulate the biological characteristics of converting the phenotype of the immune microenvironment, and to study the anti-tumor effect and possible molecular mechanism. In this study, αPDL1 antibody conjugates markedly increased the cell uptake of NPs. The produced αPDL1-PEG-PCL NPs efficiently reduced the amounts of TGF-β1 mRNA in MFC cells, converting the immune microenvironment of MFC tumors engrafted mice from the "immune-excluded phenotype" to the "immune-inflamed phenotype". PDL1-harboring gastric cancer had increased susceptibility to αPDL1. The value of this drug-controlled release system targeting the tumor microenvironment in immune checkpoint therapy of gastric cancer would provide a scientific basis for clinically applying nucleic acid drugs.

Expression of Matrix Metalloprotein 13 in Injury Model of Articular Chondrocyte in Rabbits and Analysis of Nano-Drug-Loading System.

This study aimed to analyze the application of a responsive nano-drug-loading system in injury model of articular chondrocyte in rabbits, as well as its effect on expression of matrix metalloprotein 13 (MMP13). The nanoprecipitation method was adopted to prepare camptothecin (CPT)-loaded poly ethylene glycol (PEG)-Poly caprolactone (PCL) and PEG-PCL nanoparticles without CPT. Afterward, the above mentioned nano-drug-loaded system was used to treat an in vitro scratch model of articular chondrocytes. According to different treatment plans, they were divided into groups: G0 (administered CPT-PEG-PCL nanomedicine), G1 (administered PEG-PCL drug), G2 (saline control), and G3 (healthy control). Results showed that the drug-loading capacity and efficiency of CPT-PEG-PCL was higher than that of PEG-PCL. The levels of type II collagen and hyaluronic acid in G0 was higher than that in G1 and G2. The levels of type II collagen and hyaluronic acid in G0 were not obviously different from those in G3. The level of MMP13 in G0 was lower than that in G1 and G2 and the level of tissue inhibitor of metalloproteinases 1 (TIMP1) in G0 was higher than that in G1 and G2. The proliferation activity of cells in G0 was higher than that in G1 and G2, but there was no obvious difference when compared with G3. In conclusion, CPT-PEG-PCL has stronger long-term circulation capacity and drug-loading efficiency. It can effectively up-regulate the levels of type II collagen, hyaluronic acid, and TIMP1, as well as reduce the synthesis and secretion of MMP13 and promote the repair of articular cartilage damage.

Oral Delivery of Nucleic Acids with Passive and Active Targeting to the Intestinal Tissue Using Polymer-Based Nanocarriers

Despite the apparent advantages for long-term treatment and local therapies against intestinal diseases, the oral delivery of nucleic acids has been challenging due to unfavorable physiological conditions for their stability. In this study, a novel nanodelivery system of PEG-PCL nanoparticles with encapsulated nucleic acids–mannosylated PEI (Man-PEI) complexes was developed for intestinal delivery. We complexed model nucleic acids with Man-PEI at the optimal N/P ratio of 20:1 for in vitro and in vivo analyses. Cells were transfected in vitro and analyzed for gene expression, receptor-mediated uptake, and PEG-PCL nanoparticles’ toxicity. We also evaluated the nucleic acid’s stability in the nanocarrier during formulation, and under simulated gastrointestinal environments or the presence of nucleases. Finally, we assessed the biodistribution for the PEG-PCL nanoparticles with encapsulated complexes and their ability to transfect intestinal cells in vivo. Nucleic acids complexed with Man-PEI were protected from degradation against nucleases. In comparison to the parent compound PEI, Man-PEI transfected the cells with an overall higher potency. Competition assay indicated receptor-mediated endocytosis promoted by mannose receptors. The PEG-PCL nanoparticles with Man-PEI/plasmid complexes indicated minimal cytotoxicity. The nanocarrier successfully protected the complexes in a simulated gastric fluid environment and released them in a simulated intestinal fluid environment, promoted by the presence of lipases. The oral administration of the PEG-PCL nanoparticles with encapsulated Man-PEI/plasmid complexes transfected intestinal cells with the plasmid in vivo, while presenting a time-dependent progression through the intestines. Conclusively, our carrier system can deliver genetic material to the GI tract and actively target mannose receptor overexpressing cells.

