-
International Journal of Pharmaceutics Jun 2017The use of organic-inorganic hybrid nanocarriers for controlled release of anticancer drugs has been gained a great interest, in particular, to improve the selectivity...
The use of organic-inorganic hybrid nanocarriers for controlled release of anticancer drugs has been gained a great interest, in particular, to improve the selectivity and efficacy of the drugs. In this study, iron oxide nanoparticles were prepared then surface modified via diazonium chemistry and coated with chitosan, and its derivative chitosan-grafted polylactic acid. The purpose was to increase the stability of the nanoparticles in physiological solution, heighten drug-loading capacity, prolong the release, reduce the initial burst effect and improve in vitro cytotoxicity of the model drug doxorubicin. The materials were characterized by DLS, ζ-potential, SEM, TGA, magnetization curves and release kinetics studies. Results confirmed the spherical shape, the presence of the coat and the advantages of using chitosan, particularly its amphiphilic derivative, as a coating agent, thereby surpassing the qualities of simple iron oxide nanoparticles. The coated nanoparticles exhibited great stability and high encapsulation efficiency for doxorubicin, at over 500μg per mg of carrier. Moreover, the intensity of the initial burst was clearly diminished after coating, hence represents an advantage of using the hybrid system over simple iron oxide nanoparticles. Cytotoxicity studies demonstrate the increase in cytotoxicity of doxorubicin when loaded in nanoparticles, indirectly proving the role played by the carrier and its surface properties in cell uptake.
Topics: Antineoplastic Agents; Chitosan; Doxorubicin; Drug Carriers; HeLa Cells; Humans; Nanoparticles; Surface Properties
PubMed: 28465052
DOI: 10.1016/j.ijpharm.2017.04.061 -
Journal of Pharmaceutical and... Sep 2020Regulatory guidance requires the quantification of encapsulated and free doxorubicin for a liposomal doxorubicin injection bioequivalence study. Due to the instability...
Regulatory guidance requires the quantification of encapsulated and free doxorubicin for a liposomal doxorubicin injection bioequivalence study. Due to the instability of liposome formulations in plasma samples, the release of free drug from the liposomal encapsulated doxorubicin during sample handling would result in elevation of measured free doxorubicin concentration. To prevent the potential release of free drug, stabilizer reagents and procedures were successfully developed and validated to adequately stabilize liposomal drugs in plasma samples during sample collection, storage and extraction. Three LC-MS/MS methods were developed and fully validated for direct quantitation of free, encapsulated and total doxorubicin concentrations in human plasma according to relevant regulatory guidance: Method 1: Quantitation of free doxorubicin and doxorubicinol at a linear range of 1-400 ng/mL and 0.5-10 ng/mL, respectively, from stabilizer treated plasma samples using solid phase extraction (SPE); Method 2: Quantitation of encapsulated doxorubicin at a linear range of 50-50,000 ng/mL from the stabilizer treated plasma sample using SPE followed by PPE extraction method; Method 3: Quantitation of total concentration of doxorubicin from untreated plasma samples at a linear range of 50-50,000 ng/mL using PPE. All three methods were successfully used to support a bioequivalence study between Caelyx® and Duomeisu® (Doxorubicin Hydrochloride Liposomal injection, generic doxorubicin formulation produced by CSPC). Incurred sample reanalysis (ISR) passing rate for total doxorubicin, free doxorubicin/doxorubicinol, and encapsulated doxorubicin methods were 100 %, 84.7 %/100 %, and 98.5 %, respectively. The measured total doxorubicin concentrations matched the sum of free and encapsulated doxorubicin concentrations.
Topics: Chromatography, Liquid; Doxorubicin; Humans; Liposomes; Polyethylene Glycols; Tandem Mass Spectrometry
PubMed: 32663760
DOI: 10.1016/j.jpba.2020.113388 -
Journal of Materials Chemistry. B Mar 2023Based on disulfide-enriched multiblock copolymer vesicles, we present a straightforward sequential drug delivery system with dual-redox response that releases...
Based on disulfide-enriched multiblock copolymer vesicles, we present a straightforward sequential drug delivery system with dual-redox response that releases hydrophilic doxorubicin hydrochloride (DOX·HCl) and hydrophobic paclitaxel (PTX) under oxidative and reductive conditions, respectively. When compared to concurrent therapeutic delivery, the spatiotemporal control of drug release allows for an improved combination antitumor effect. The simple and smart nanocarrier has promising applications in the field of cancer therapy.
