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Gelatinase-stimuli strategy enhances the tumor delivery and therapeutic efficacy of docetaxel-loaded poly(ethylene glycol)-poly(ɛ-caprolactone) nanoparticles.

ABSTRACT: Nanoscale drug carriers have been extensively developed to improve drug therapeutic efficiency. However, delivery of chemotherapeutic agents to tumor tissues and cells has not been favorably managed. In this study, we developed a novel "intelligent" nanoparticle, consisting of a gelatinase-cleavage peptide with poly(ethylene glycol) (PEG) and poly(ɛ-caprolactone) (PCL)-based structure for tumor-targeted docetaxel delivery (DOC-TNPs). The docetaxel-loaded PEG-PCL nanoparticles (DOC-NPs) that did not display gelatinase-stimuli behaviors were used as a control. We found clear evidence that the DOC-TNPs were transformed by gelatinases, allowing drug release and enhancing the cellular uptake of DOC (P < 0.01). In vivo biodistribution study demonstrated that targeted DOC-TNPs could accumulate and remain in the tumor regions, whereas non-targeted DOC-NPs rapidly eliminated from the tumor tissues. DOC-TNPs exhibited higher tumor growth suppression than commercialized Taxotere(®) (docetaxel; Jiangsu Hengrui Medicine Company, Jiangsu, China) and DOC-NPs on hepatic H22 tumor model via intravenous administration (P < 0.01). Both in vitro and in vivo experiments suggest that the gelatinase-mediated nanoscale delivery system is promising for improvement of antitumor efficacy in various overexpressed gelatinase cancers.

SUBMITTER: Liu Q

PROVIDER: S-EPMC3265997 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Electrospun chitosan-graft-poly (ɛ-caprolactone)/poly (ɛ-caprolactone) nanofibrous scaffolds for retinal tissue engineering.

Project description:A promising therapy for retinal diseases is to employ biodegradable scaffolds to deliver retinal progenitor cells (RPCs) for repairing damaged or diseased retinal tissue. In the present study, cationic chitosan-graft-poly(ɛ-caprolactone)/polycaprolactone (CS-PCL/PCL) hybrid scaffolds were successfully prepared by electrospinning. Characterization of the obtained nanofibrous scaffolds indicated that zeta-potential, fiber diameter, and the content of amino groups on their surface were closely correlated with the amount of CS-PCL in CS-PCL/PCL scaffolds. To assess the cell-scaffold interaction, mice RPCs (mRPCs) were cultured on the electrospun scaffolds for 7 days. In-vitro proliferation assays revealed that mRPCs proliferated faster on the CS-PCL/PCL (20/80) scaffolds than the other electrospun scaffolds. Scanning electron microscopy and the real-time quantitative polymerase chain reaction results showed that mRPCs grown on CS-PCL/PCL (20/80) scaffolds were more likely to differentiate towards retinal neurons than those on PCL scaffolds. Taken together, these results suggest that CS-PCL/PCL(20/80) scaffolds have potential application in retinal tissue engineering.

| S-EPMC3075910 | biostudies-literature

π-π-Stacked Poly(ε-caprolactone)-b-poly(ethylene glycol) Micelles Loaded with a Photosensitizer for Photodynamic Therapy.

Project description:To improve the in vivo stability of poly(-caprolactone)-b-poly(ethylene glycol) (PCL-PEG)-based micelles and cargo retention by π-π stacking interactions, pendant aromatic rings were introduced by copolymerization of -caprolactone with benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate (TMC-Bz). It was shown that the incorporation of aromatic rings yielded smaller micelles (18-30 nm) with better colloidal stability in PBS than micelles without aromatic groups. The circulation time of i.v. injected micelles containing multiple pendant aromatic groups was longer (t½-α: ~0.7 h; t½-β: 2.9 h) than that of micelles with a single terminal aromatic group (t½ < 0.3 h). In addition, the in vitro partitioning of the encapsulated photosensitizer (meta-tetra(hydroxyphenyl)chlorin, mTHPC) between micelles and human plasma was favored towards micelles for those that contained the pendant aromatic groups. However, this was not sufficient to fully retain mTHPC in the micelles in vivo, as indicated by similar biodistribution patterns of micellar mTHPC compared to free mTHPC, and unequal biodistribution patterns of mTHPC and the host micelles. Our study points out that more detailed in vitro methods are necessary to more reliably predict in vivo outcomes. Furthermore, additional measures beyond π-π stacking are needed to stably incorporate mTHPC in micelles in order to benefit from the use of micelles as targeted delivery systems.

| S-EPMC7238042 | biostudies-literature

Verteporfin-Loaded Poly(ethylene glycol)-Poly(beta-amino ester)-Poly(ethylene glycol) Triblock Micelles for Cancer Therapy.