Targeted Nanoparticles Harboring Jasmine-Oil-Entrapped Paclitaxel for Elimination of Lung Cancer Cells.

Selectively targeted drug delivery systems are preferable chemotherapeutic platforms, as they specifically deliver the drug cargo into tumor cells, while minimizing untoward toxic effects. However, these delivery systems suffer from insufficient encapsulation efficiency (EE), encapsulation capacity (EC), and premature drug release. Herein, we coencapsulated paclitaxel (PTX) and Jasmine oil (JO) within PEG-PCL nanoparticles (NPs), with an average diameter < 50 nm, selectively targeted to non-small cell lung cancer (NSCLC) cells, via S15-aptamer (APT) decoration. JO was selected as an “adhesive” oily core to enhance PTX entrapment, as JO and PTX share similar hydrophobicity and terpenoid structure. JO markedly enhanced EE of PTX from 23% to 87.8% and EC from 35 ± 6 to 74 ± 8 µg PTX/mg PEG-PCL. JO also markedly increased the residual amount of PTX after 69 h, from 18.3% to 65%. Moreover, PTX cytotoxicity against human NSCLC A549 cells was significantly enhanced due to the co-encapsulation with JO; the IC50 value for PTX encapsulated within JO-containing APT-NPs was 20-fold lower than that for APT-NPs lacking JO. Remarkably, JO-containing APT-NPs displayed a 6-fold more potent cell-killing, relatively to the free-drug. Collectively, these findings reveal a marked synergistic contribution of JO to the cytotoxic activity of APT-NP-based systems, for targeted PTX delivery against NSCLC, which may be readily applied to various hydrophobic chemotherapeutics.

Biodegradable diblock copolymeric PEG-PCL nanoparticles: Synthesis, characterization and applications as anticancer drug delivery agents

Poly (ethylene glycol) methyl ether-block-poly (Ɛ-caprolactone) copolymers are useful biomedical materials owing to their amphiphilic nature, biodegradability, biocompatibility and also due to their semi-crystalline form having a low glass transition temperature. Due to their slow drug release profile, PEG-PCL copolymers are excellent candidates for sustained delivery applications over a period of time of more than a year. This unique property has provoked their relevance specially in the area of anticancer drug delivery applications in the form of various nanoaggregates like microspheres, nanogels, nanospheres, polymersomes, micelles, etc. A large variety of anticancer drugs/bioactives have been encapsulated in PEG-PCL copolymers for developing effective anticancer drug delivery systems and also for producing controlled drug release profiles. In recent times, PEG-PCL copolymers based nanoparticles have shown tremendous advancements as anticancer drug delivery vehicles owing to their higher drug loading capacities of the hydrophobic drugs, enhanced bioavailability, keeping away from being overpowered by way of phagocytes, decreased blasted discharge, and also in increasing the scattering time of drug within the blood stream during their systemic inoculation. These nano-formulated drug delivery systems can be used for the delivery of anticancer drugs at a specific site in a targeted approach. The developed nano-formulations possess promising potential in the treatment of cancer with improved anticancer efficacy and reduced toxicity invivo. In the current review, our main focus is to highlight the development and synthesis of different types of PEG-PCL copolymers (both conventional and greener approaches) along with the physico-chemical characterization techniques used primarily for the PEG-PCL co-polymeric systems. We have also summarized the uses of PEG-PCL co-polymeric nano formulations with various anticancer drugs as drug delivery platforms in the area of anticancer chemotherapy.