Topics: Disulfides; Drug Delivery Systems; Paclitaxel; Doxorubicin; Polymers; Oxidation-Reduction
PubMed: 36794489
DOI: 10.1039/d2tb02686d -
Platelets Dec 2023Platelet extracellular vesicles (PEVs) are an emerging delivery vehi for anticancer drugs due to their ability to target and remain in the tumor microenvironment....
Platelet extracellular vesicles (PEVs) are an emerging delivery vehi for anticancer drugs due to their ability to target and remain in the tumor microenvironment. However, there is still a lack of understanding regarding yields, safety, drug loading efficiencies, and efficacy of PEVs. In this study, various methods were compared to generate PEVs from clinical-grade platelets, and their properties were examined as vehicles for doxorubicin (DOX). Sonication and extrusion produced the most PEVs, with means of 496 and 493 PEVs per platelet (PLT), respectively, compared to 145 and 33 by freeze/thaw and incubation, respectively. The PEVs were loaded with DOX through incubation and purified by chromatography. The size and concentration of the PEVs and PEV-DOX were analyzed using dynamic light scattering and nanoparticle tracking analysis. The results showed that the population sizes and concentrations of PEVs and PEV-DOX were in the ranges of 120-150 nm and 1.2-6.2 × 10 particles/mL for all preparations. The loading of DOX determined using fluorospectrometry was found to be 2.1 × 10, 1.7 × 10, and 0.9 × 10 molecules/EV using freeze/thaw, extrusion, and sonication, respectively. The internalization of PEVs was determined to occur through clathrin-mediated endocytosis. PEV-DOX were more efficiently taken up by MDA-MB-231 breast cancer cells compared to MCF7/ADR breast cancer cells and NIH/3T3 cells. DOX-PEVs showed higher anticancer activity against MDA-MB-231 cells than against MCF7/ADR or NIH/3T3 cells and better than acommercial liposomal DOX formulation. In conclusion, this study demonstrates that PEVs generated by PLTs using extrusion, freeze/thaw, or sonication can efficiently load DOX and kill breast cancer cells, providing a promising strategy for further evaluation in preclinical animal models. The study findings suggest that sonication and extrusion are the most efficient methods to generate PEVs and that PEVs loaded with DOX exhibit significant anticancer activity against MDA-MB-231 breast cancer cells.
Topics: Mice; Animals; Blood Platelets; Antineoplastic Agents; Doxorubicin; Extracellular Vesicles; Nanoparticles
PubMed: 37580876
DOI: 10.1080/09537104.2023.2237134 -
Molecular Pharmaceutics Jun 2023Nanomedicine represents a promising way to devise better drug delivery systems (DDSs), and the development of cell/tissue-based lipid carriers is a promising strategy....
Nanomedicine represents a promising way to devise better drug delivery systems (DDSs), and the development of cell/tissue-based lipid carriers is a promising strategy. In this study, the author proposes the concept of reconstituted lipid nanoparticles (rLNPs) and offers a facile preparation method. The results demonstrated that the preparation of ultrasmall (∼20 nm) rLNPs can be highly reproducible from both cells (a mouse breast cancer cell line, 4T1) and tissue (mouse liver tissue). As a selected model platform, rLNPs derived from mouse liver tissue can be further labeled with imaging molecules (indocyanine green and coumarin 6) and modified with targeting moiety (biotin). Moreover, rLNPs were proved to be highly biocompatible and able to load various drugs, such as doxorubicin hydrochloride (Dox) and curcumin (Cur). Most importantly, Dox-loaded rLNPs (rLNPs/Dox) exerted good in vitro and in vivo anticancer performances Therefore, rLNPs might be a potential versatile carrier for the construction of different DDSs and treatment of a variety of diseases.
Topics: Mice; Animals; Drug Delivery Systems; Doxorubicin; Nanoparticles; Liposomes; Curcumin; Drug Carriers; Cell Line, Tumor; Neoplasms
PubMed: 37141631
DOI: 10.1021/acs.molpharmaceut.2c01033 -
Journal of Oncology Pharmacy Practice :... Jun 2019The EPOCH regimen, consisting of vincristine sulfate, doxorubicin hydrochloride, and etoposide phosphate, is typically administered by continuous infusion over four days...
Stability of vincristine sulfate, doxorubicin hydrochloride and etoposide phosphate admixtures in polyisoprene elastomeric pump supporting transition of the EPOCH regimen to outpatient care.
