-
Nanomedicine (London, England) Aug 2022Exosomes are extracellular vesicles with the ability to encapsulate bioactive molecules, such as therapeutics. This study identified a new exosome mediated route of...
Exosomes are extracellular vesicles with the ability to encapsulate bioactive molecules, such as therapeutics. This study identified a new exosome mediated route of doxorubicin and poly(N-(2-hydroxypropyl)methacrylamide) (pHPMA)-bound doxorubicin trafficking in the tumor mass. Exosome loading was achieved via incubation of the therapeutics with an adherent human breast adenocarcinoma cell line and its derived spheroids. Exosomes were characterized using HPLC, nanoparticle tracking analysis (NTA) and western blotting. The therapeutics were successfully loaded into exosomes. Spheroids secreted significantly more exosomes than adherent cells and showed decreased viability after treatment with therapeutic-loaded exosomes, which confirmed successful transmission. To the best of our knowledge, this study provides the first evidence of pHPMA-drug conjugate secretion by extracellular vesicles.
Topics: Humans; Polymers; Exosomes; Doxorubicin; Adenocarcinoma; Cell Line, Tumor
PubMed: 36255034
DOI: 10.2217/nnm-2022-0081 -
Carbohydrate Polymers Dec 2022High swelling hydrogel networks (HSHNs) are materials with the ability to high swelling and outstanding candidates for sustained drug delivery systems (DDSs). The...
High swelling hydrogel networks (HSHNs) are materials with the ability to high swelling and outstanding candidates for sustained drug delivery systems (DDSs). The present paper demonstrates three different chitosan nanohydrogel networks (CNHN I-III) prepared through covalent and non-covalent interactions. These hydrogels have a high swelling ratio (up to 38-fold their dry weight) in various conditions. Two types of these hydrogels (CNHN I and II), swelled rapidly in an acidic environment, were able to successfully load an extraordinary amount (up to 95 %) of a model drug doxorubicin hydrochloride (DOX.HCl) at a 1:1 ratio (wt./wt.). The CNHN III had substantial swelling in pH 7.4, with a loading capacity of 92 % 5-fluorouracil (5-FU) at a 1:1 ratio (wt./wt.). The CNHN I and II have been considered for systemic drug delivery, while the CNHN III is one of the best candidates for oral drug delivery.
Topics: Chitosan; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Fluorouracil; Hydrogels; Hydrogen-Ion Concentration
PubMed: 36241333
DOI: 10.1016/j.carbpol.2022.120143 -
Small (Weinheim An Der Bergstrasse,... Nov 2023Multidrug combination therapy provides an effective strategy for malignant tumor treatment. This paper presents the development of a biodegradable microrobot for...
Multidrug combination therapy provides an effective strategy for malignant tumor treatment. This paper presents the development of a biodegradable microrobot for on-demand multidrug delivery. By combining magnetic targeting transportation with tumor therapy, it is hypothesized that loading multiple drugs on different regions of a single magnetic microrobot can enhance a synergistic effect for cancer treatment. The synergistic effect of using two drugs together is greater than that of using each drug separately. Here, a 3D-printed microrobot inspired by the fish structure with three hydrogel components: skeleton, head, and body structures is demonstrated. Made of iron oxide (Fe O ) nanoparticles embedded in poly(ethylene glycol) diacrylate (PEGDA), the skeleton can respond to magnetic fields for microrobot actuation and drug-targeted delivery. The drug storage structures, head, and body, made by biodegradable gelatin methacryloyl (GelMA) exhibit enzyme-responsive cargo release. The multidrug delivery microrobots carrying acetylsalicylic acid (ASA) and doxorubicin (DOX) in drug storage structures, respectively, exhibit the excellent synergistic effects of ASA and DOX by accelerating HeLa cell apoptosis and inhibiting HeLa cell metastasis. In vivo studies indicate that the microrobots improve the efficiency of tumor inhibition and induce a response to anti-angiogenesis. The versatile multidrug delivery microrobot conceptualized here provides a way for developing effective combination therapy for cancer.
Topics: Humans; Animals; HeLa Cells; Drug Delivery Systems; Polyethylene Glycols; Hydrogels; Doxorubicin; Neoplasms
PubMed: 37423966
DOI: 10.1002/smll.202301889 -
Nanoscale Mar 2022We demonstrate the use of water-soluble C-β-cyclodextrin conjugates to encapsulate and deliver doxorubicin to the cell nucleus. The behaviour of the fullerene...
We demonstrate the use of water-soluble C-β-cyclodextrin conjugates to encapsulate and deliver doxorubicin to the cell nucleus. The behaviour of the fullerene aggregates inside cells is dictated by the functionalization of the C cage. While both the C conjugates are taken up by lysosomes upon cellular entry, only the one with a hydroxylated cage rapidly escaped the lysosome. The drug delivery system (DDS) with a hydroxylated C cage showed significantly enhanced doxorubicin delivery to the cell nucleus, whereas the DDS with a hydrophobic C cage was trapped in the lysosome for a longer time and showed significantly reduced doxorubicin delivery to the nucleus. This study opens new paths towards advanced fullerene-based DDSs for small molecule drugs.