Oral delivery of WR-1065 by ROS-responsive PEG-PCL nanoparticles for radioprotection

When a burst of reactive oxygen species (ROS) is induced after radiation exposure, a sufficient radioprotector drug must be quickly released to neutralize the ROS. An oral polymeric carrier of poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone) was synthesized via the ROS-response linker thioketal (TK-linked PCEC) and used for delivery of the drug WR-1065. The drug-loaded nanoparticles (PCEC/WR-1065 NPs) had high WR-1065 content (19.7 % w/w) in the core and a particle size of 183 nm. The PCEC/WR-1065 NPs could protect the drug from degradation at gastric pH. More than 70 % of the TK-linked PCEC copolymer could be cleaved in 1 h. Therefore, a sufficient amount of WR-1065 could be quickly released from the PCEC/WR-1065 NPs to neutralize the burst of free radicals generated under irradiation. The in vitro cell uptake results of TK-linked PCEC NPs indicated that the NPs could be efficiently endocytosized by Caco-2 cells. Oral administration of the PCEC/WR-1065 led to survival benefit as well as protective effects on hematopoiesis and main organs with respect to the irradiation and oral free WR-1065 groups after 7.2 and 8.0 Gy total body irradiation, respectively. In vivo biodistribution studies indicated that the PCEC/WR-1065 NPs accumulated mainly in intestinal tissue. These results suggest that the design presented here provides a promising oral ROS-sensitive platform for acute radiation syndrome.

507P - In vivo evaluation of cisplatin-loaded PEG-PCL block copolymeric nanoparticles for anticancer drug delivery

BackgroundCisplatin has proved itself an effective therapeutic approach in a variety of solid tumors. However, its therapeutic concentration was limited since the presence of variant inevitable side effects. Nanoparticles (NPs) developed from amphiphilic copolymers have drawn great attention for prolonging drug residency in blood circulation, increasing tumor accumulation, reducing serum protein adherence and preventing uptake by the reticuloendothelial system (RES). Previously, we synthesized polyethylene glycol (PEG)- polycaprolactone (PCL) NPs as anticancer drug and had confirmed its efficacy in vitro. To comprehensively study the influences of cisplatin-loaded PEG-PCL copolymeric NPs, we enlarge the amount of murine models and applied more physical tests to offer a broader view of the impact that cisplatin-loaded PEG-PCL copolymeric NPs brought about. MethodsWe observed the physical alteration of hepatoma-bearing mice and the tumors after administration of cisplatin-loaded PEG-PCL nanoparticles (NPs). Cell uptake and apoptotic rates were measured through fluorescence microscopy and flowcytometry. Murine blood was collected and examined. Positron emission tomography/computed tomography (PET/CT) was utilized for the detection of tumor metabolic status. ResultsThe biopsy and the measurement of tumor volume and murine weights have confirmed the therapeutic efficacy of cisplatin-loaded NPs and was positively related to the dosage of cisplatin. Fluorescence microscope images indicated a better cellular uptake rate of cisplatin-loaded NPs with intracellularly-aggregated, heterogeneous rhodamine B observed in LoVo cells. A decline of apoptotic rates in cisplatin-loaded NPs was measured. Blood tests exhibited less side effects in cisplatin-loaded NPs with higher level of white blood cells and lower aspartate transaminase (AST). PET/CT images revealed less intensity of FDG uptake in murine received higher dosage of cisplatin-loaded NPs. ConclusionsNanoparticles prepared from PEG-PCL/PCL hybrids could be a promising drug carrier for intratumoral delivery with greater efficacy and less side effects. This study provides a theoretical basis for possible clinical application. Legal entity responsible for the studyComprehensive Cancer Center of Drum-Tower Hospital Comprehensive Cancer Center of Drum-Tower Hospital Comprehensive Cancer Center of Drum-Tower Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Celastrol-loaded PEG-PCL nanomicelles ameliorate inflammation, lipid accumulation, insulin resistance and gastrointestinal injury in diet-induced obese mice