BACKGROUND
The EPOCH regimen, consisting of vincristine sulfate, doxorubicin hydrochloride, and etoposide phosphate, is typically administered by continuous infusion over four days to oncology inpatients. If the EPOCH regimen was available to be administered through portable elastomeric pumps, chemotherapy could be transitioned to an outpatient setting, reducing inpatient bed days and overall healthcare costs. However, a lack of stability data for the admixtures in the elastomeric infusion devices currently prevents the transition of the regime to an outpatient setting. The purpose of this study is to determine the physical and chemical stability of the admixture in polyisoprene elastomeric pumps under different storage conditions to support the transition of the EPOCH regime to an outpatient setting.
METHODS
The physico-chemical stability of three admixtures at a range of clinically relevant concentrations compounded in polyisoprene elastomeric infusors was determined when refrigerated at 2-6℃ over a 14-day period followed by 35℃ up to 7 days in the dark, and under standardized fluorescent light to simulate scenarios in clinical practice.
RESULTS
All tested admixtures were compatible and the drugs were stable in the elastomeric infusors for up to 14 days when stored at 2-6℃ followed by 7 days at 35℃ in the dark, with nominal losses of <5%. The major degradant of etoposide phosphate was its active form etoposide. There was no degradation (<1% loss) found when the admixture was exposed to a standardized fluorescent light dose of 80 klux-h (25℃) for 10 h. The temperature and light conditions the infusors were exposed to during the stability study were more severe than the conditions determine during clinical administration.
CONCLUSION
The extended stability of the three infusional admixtures compounded in elastomeric infusion pumps demonstrated herein permits advance preparation and storage of these drugs, reducing pharmacy compounding resources. The demonstrated stability at 35℃ and under light exposure, conditions more severe than those experienced during clinical practice, support continuous infusions for up to seven days from the elastomeric infusors without a loss of potency. The proven stability of the EPOCH regimens in the tested elastomeric infusion device supports the transition of treatment to an outpatient setting which will reduce inpatient bed days and overall healthcare costs.
Topics: Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Stability; Elastomers; Etoposide; Humans; Infusion Pumps; Organophosphorus Compounds; Vincristine
PubMed: 29540104
DOI: 10.1177/1078155218764285 -
Biomacromolecules May 2023Responsive drug release and low toxicity of drug carriers are important for designing controlled release systems. Here, a double functional diffractive -nitrobenzyl,...
Responsive drug release and low toxicity of drug carriers are important for designing controlled release systems. Here, a double functional diffractive -nitrobenzyl, containing multiple electron-donating groups as a crosslinker and methacrylic acid (MAA) as a monomer, was used to decorate upconversion nanoparticles (UCNPs) to produce robust poly -nitrobenzyl@UCNP nanocapsules using the distillation-precipitation polymerization and templating method. Poly -nitrobenzyl@UCNP nanocapsules with a robust yolk-shell structure exhibited near-infrared (NIR) light-/pH-responsive properties. When the nanocapsules were exposed to 980 nm NIR irradiation, the loaded drug was efficiently released by altering the shell of the nanocapsules. The photodegradation kinetics of the poly -nitrobenzyl@UCNP nanocapsules were studied. The anticancer drug, doxorubicin hydrochloride (DOX), was loaded at pH 8.0 with a loading efficiency of 13.2 wt %. The Baker-Lonsdale model was used to determine the diffusion coefficients under different release conditions to facilitate the design of dual-responsive drug release devices or systems. Additionally, cytotoxicity studies showed that the drug release of DOX could be efficiently triggered by NIR to kill cancer cells in a controlled manner.
Topics: Nanocapsules; Drug Liberation; Antineoplastic Agents; Doxorubicin; Nanoparticles; Polymers; Hydrogen-Ion Concentration
PubMed: 37104701
DOI: 10.1021/acs.biomac.2c01404 -
The Journal of Physical Chemistry. B Nov 2023For the design of an efficient drug delivery system utilizing an ionic liquid (IL) as a carrier, it is prudent to gain molecular/atomistic level insights of a drug with...
Comprehensive NMR Investigation of Imidazolium-Based Ionic Liquids [BMIM][OSU] and [BMIM][Cl] Impact on Binding and Dynamics of the Anticancer Drug Doxorubicin Hydrochloride.