Topics: Cell Nucleus; Doxorubicin; Drug Delivery Systems; Fullerenes; beta-Cyclodextrins
PubMed: 35262142
DOI: 10.1039/d2nr00777k -
Journal of Nanoscience and... May 2021Hierarchical nanoparticles are of great interest because they possess unique physicochemical properties and multiple functionalities, providing a wealth of possibilities...
Hierarchical nanoparticles are of great interest because they possess unique physicochemical properties and multiple functionalities, providing a wealth of possibilities for various applications. In this work, we have developed a well-designed method to prepare hierarchical magnetic nanoparticles Fe₃O₄@mSiO₂@CS by integrating a solvothermal method for synthesizing the Fe₃O₄ core, a dualtemplating micelle system for preparing a layer of mesoporous silica (mSiO₂) shell, and a silane coupling method via -glycidoxypropyltrimethoxysilane for binding a chitosan (CS) layer on the silica surface. The porous hierarchical nanoparticles were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), dynamic light scattering nanoparticle size analyzer, and specific surface area and pore size analyzer. The loading capacity and the release behavior of the as-prepared nanoparticles for doxorubicin hydrochloride were studied, and it was found that the drug release rate was faster at pH 6.0 than at pH 7.4, revealing the pH-responsive property of the nanoparticles.
Topics: Chitosan; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogen-Ion Concentration; Nanoparticles; Silicon Dioxide; Spectroscopy, Fourier Transform Infrared
PubMed: 33653475
DOI: 10.1166/jnn.2021.19154 -
The Journal of Pharmacy and Pharmacology Sep 2021The study was to construct reduction-responsive chondroitin sulfate A (CSA)-conjugated TOS (CST) micelles with disulfide bond linkage, which was used for controlled...
OBJECTIVES
The study was to construct reduction-responsive chondroitin sulfate A (CSA)-conjugated TOS (CST) micelles with disulfide bond linkage, which was used for controlled doxorubicin (DOX) release and improved drug efficacy in vivo.
METHODS
CST and non-responsive CSA-conjugated TOS (CAT) were synthesized, and the chemical structure was confirmed by Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, fluorescence spectrophotometer and dynamic light scattering. Antitumour drug DOX was physically encapsulated into CST and CSA by dialysis method. Cell uptake of DOX-based formulations was investigated by confocal laser scanning microscopy. In vitro cytotoxicity was studied in A549 and AGS cells. Furthermore, antitumour activity was evaluated in A549-bearing mice.
KEY FINDINGS
CST and CAT can form self-assembled micelles, and have low value of critical micelle concentration. Notably, DOX-containing CST (D-CST) micelles demonstrated reduction-triggered drug release in glutathione-containing media. Further, reduction-responsive uptake of D-CST was observed in A549 cells. In addition, D-CST induced stronger cytotoxicity (P < 0.05) than DOX-loaded CAT (D-CAT) against A549 and AGS cells. Moreover, D-CST exhibited significantly stronger antitumour activity in A549-bearing nude mice than doxorubicin hydrochloride and D-CAT.
CONCLUSIONS
The reduction-responsive CST micelles enhanced the DOX effect at tumour site and controlled drug release.
Topics: A549 Cells; Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Chondroitin Sulfates; Delayed-Action Preparations; Disulfides; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Micelles; Neoplasms; Polymers; Stomach Neoplasms; Xenograft Model Antitumor Assays; alpha-Tocopherol; Mice
PubMed: 34254648
DOI: 10.1093/jpp/rgab096 -
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 -
Biochemistry. Biokhimiia May 2022Despite a high efficacy of chemotherapy in cancer treatment, acquired resistance of tumors to certain chemotherapeutic agents and frequent side effects remain the major...
Despite a high efficacy of chemotherapy in cancer treatment, acquired resistance of tumors to certain chemotherapeutic agents and frequent side effects remain the major factors of unfavorable prognosis in most cancer patients with unresectable, metastatic and recurrent forms of the disease. The discovery of novel molecular targets in tumors and development of new therapeutic approaches to enhance the efficiency of chemotherapeutic agents remain the biggest challenges in current oncology. Here we examined the ability of pyrrole-based heterocyclic compound 2-APC to sensitize tumor cells to the topoisomerase II inhibitor doxorubicin. The study was performed on human cancer cell lines treated with 2-APC, paclitaxel, and doxorubicin. Expression of DNA repair was investigated by Western blotting, whereas protein-protein interactions were examined by co-immunoprecipitation. The synergism between the chemotherapeutic agents was assessed with the Synergy Finder program. Doxorubicin exhibited moderate cytotoxic effect against cancer cell lines (in particular, osteosarcoma cell lines). 2-APC in non-toxic concentrations substantially potentiated the cytotoxic effect of doxorubicin and induced apoptosis of cancer cells. This activity of 2-APC was due to its ability to impair DNA damage repair by decreasing the content of Rad51 recombinase via promoting its proteasomal degradation. Similar effects were observed for paclitaxel, which affects tubulin polymerization. Therefore, chemotherapeutic agents and chemical compounds interfering with the microtubule dynamics can potentiate the cytotoxic effects of DNA-damaging chemotherapeutic agents via impairment of DNA damage repair mechanisms in cancer cells.
Topics: Antineoplastic Agents; DNA Damage; DNA Repair; Doxorubicin; Humans; Neoplasms; Paclitaxel; Pyrroles
PubMed: 35790377
DOI: 10.1134/S0006297922050017 -
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