Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for targeted therapy of bone metastatic cancer.
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ABSTRACT:
SUBMITTER: Ye WL
PROVIDER: S-EPMC4588583 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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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
Project description:A novel pH-sensitive polymeric micellar system composed of poly(L-histidine)-b-poly(ethylene glycol) and poly(L-lactide)-b-poly(ethylene glycol) block copolymers was studied by dynamic/static light scattering, spectrofluorimetry and differential scanning calorimetry. The mixed micelles displayed ultra Ph Sensitivity Which Could Be Tuned By Varying The Mixing Ratio Of The Two Polymers. In Particular, Mixed Micelles Composed Of 25 Wt.% Poly(L-lactide)-b-poly(ethylene glycol) exhibited desirable pH dependency which could be used as a drug delivery system that selectively targeted the extracellular pH of acidic solid tumors. Micelles were quite stable from pH 7.4 to 7.0 but underwent a two-stage destabilization as pH decreased further. A significant increase in size and aggregation number was observed when pH dropped to 6.8. Further disruption of the micelle core eventually caused phase separation in the micelle core and dissociation of ionized poly(L-histidine)-b-poly(ethylene glycol) molecules from the micelles as pH decreased to 6.0. Increased electrostatic repulsions which arise from the progressive protonation of imidazole rings overwhelming the hydrophobic interactions among uncharged neutral blocks is considered to be the mechanism for destabilization of the micelle core.
| S-EPMC2276666 | biostudies-literature
Project description:BackgroundThermosensitive micelles with rigid cores that exhibit a reversible lower critical solution temperature at 30-35 °C can be applied for drug delivery.MethodHydrophilic monomethoxy poly(ethylene glycol) was conjugated to hydrophobic deoxycholic acid to prepare monomethoxy poly(ethylene glycol)-deoxycholic acid (mPEG-DC). Micelle formation and thermosensitive solution behavior were studied using various methods, including hydrophobic dye solubilization, transmission electron microscopy, dynamic light scattering, turbidity measurement, microcalorimetry, and 1H-NMR spectroscopy. Drug release from the thermosensitive micelles was demonstrated using estradiol, a model drug.ResultsThe mPEG-DC formed micelles with a critical micelle concentration of 0.05 wt.% and an average size of 15 nm. Aqueous mPEG-DC solutions exhibit a lower critical solution temperature (LCST) that is independent of concentration and reversible over heating and cooling cycles. The LCST transition is an entropically driven process involving dehydration of the PEG shell. The thermosensitive mPEG-DC micelles with rigid DC cores were applied as an estradiol delivery system in which estradiol was released, without initial burst, over the 16 days in a diffusion-controlled manner.ConclusionsThis study suggests that mPEG-DCs form thermosensitive micelles with rigid cores that can function as an excellent diffusion-controlled hydrophobic drug delivery system without initial burst release. Thermosensitive core-rigid micelles of monomethoxy poly(ethylene glycol)-deoxy cholic acid.
| S-EPMC9052506 | biostudies-literature
Project description:In this work, micelles composed of doxorubicin-conjugated Y-shaped copolymers (YMs) linked via an acid-labile linker were constructed. Y-shaped copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin)2 and linear copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin) were synthesized and characterized. Particle size, size distribution, morphology, drug loading content (DLC) and drug release of the micelles were determined. Alterations in size and DLC of the micelles could be achieved by varying the hydrophobic block lengths. Moreover, at fixed DLCs, YMs showed a smaller diameter than micelles composed of linear copolymers (LMs). Also, all prepared micelles showed sustained release behaviors under physiological conditions over 72 h. DOX loaded in YMs was released more completely, with 30% more drug released in acid. The anti-tumor efficacy of the micelles against HeLa cells was evaluated by MTT assays, and YMs exhibited stronger cytotoxic effects than LMs in a dose- and time-dependent manner. Cellular uptake studied by CLSM indicated that YMs and LMs were readily taken up by HeLa cells. According to the results of this study, doxorubicin-conjugated Y-shaped PEG-(polypeptide)2 copolymers showed advantages over linear copolymers, like assembling into smaller nanoparticles, faster drug release in acid, which may correspond to higher cellular uptake and enhanced extracellular/intracellular drug release, indicating their potential in constructing nano-sized drug delivery systems.