For the design of an efficient drug delivery system utilizing an ionic liquid (IL) as a carrier, it is prudent to gain molecular/atomistic level insights of a drug with IL in terms of binding and dynamics. In this scenario, the influence of anionic counterpart of imidazolium-based ILs, namely, 1-butyl-3-methyl-imidazolium octyl sulfate [BMIM][OSU] and 1-butyl-3-methyl-imidazolium chloride [BMIM][Cl] in their submicellar region ([IL] = 20 mM) on the model water-soluble anticancer drug doxorubicin hydrochloride (DOX) was probed by employing an arsenal of nuclear magnetic resonance (NMR) approaches. The salient feature of the present study includes the significant interaction of DOX with [BMIM][OSU], whereas the lack of such an interaction with [BMIM][Cl] is gauged by H NMR translation self-diffusometry and is further corroborated by C chemical shift perturbation. The two-step model was utilized to estimate the bound fraction (p) and equivalent partition coefficient () of DOX with [BMIM][OSU]. A combination of selective and nonselective spin-lattice relaxation rates ( and , respectively) enables to gauze the significant interaction of DOX with [BMIM][OSU] over [BMIM][Cl]. Furthermore, 1D transient and truncated driven nuclear Overhauser enhancement (NOE) data analyses in the initial rate limit permits the evaluation of the cross-relaxation efficacy of DOX with the investigated ILs. An Arrhenius-type temperature dependence of the drug's self-diffusion was observed for DOX, DOX-[BMIM][OSU], and DOX-[BMIM][Cl] aqueous mixtures and the corresponding activation energies were evaluated.
Topics: Ionic Liquids; Doxorubicin; Magnetic Resonance Spectroscopy; Magnetic Resonance Imaging; Water; Antineoplastic Agents
PubMed: 37975332
DOI: 10.1021/acs.jpcb.3c06036 -
Macromolecular Rapid Communications Mar 2021The versatility of the Passerini three component reaction (Passerini-3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self-assembles...
The versatility of the Passerini three component reaction (Passerini-3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self-assembles into polymersomes. Carboxy-functionalized poly(ethylene glycol) methyl ether is reacted with AB-type bifunctional monomers and tert-butyl isocyanide in a single process via Passerini-3CR. The resultant diblock copolymer (P1) is obtained in good yield and molar mass dispersity and is well tolerated in model cell lines. The Passerini-3CR versatility and reproducibility are shown by the synthesis of P2, P3, and P4 copolymers. The ability of the Passerini P1 polymersomes to incorporate hydrophilic molecules is verified by loading doxorubicin hydrochloride in P1DOX polymersomes. The flexibility of the synthesis is further demonstrated by simple post-functionalization with a dye, Cyanine-5 (Cy5). The obtained P1-Cy5 polymersomes rapidly internalize in 2D cell monolayers and penetrate deep into 3D spheroids of MDA-MB-231 triple-negative breast cancer cells. P1-Cy5 polymersomes injected systemically in healthy mice are well tolerated and no visible adverse effects are seen under the conditions tested. These data demonstrate that new, biodegradable, biocompatible polymersomes having properties suitable for future use in drug delivery can be easily synthesized by the Passerini-3CR.
Topics: Animals; Doxorubicin; Drug Delivery Systems; Hydrophobic and Hydrophilic Interactions; Mice; Polymers; Reproducibility of Results
PubMed: 33249682
DOI: 10.1002/marc.202000321 -
PloS One 2019Doxorubicin (DOX) is a widely used chemotherapeutic anticancer drug. Its intrinsic fluorescence properties enable investigation of tumor response, drug distribution and...
Doxorubicin (DOX) is a widely used chemotherapeutic anticancer drug. Its intrinsic fluorescence properties enable investigation of tumor response, drug distribution and metabolism. First phantom studies in vitro showed optoacoustic property of DOX. We therefore aimed to further investigate the optoacoustic properties of DOX in biological tissue in order to explore its potential as theranostic agent. We analysed doxorubicin hydrochloride (Dox·HCl) and liposomal encapsulated doxorubicin hydrochloride (Dox·Lipo), two common drugs for anti-cancer treatment in clinical medicine. Optoacoustic measurements revealed a strong signal of both doxorubicin substrates at 488 nm excitation wavelength. Post mortem analysis of intra-tumoral injections of DOX revealed a detectable optoacoustic signal even at three days after the injection. We thereby demonstrate the general feasibility of doxorubicin detection in biological tissue by means of optoacoustic tomography, which could be applied for high resolution imaging at mesoscopic depths dictated by effective penetration of visible light into the biological tissues.
Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Doxorubicin; Feasibility Studies; Female; Humans; Injections, Intralesional; Mice; Neoplasms; Photoacoustic Techniques; Pilot Projects; Polyethylene Glycols; Theranostic Nanomedicine; Tomography
PubMed: 31150471
DOI: 10.1371/journal.pone.0217576