Project description:Amphiphilic polymers can be used to form micelles to deliver water-insoluble drugs. A biodegradable poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE)-PEG triblock copolymer was developed that is useful for drug delivery. It was shown to successfully encapsulate and pH-dependently release a water-insoluble, small molecule anticancer drug, verteporfin. PEG-PBAE-PEG micelle morphology was also controlled through variations to the hydrophobicity of the central PBAE block of the copolymer in order to evade macrophage uptake. Spherical micelles were 50 nm in diameter, while filamentous micelles were 31 nm in width with an average aspect ratio of 20. When delivered to RAW 264.7 mouse macrophages, filamentous micelles exhibited a 89% drop in cellular uptake percentage and a 5.6-fold drop in normalized geometric mean cellular uptake compared to spherical micelles. This demonstrates the potential of high-aspect-ratio, anisotropically shaped PEG-PBAE-PEG micelles to evade macrophage-mediated clearance. Both spherical and filamentous micelles also showed therapeutic efficacy in human triple-negative breast cancer and small cell lung cancer cells without requiring photodynamic therapy to achieve an anticancer effect. Both spherical and filamentous micelles were more effective in killing lung cancer cells than breast cancer cells at equivalent verteporfin concentrations, while spherical micelles were shown to be more effective than filamentous micelles against both cancer cells. Spherical and filamentous micelles at 5 and 10 ?M respective verteporfin concentration resulted in 100% cell killing of lung cancer cells, but both micelles required a higher verteporfin concentration of 20 ?M to kill breast cancer cells at the levels of 80% and 50% respectively. This work demonstrates the potential of PEG-PBAE-PEG as a biodegradable, anisotropic drug delivery system as well as the in vitro use of verteporfin-loaded micelles for cancer therapy.

| S-EPMC6249031 | biostudies-literature

Interfacial properties and micellization of triblock poly(ethylene glycol)-poly(?-caprolactone)-polyethyleneimine copolymers.

Project description:Graphical abstractThis paper found the correlation between molecular arrangement and self-assembly and inspired us to tune block compositions to achieve desired nanostructure and drug loading.Image 1

| S-EPMC7332608 | biostudies-literature

Docetaxel-Loaded Methoxy poly(ethylene glycol)-poly (L-lactic Acid) Nanoparticles for Breast Cancer: Synthesis, Characterization, Method Validation, and Cytotoxicity

Project description: Not available

| S-EPMC10675362 | biostudies-literature

Thermoresponsive Poly(?-Caprolactone)-Poly(Ethylene/Propylene Glycol) Copolymers as Injectable Hydrogels for Cell Therapies.

Project description:Injectable, thermoresponsive hydrogels are promising candidates for the delivery, maintenance and controlled release of adoptive cell therapies. Therefore, there is significant interest in the development of cytocompatible and biodegradable thermoresponsive hydrogels with appropriate gelling characteristics. Towards this end, a series of thermoresponsive copolymers consisting of poly(caprolactone) (PCL), poly(ethylene glycol) (PEG) and poly(propylene glycol) (PPG) segments, with various PEG:PPG ratios, were synthesised via ring-opening polymerisation (ROP) of ?-caprolactone and epoxy-functionalised PEG and PPG derivatives. The resultant PCL-PEG-PPG copolymers were characterised via proton nuclear magnetic resonance (1H NMR) spectroscopy, gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). The thermoresponsive characteristics of the aqueous copolymer solutions at various concentrations was investigated using the inversion method. Whilst all of the copolymers displayed thermoresponsive properties, the copolymer with a ratio of 1:2 PEG:PPG exhibited an appropriate sol-gel transition (28 °C) at a relatively low concentration (10 wt%), and remained a gel at 37 °C. Furthermore, the copolymers were shown to be enzymatically degradable in the presence of lipases and could be used for the encapsulation of CD4+ T-cell lymphocytes. These results demonstrate that the thermoresponsive PCL-PEG-PPG hydrogels may be suitable for use as an adoptive cell therapy (ACT) delivery vehicle.

| S-EPMC7077385 | biostudies-literature

Poly(ethylene glycol)-poly(vinyl alcohol)-adamantanate: synthesis and stimuli-responsive micelle properties.

Project description:A pH-sensitive amphiphilic polymer based on poly(vinyl alcohol) (PVA), modified with poly(ethylene glycol) (PEG) and adamantane (Ad) pendant groups, has been synthesized and the self-assembly properties of this PEG-PVA-Ad construct investigated. PEG-PVA-Ad polymer forms micelles via self-assembly at concentrations as low as 26 mg L-1. These polymer micelles can be destroyed by low pH or the addition of ?-CD.

| S-EPMC6906925 | biostudies-literature

Effect of Molecular Weight on Gelling and Viscoelastic Properties of Poly(caprolactone)-b-Poly(ethylene glycol)-b-Poly(caprolactone) (PCL-PEG-PCL) Hydrogels.