| S-EPMC6271086 | biostudies-literature
Project description:Self-assembled monolayers (SAMs) can be formed at the interface between solids and fluids, and are often used to modify the surface properties of the solid. One of the most widely employed SAM systems is exploiting thiol-gold chemistry, which, together with alkane-chain-based molecules, provides a reliable way of SAM formation to modify the surface properties of electrodes. Oligo ethylene-glycol (OEG) terminated alkanethiol monolayers have shown excellent antifouling properties and have been used extensively for the coating of biosensor electrodes to minimize nonspecific binding. Here, we report the investigation of the dielectric properties of COOH-capped OEG monolayers and demonstrate a strategy to improve the dielectric properties significantly by mixing the OEG SAM with small concentrations of 11-mercaptoundecanol (MUD). The monolayer properties and composition were characterized by means of impedance spectroscopy, water contact angle, ellipsometry and X-ray photoelectron spectroscopy. An equivalent circuit model is proposed to interpret the EIS data and to determine the conductivity of the monolayer. We find that for increasing MUD concentrations up to about 5% the resistivity of the SAM steadily increases, which together with a considerable decrease of the phase of the impedance, demonstrates significantly improved dielectric properties of the monolayer. Such monolayers will find widespread use in applications which depend critically on good dielectric properties such as capacitive biosensor.
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Project description:Engineering controllable cellular interactions into nanoscale drug delivery systems is key to enable their full potential. Here, using folic acid (FA) as a model targeting ligand and dendron micelles (DM) as a nanoparticle (NP) platform, we present a comprehensive experimental and modeling investigation of the structural properties of DMs that govern the formation of controllable, FA-mediated cellular interactions. Our experimental results demonstrate that a high level of control over the specific cell interactions of FA-targeted DMs can be achieved through modulation of the PEG corona length and the FA content. Using various molecular weight PEGs (0.6K, 1K, and 2K g/mol) and contents of dendron-FA conjugate incorporated into DMs (0, 5, 10, 25 wt %), the cell interactions of the targeted DMs could be controlled to exhibit minimal to >25-fold enhancement over nontargeted DMs. Molecular dynamics simulations indicated that structural characteristics, such as solvent accessible surface area of FA, local PEG density near FA, and FA mobility, account in part for the experimental differences in cellular interactions. The molecular structure that allows FA to depart from the surface of DMs to facilitate the initial cell surface binding was revealed to be the most important contributor for determining FA-mediated cellular interactions of DMs. The modular properties of DMs in controlling their specific cell interactions support the potential of DMs as a delivery platform and offer design cues for future development of targeted NPs.
| S-EPMC6800011 | biostudies-literature
Project description:Noninvasive near-infrared (NIR) fluorescence imaging is a promising technique for the intraoperative assessment of solid tumor removal. We incorporated a lipophilic NIR probe, 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR), in poly(ethylene glycol)-b-poly(?-caprolactone) (PEG-b-PCL) micelles, resulting in DiR solubilization in water, occupying nanoscopic PEG-b-PCL micelles. DiR in a self-quenched or nonquenched state showed different kinetics of release from PEG-b-PCL micelles in vitro; however, both obtained high tumor delineation (tumor-to-muscle ratio of 30-43 from collected organs). These results suggest that PEG-b-PCL micelles with DiR are a promising nanosized imaging agent that will provide a basis for enhanced surgical guidance via NIR visualization of tumors.In this paper, noninvasive near-infrared fluorescence imaging coupled with specific lipophilic probes is discussed as a promising technique for intraoperative assessment of solid tumor removal, leading to optimized outcomes for in toto removal of tumors.