Botanical triterpene celastrol is a candidate drug for the treatment of obesity, except for concerns over the safety in clinical application. The present study was designed to investigate the anti-obesity, anti-inflammatory and toxic activities of celastrol-loaded nanomicelles (nano-celastrol) in diet-induced obese mice. Celastrol was loaded into PEG-PCL nanoparticles, yielding nano-celastrol with optimal size, spherical morphology, good bioavailability, slower peak time and clearance in mice. Nano-celastrol (5 or 7.5 mg/kg/d of celastrol) was administered into diet-induced obese C57BL/6 N male mice for 3 weeks. As result, higher dose nano-celastrol reduced body weight and body fat mass in an equally effective manner as regular celastrol, although lower dose nano-celastrol showed less activity. Similarly, nano-celastrol improved glucose tolerance in mice equally well as regular celastrol, whereas higher dose nano-celastrol improved the response to insulin. As for macrophage M1/M2 polarization in liver, nano-celastrol reduced the expression of macrophage M1 biomarkers (e.g., IL-6, IL-1β, TNF-α, iNOS) in a dose-dependent manner and marginally increased the expression of macrophage M2 biomarkers (e.g., Arg-1, IL-10). Moreover, celastrol could cause anus irritation and disturb intestinal and colonic integrity, whereas nano-celastrol did not cause any injury to mice. Collectively, nano-celastrol represents a translatable therapeutic opportunity for treating diet-induced obesity in humans.

Enhanced Nanoencapsulation of Sepiapterin within PEG-PCL Nanoparticles by Complexation with Triacetyl-Beta Cyclodextrin.

In this work, we aimed to improve the encapsulation efficiency of sepiapterin (SP), the natural precursor of the essential cofactor tetrahydrobiopterin (BH4) that displays mild water-solubility and a short biological half-life, within methoxy-poly(ethylene-glycol)-poly(epsilon-caprolactone)(mPEG-PCL) nanoparticles (NPs) by means of its complexation and hydrophobization with 2,3,6-triacetyl-β-cyclodextrin (TAβCD). For this, SP/TAβCD complexes were produced by spray-drying of SP/TAβCD binary solutions in ethanol using the Nano Spray Dryer B-90 HP. Dry powders were characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and transmission and scanning electron microscopy (TEM and SEM, respectively) and compared to the pristine components and their physical mixtures (PMs). Next, SP was encapsulated within mPEG-PCL NPs by nano-precipitation of an SP/TAβCD complex/mPEG-PCL solution. In addition to the nano-encapsulation of a preformed complex within the polymeric NPs, we assessed an alternative encapsulation approach called drying with copolymer (DWC) in which pristine SP, TAβCD, and mPEG-PCL were co-dissolved in a mixture of acetone and methanol at the desired weight ratio, dried under vacuum, re-dissolved, and nano-precipitated in water. The dissolution-drying step was aimed to promote the formation of molecular hydrophobic interactions between SP, TAβCD, and the PCL blocks in the copolymer. SP-loaded mPEG-PCL NPs were characterized by dynamic light scattering (DLS) and SEM. NPs with a size of 74–75 nm and standard deviation (S.D., a measure of the peak width) of 21–22 nm were obtained when an SP:TAβCD (1:1 molar ratio) spray-dried complex was used for the nano-encapsulation and SEM analysis revealed the absence of free SP crystals. The encapsulation efficiency (%EE) and drug loading (%DL) were 85% and 2.6%, respectively, as opposed to the much lower values (14% and 0.6%, respectively) achieved with pristine SP. Moreover, the NPs sustained the SP release with relatively low burst effect of 20%. Overall, our results confirmed that spray-drying of SP/TAβCD solutions at the appropriate molar ratio leads to the hydrophobization of the relatively hydrophilic SP molecule, enabling its encapsulation within mPEG-PCL NPs and paves the way for the use of this strategy in the development of novel drug delivery systems of this vital biological precursor.

Polymeric nanoparticles decorated with BDNF-derived peptide for neuron-targeted delivery of PTEN inhibitor

Biodegradable nanoparticles (PEG-PCL) decorated with tetra peptides (IKRG) on the surface were evaluated for their potential to deliver drugs into neurons for neural regeneration. The chosen 4-amino-acid peptide sequence was reported previously to mimic the function of BDNF (brain-derived neurotrophic factor) and target TrkB receptors that are present in abundance in neurons. Enhanced uptake for peptide-modified nanoparticles was observed in TrkB-positive PC12 cells but not in TrkB-negative HeLa cells. The modified nanoparticles were internalized selectively into neurons of dorsal root ganglion (DRG) and at a significantly higher rate. VO-OHpic, an inhibitor of PTEN (Phosphatase and tension homolog deleted on chromosome 10), was encapsulated into the modified nanoparticles and released over 14 days. Prolonged and enhanced neural regenerative effect, as confirmed by increased pAKT expression and increased neurite density, was observed when DRGs were treated with drug-containing nanoparticles. This was attributed to the increased and targeted cellular uptake and sustainable release by the peptide-modified nanoparticles. Furthermore, nanoparticle encapsulation was found to reduce the cytotoxicity of the free drug to the neurons. Our findings support that the BDNF-derived peptide modified PEG-PCL nanoparticles are promising carriers for localized and controlled drug delivery to peripheral neurons.