Project description:Hydrogels based on poly(caprolactone)-b-poly(ethylene glycol)-b-poly(caprolactone) (PCL-PEG-PCL) have been evaluated extensively as potential injectable fillers or depots for controlled release of drugs. Common drawbacks of these copolymer systems include instability of aqueous solutions and low mechanical strength of gels, issues which are commonly overcome by adding pendant groups to the end of the copolymer chains. Here, a systematic study of the effects of increasing polymer molecular weight (MW) is presented, utilizing PEG blocks of MW 2, 4 or 8 kDa. Triblock copolymers were prepared by the ring-opening polymerization of Ɛ-caprolactone by PEG. Copolymers prepared with PEG MW 2 kDa did not form hydrogels at any copolymer molecular weight. Copolymers prepared with PEG MW 4 kDa formed gels at MW between 11 and 13.5 kDa, and copolymers prepared with PEG MW 8 kDa formed gels at MW between 16 and 18 kDa. Copolymers with PEG block 8 kDa formed hydrogels with high viscosity (17,000 Pa·s) and mechanical strength (G' = 14,000 Pa). The increased gel strength afforded by increased molecular weight represents a simple modification of the reactants used in the reaction feed without added synthetic or purification steps. Shear-thinning of PCL-PEG-PCL triblock copolymer hydrogels allowed for injection through a standard 23G syringe, allowing for potential use as dermal fillers or drug delivery depots.

| S-EPMC7650642 | biostudies-literature

Amphiphilic Polymer Conetwork Gel Films Based on Tetra-Poly(ethylene Glycol) and Tetra-Poly(ε-Caprolactone).

Project description:The preparation and investigation of gel films from a model amphiphilic polymer conetwork (ACN) grant a deeper control and understanding of the structure-property relationship in the bulk phase and at the interface of materials with promising applications. In order to allow the simultaneous transport of hydrophilic and hydrophobic substances, polymeric networks with finely distributed hydrophilic and hydrophobic components are very suitable. When designing new soft materials such as coatings, in addition to the structure in the bulk phase, the structure at the interface plays a critical role. In this study, two alternating tetra-arm star polymers poly(ε-caprolactone) (tetra-PCL-Ox) and amino-terminated poly(ethylene glycol) (tetra-PEG-NH2) form an amphiphilic polymer conetwork. The correlation between different synthesis strategies for gel films of this ACN model system and their resulting properties will be described. Through various spin coating techniques, control over film thickness and roughness is achievable and highlights differences to macroscopic gel samples. Atomic force microscopy (AFM) measurements reveal the effect of solvents of different polarities on the swelling ability and surface structure. This correlates with AFM investigations of the mechanical properties on ACN gel films, demonstrating a strong effect on the resulting elastic modulus E, depending on the presence or absence of a good solvent during synthesis. Furthermore, a higher E modulus is obtained in the presence of the selective solvent water, compared to the non-selective solvent toluene. This observation is explained through selective swelling of the tetra-arm star polymers displaying a different hydrophobicity.

| S-EPMC9269314 | biostudies-literature

Preparation and characterization of functionalized heparin-loaded poly-Ɛ-caprolactone fibrous mats to prevent infection with human papillomaviruses.

Project description:In this study, heparin-loaded poly-ɛ-caprolactone (PCL) fibrous mats were prepared and characterized based on their physical, cytotoxic, thermal, and biological properties. The main objective of the work described here was to test the hypothesis that incorporation of heparin into a PCL carrier could serve as bio-compatible material capable of inhibiting Human Papillomavirus (HPV) infection. The idea of firmly anchoring heparin to capture soluble virus, vs. a slow heparin release to inhibit a virus in solution was tested. Thus, one material was produced via conventional heparin matrix encapsulation and electrohydrodynamic fiber processing in one step. A second type of material was obtained via heparin crosslinking. This was achieved by running a carbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling reaction on preformed PCL fibers. In vitro HPV16 L1 protein binding capacity studies were performed. Infectivity assays were done using HPV16 pseudoviruses (PsVs) carrying a GFP plasmid to directly test the ability of the fibrous mats to prevent internalization of HPV PsVs. The crosslinked heparin material presented a dissociation constant (Kd) value comparable to those found in the literature for different heparin-protein L1 peptide interactions. Both materials significantly reduced internalization of HPV PsVs, with a reduction of 94% of PsVs internalization when matrix encapsulated heparin-loaded material was present. Differences in performance between the two proposed structures are discussed.

| S-EPMC6028096 | biostudies-literature

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