| S-EPMC3193583 | biostudies-literature
Project description:The present studies noninvasively investigate the passive tumor distribution potential of a series of poly(ethylene glycol) (PEG) nanocarriers using a SkinSkan spectrofluorometer and an In Vivo Imaging System (IVIS) 100. Fluorescein conjugated PEG nanocarriers of varying molecular weights (10, 20, 30, 40, and 60 kDa) were prepared and characterized. The nanocarriers were administered intravenously to female balb/c mice bearing subcutaneous 4T1 tumors. Passive distribution was measured in vivo (λ(exc), 480 nm; λ(em), 515-520 nm) from the tumor and a contralateral skin site (i.e., control site). The signal intensity from the tumor was always significantly higher than that from the contralateral site. Trends in results between the two methods were consistent with tumor distribution increasing in a molecular weight-dependent manner (10 < 20 < 30 ≪ 40 ≪ 60 kDa). The 10 kDa nanocarrier was not detected in tumors at 24 h, whereas 40-60 kDa nanocarriers were detected in tumors for up to 96 h. The 30, 40, and 60 kDa nanocarriers showed 2.1, 5.3, and 4.1 times higher passive distribution in tumors at 24 h, respectively, as compared to the 20 kDa nanocarrier. The 60 kDa nanocarrier exhibited 1.5 times higher tumor distribution than 40 kDa nanocarrier at 96 h. Thus, PEG nanocarriers (40 and 60 kDa) with molecular weights close to or above the renal exclusion limit, which for globular proteins is ≥45 kDa, showed significantly higher tumor distribution than those below it. The hydrodynamic radii of PEG polymers, measured using dynamic light scattering (DLS), showed that nanocarriers obtained from polymers with hydrodynamic radii ≥8 nm exhibited higher tumor distribution. Ex vivo mass balance studies revealed that nanocarrier tissue distribution followed the rank order tumor > lung > spleen > liver > kidney > muscle > heart, thus validating the in vivo studies. The results of the current studies suggest that noninvasive dermal imaging of tumors provides a reliable and rapid method for the initial screening of nanocarrier tumor distribution pharmacokinetics.
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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
Project description:The use of pH-responsive polymeric micelles is a promising approach to afford the targeted, pH-mediated delivery of hydrophobic drugs within the low-pH tumour milieu and intracellular organelles of cancer cells. However, even for a common pH-responsive polymeric micelle system-e.g., those utilising poly(ethylene glycol)-b-poly(2-vinylpyridine) (PEG-b-PVP) diblock copolymers-there is a lack of available data describing the compatibility of hydrophobic drugs, as well as the relationships between copolymer microstructure and drug compatibility. Furthermore, synthesis of the constituent pH-responsive copolymers generally requires complex temperature control or degassing procedures that limit their accessibility. Herein we report the facile synthesis of a series of diblock copolymers via visible-light-mediated photocontrolled reversible addition-fragmentation chain-transfer polymerisation, with a constant PEG block length (90 repeat units (RUs)) and varying PVP block lengths (46-235 RUs). All copolymers exhibited narrow dispersity values (Đ ≤ 1.23) and formed polymeric micelles with low polydispersity index (PDI) values (typically <0.20) at physiological pH (7.4), within a suitable size range for passive tumour targeting (<130 nm). The encapsulation and release of three hydrophobic drugs (cyclin-dependent kinase inhibitor (CDKI)-73, gossypol, and doxorubicin) were investigated in vitro at pH 7.4-4.5 to simulate drug release within the tumour milieu and cancer cell endosome. Marked differences in drug encapsulation and release were observed when the PVP block length was increased from 86 to 235 RUs. With a PVP block length of 235 RUs, the micelles exhibited differing encapsulation and release properties for each drug. Minimal release was observed for doxorubicin (10%, pH 4.5) and CDKI-73 exhibited moderate release (77%, pH 4.5), whereas gossypol exhibited the best combination of encapsulation efficiency (83%) and release (91% pH 4.5) overall. These data demonstrate the drug selectivity of the PVP core, where both the block molecular weight and hydrophobicity of the core (and accordingly the hydrophobicity of the drug) have a significant effect on drug encapsulation and release. These systems remain a promising means of achieving targeted, pH-responsive drug delivery-albeit for select, compatible hydrophobic drugs-which warrants their further investigation to develop and evaluate clinically relevant micelle systems.
| S-EPMC10056943 | biostudies-literature