Recombinant Tissue Plasminogen Activator-conjugated Nanoparticles Effectively Targets Thrombolysis in a Rat Model of Middle Cerebral Artery Occlusion.

The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a fibrin-targeted nanoparticle (NP) drug delivery system for thrombosis combination therapy. We conjugated rtPA to poly(ethylene glycol)- poly(e-caprolactone) (PEG-PCL) nanoparticles (rtPA-NP) and investigated its physicochemical characteristics such as particle size, zeta potential, enzyme activity of conjugated rtPA and its storage stability at 4°C. The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP, the properties to fibrin targeting and its influences on systemic hemostasis in vivo. The results showed that rtPA-NP equivalent to 10% of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit (P<0.001). RtPA-NP did not influence the in vivo hemostasis or coagulation system. The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA. These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.

Shedding light on surface exposition of poly(ethylene glycol) and folate targeting units on nanoparticles of poly(ε-caprolactone) diblock copolymers: Beyond a paradigm

Polymeric nanoparticles (NPs) of poly(ε-caprolactone) (PCL) covered with a hydrophilic poly(ethylene glycol) (PEG) shell are usually prepared from diblock PEG-PCL copolymers through different techniques. Furthermore PEG, NPs can be decorated with targeting ligands to accumulate in specific cell lines. However, the density and conformation of PEG on the surface and its impact on the exposition of small targeting ligands has been poorly considered so far although this has a huge impact on biological behaviour. Here, we focus on PEG-PCL NPs and their folate-targeted version to encourage accumulation in cancer cells overexpressing folate receptor α. NPs were prepared with mixtures of PEG-PCL with different PEG length (short 1.0kDa, long 2.0kDa,) and a folate-functionalized PEG-PCL (PEG 1.5kDa) by the widely employed solvent displacement method. In depth characterization of NPs surface by 1H NMR, fluorescence and photon correlation spectroscopy evidenced a PEGylation extent below 7% with PEG in a mushroom conformation and the presence of folate more exposed to water pool in the case of copolymer with short PEG. NPs with short PEG adsorbed HSA forming a soft corona without aggregating. Although limited, PEGylation overall reduced NPs uptake in human macrophages. Uptake of NPs exposing folate prepared with short PEG was higher in KB cells (FR+) than in A549 (FR−), occurred via FR-receptor and involved lipid rafts-dependent endocytosis. In conclusion, the present results demonstrate that PEG length critically affects protein interaction and folate exposition with a logical impact on receptor-mediated cell uptake. Our study highlights that the too simplistic view suggesting that PEG-PCL gives PEG-coated NPs needs to be re-examined in the light of actual surface properties, which should always be considered case-by-case.

Preparation and in vivo evaluation of anti-plasmodial properties of artemisinin-loaded PCL–PEG–PCL nanoparticles

Purpose: Artemisinin (ART) has anti-inflammatory, antimicrobial, antioxidant, anti-amyloid, and anti-malarial effects, but its application is limited due to its low water solubility and poor oral bioavailability. In this study, the bioavailability, water solubility, and anti-plasmodial property of ART were improved by PCL–PEG–PCL tri-block copolymers.Methods: The structure of the copolymers was characterized by 1H NMR, FT-IR, DSC, and GPC techniques. ART was encapsulated within micelles by a single-step nano-precipitation method, leading to the formation of ART-loaded PCL–PEG–PCL micelles. The obtained micelles were characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM). The in vivo anti-plasmodial activity of ART-loaded micelles was measured against Plasmodium berghei infected Swiss albino mice.Results: The results showed that the zeta potential of ART-loaded micelles was about −8.37 mV and the average size was 91.87 nm. ART was encapsulated into PCL–PEG–PCL micelles with a loading capacity of 19.33 ± 0.015% and encapsulation efficacy of 87.21 ± 3.32%. In vivo anti-plasmodial results against P. berghei showed that multiple injections of ART-loaded micelles could prolong the circulation time and increase the therapeutic efficacy of ART.Conclusion: These results suggested that PCL–PEG–PCL micelles would be a potential carrier for ART for the treatment of malaria.

Co-delivery of hydrophilic and hydrophobic drugs by micelles: a new approach using drug conjugated PEG–PCLNanoparticles

Co-delivery strategy has been proposed to minimize the amount of each drug and to achieve the synergistic effect for cancer therapies. A conjugate of the antitumor drug, doxorubicin, with diblock methoxy poly (ethylene glycol)-poly caprolactone (mPEG-PCL) copolymer was synthesized by the reaction of mPEG–PCL copolymer with doxorubicin in the presence of p-nitrophenylchloroformate. The conjugated copolymer was characterized in vitro by 1H-NMR, FTIR, DSC and GPC techniques. Then, the doxorubicin conjugated mPEG–PCL(DOX–mPEG-PCL) was self-assembled into micelles in the presence of curcumin in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM).The encapsulation efficiency of doxorubicin and curcumin were 82.31 ± 3.32 and 78.15 ± 3.14%, respectively. The results revealed that the micelles formed by the DOX–mPEG-PCL with and without curcumin have spherical structure with average size of 116 and 134 nm respectively. The release behavior of curcumin and doxorubicin loaded to micelles were investigated in a different media. The release rate of micelles consisted of the conjugated copolymer was pH dependent as it was higher at lower pH than in neutral condition. Another feature of the conjugated micelles was a sustained release profile. The cytotoxicity of micelles were evaluated by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, atetrazole) assay on lung cancer A549 cell lines. In vitro cytotoxicity assay showed that the mPEG–PCL copolymer did not affect the growth of A549 cells. The cytotoxic activity of the micelles against A549 cells was greater than free doxorubicin and free curcumin.

Design of amphiphilic PCL-PEG-PCL block copolymers as vehicles of Ginkgolide B and their brain-targeting studies

The amphiphilic PEG-b-PCL block copolymers were synthesized by ring-opening polymerization. The specific and selective antagonists of platelet activating factor, Ginkgolide B (GB), was successfully encapsulated in the synthesized PEG-PCL nanoparticles (NPs) with high Encapsulation Efficiency and Drug Loading. The synthesis of different PEG-PCL copolymers were confirmed with FTIR and 1H NMR spectra. The morphology and particles size distribution of cargo-free PEG-PCL NPs were studied by transmission electron microscope (TEM) analysis and Malvern laser particle analyzer. The bio-distribution and pharmacodynamics studies of GB were studied with Wistar mice as the animal models via tail injecting of GB-PEG-PCL NPs. Results from Malvern laser particle analyzer and TEM analysis illustrated that the cargo-free NPs showed narrow distribution and well separated particles size of about 60 nm in diameter. The in vitro experiment of GB-PEG-PCL NPs exhibited an extended release behavior. The bio-distribution data suggested that Tween-80 covered GB-PEG-PCL NPs showed a brain-targeting behavior. The pharmacodynamics results confirmed that the GB-PEG-PCL NPs had an obvious cerebral protection effect.

Gambogic acid-loaded PEG–PCL nanoparticles act as an effective antitumor agent against gastric cancer

Poor water solubility and side effects hampered the clinical application of gambogic acid (GA) in cancer therapy. Accordingly, GA-loaded polyethylene glycol-poly(ɛ-caprolactone) (PEG–PCL) nanoparticles (GA-NPs) were developed and administered peritumorally to evaluate their antitumor activity. The particle size, polydispersity index, encapsulation efficiency and loading capacity of GA-NPs were 143.78 ± 0.054 nm, 0.179 ± 0.004, 81.3 ± 2.5% and 14.8 ± 0.6%, respectively. In addition, GA-NPs showed excellent stability, good biocompatibility and sustained release profile. Endocytosis studies in vitro demonstrated that the GA-NPs were effectively taken up by tumor cells in a time-dependent manner. In vivo real-time imaging showed that the nanoparticles effectively accumulated within the tumor tissue after peritumoral administration. The cytotoxicity study revealed that the GA-NPs effectively inhibited the proliferation of gastric cancer cells. In vivo antitumor therapy with peritumoral injection of GA-NPs exhibited superior antitumor activity compared with free GA. Moreover, no toxicity was detected in any treatment group. Histological studies confirmed a lower cell density and a higher number of apoptotic cells in the GA-NPs group compared with the free GA group. Furthermore, the expression level of the cysteine proteases 3 precursor (pro-caspase3), a crucial component of cellular apoptotic pathways, was efficiently reduced in mice treated with GA-NPs. In conclusion, the GA-NPs system provided an efficient drug delivery platform for chemotherapy.

Pharmacokinetics and in vitro and in vivo delivery of sulforaphane by PCL–PEG–PCL copolymeric-based micelles

A reliable and efficient drug delivery system using PCL–PEG–PCL copolymers was established for the anti-cancer compound sulforaphane (SF) in this study. Encapsulated SF by PCL–PEG–PCL nanoparticles led to formation of SF-loaded PCL–PEG–PCL micelles. Micelles characterization and stability, the particle size and their morphology were determined by DLS and AFM. The loading efficiency of SF was 19.33 ± 1.28%. The results of AFM showed that the micelles had spherical shapes with the size of 107 nm. In vitro release of SF from SF-entrapped micelles was remarkably sustained. The cytotoxicity of free SF, PCL–PEG–PCL and SF/PCL–PEG–PCL micelles was analysis by MTT colorimetric assay on MCF-7, 4T1 and MCF10A cell lines. Expression levels of BCL-2, PARP, COX-2, Caspase-9 and ACTB genes were quantified by real-time PCR. Flow cytometry analysis was performed using the Annexin V-FITC Apoptosis Detection Kit to evaluate the apoptotic effects of free SF compared with SF/PCL–PEG–PCL micelles. Study of the in vivo pharmacokinetics of the SF-loaded micelles was carried out on SF-loaded PCL–PEG–PCL micelles in comparison with free SF. The results of in vivo experiments indicated that the SF loaded micelles significantly reduced the tumor size. In vivo results showed that the multiple injections of SF-loaded micelles could prolong the circulation period and increase the therapeutic efficacy of SF. Also, in comparison with the free-SF solution, encapsulation of the SF in micelles increased the mean residence time from 0.5 to 4 h and the area under the concentration–time curve up to 50 folds.

Engineering biodegradable guanidyl-decorated PEG-PCL nanoparticles as robust exogenous activators of DCs and antigen cross-presentation

Nanoparticles (NPs)-based adjuvants are attracting much attention in the development of vaccines. Previously, we reported a type of guanidyl-decorated polymeric NPs used as antigen delivery carriers for the first time. However, its un-degradability may restrict potential clinical translation. More importantly, the specific cellular pathway by which dendritic cells (DCs) endocytosed these NPs and the relationship among guanidyl with the antigen cross-presentation, cytokine secretion, and lymph node targeting still remain unclear. Here, we show NPs assembled by biodegradable methoxyl poly(ethylene glycol)-block-poly(ε-caprolactone)-graft-poly(2-(guanidyl) ethyl methacrylate) (mPEG-b-PCL-g-PGEM, PECG) copolymers can robustly activate DCs and promote their maturation; additionally antigen cross-presentation was improved both in vitro and in vivo. Significantly, our results also demonstrate the increase of surface guanidyl on nanoparticles modulates the depot effect and lymph node drainage of PECG NPs-based adjuvants, as well as immune responses, by regulating the secretion of cytokines including IFN-γ and TNF-α. Our study provides insights into the action of guanidyl-decorated nanoscale adjuvants and new adjuvants for vaccines containing protein antigens. We anticipate the strategy of guanidyl decoration to be a starting point for the development of more exciting immunoadjuvants.