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International Journal of Nanomedicine 2021Glioblastoma multiforme (GBM) poorly responds to chemotherapy owing to the existence of blood-brain barriers (BBB). It has been a long desire to develop BBB-permeable...
PURPOSE
Glioblastoma multiforme (GBM) poorly responds to chemotherapy owing to the existence of blood-brain barriers (BBB). It has been a long desire to develop BBB-permeable vehicles to facilitate drug targeting to GBM.
METHOD AND RESULTS
Here, we report that doxorubicin hydrochloride loaded in ApoE peptide-functionalized reduction-sensitive polymersomes (ApoE-PS-DOX) induces potent therapy of orthotopic U-87 MG model in nude mice. ApoE-PS-DOX with varying amount of ApoE (10~30 mol%) all had stable DOX loading and small sizes (< 90 nm). As revealed by flow cytometry, confocal microscopy, apoptosis and MTT assays, ApoE-PS-DOX with 20 mol.% ApoE induced the best cellular uptake and inhibitory effect to U-87 MG cells, which were much better than the non-targeted PS-DOX and liposomal doxorubicin (Lipo-DOX) used in the clinic. ApoE-PS-DOX revealed a pharmacokinetic profile comparable to PS-DOX but induced considerably better growth inhibition of orthotopically xenografted U-87 MG tumors in nude mice than PS-DOX and Lipo-DOX, leading to significant survival benefits with a median survival time of 44 days, which was almost doubled relative to the phosphate-buffered saline (PBS) group. Moreover, in contrast to mice treated with Lipo-DOX and PS-DOX, ApoE-PS-DOX group exhibited little body weight loss, signifying that ApoE-PS-DOX not only has low side effects but also can effectively inhibit glioblastoma invasion.
CONCLUSION
This ApoE-docked multifunctional polymersomal doxorubicin induces potent and safe chemotherapy of orthotopic U-87 MG model in nude mice offering an alternative treatment modality for GBM.
Topics: Animals; Apolipoproteins E; Blood-Brain Barrier; Cell Line, Tumor; Cell Transformation, Neoplastic; Doxorubicin; Drug Carriers; Glioblastoma; Humans; Mice; Mice, Nude; Oxidation-Reduction; Polymers
PubMed: 34163162
DOI: 10.2147/IJN.S314895 -
Journal of Biomaterials Applications Mar 2018Dual-drug-loaded pH-responsive fiber scaffolds were successfully prepared by coaxial electrospinning. These were designed with the aim of being sutured into the...
Dual-drug-loaded pH-responsive fiber scaffolds were successfully prepared by coaxial electrospinning. These were designed with the aim of being sutured into the resection site after tumor removal, to aid recovery and prevent cancer recurrence. The shell was made up of a mixture of gelatin and sodium bicarbonate (added to provide pH-sensitivity), and was loaded with the anti-inflammatory drug ciprofloxacin; the core comprised poly(lactide-co-ε-caprolactone) with the chemotherapeutic doxorubicin hydrochloride. Scanning electron microscopy revealed most fibers were smooth and homogeneous. Transmission electron microscopy demonstrated the presence of a clear core/shell structure. The fiber scaffolds were further characterized using infrared spectroscopy and X-ray diffraction, which proved that both drugs were present in the fibers in the amorphous form. The gelatin shells were cross-linked with glutaraldehyde to enhance their stability, and water contact angle measurements used to confirm they remained hydrophilic after this process, with angles between 10 and 35°. This is important for onward applications, since a hydrophilic surface is known to encourage cell proliferation. During in vitro drug release studies, a rapid and acid-responsive release of ciprofloxacin was seen, accompanied by sustained and long-term doxorubicin release. Both the release profiles and the mechanical strength of the fibers can effectively be tuned through the sodium bicarbonate content of the fibers: for instance, the break stress varies from 2.00 MPa to 2.57 MPa with an increase in sodium bicarbonate content. The pH values of aqueous media exposed to the scaffolds decrease only slightly, by less than 0.5 pH units, over the two-month timescale, suggesting that only minimal fiber degradation occurs during this time. The fiber scaffolds also have good biocompatibility, as revealed by in vitro cytotoxicity experiments. Overall, our results demonstrate that the novel scaffolds reported here are promising pH-sensitive drug delivery systems, and may be candidates for use after tumor resection surgery.
Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Cell Line; Cell Line, Tumor; Ciprofloxacin; Delayed-Action Preparations; Doxorubicin; Drug Liberation; Gelatin; Humans; Hydrogen-Ion Concentration; Mice; Nanofibers; Neoplasms; Polyesters; Tissue Scaffolds
PubMed: 29295656
DOI: 10.1177/0885328217749962 -
Anti-cancer Agents in Medicinal... 2018Liposomal doxorubicin is widely used for treating ovarian cancer and Kaposi's sarcoma. Encapsulation of doxorubicin in highly complex polyethylene glycol-coated... (Comparative Study)
Comparative Study
BACKGROUND
Liposomal doxorubicin is widely used for treating ovarian cancer and Kaposi's sarcoma. Encapsulation of doxorubicin in highly complex polyethylene glycol-coated (stealth) liposomes prolongs residence time and avoids the systemic toxicity associated with administration of the free drug. Small variations in physicochemical properties introduced during manufacture of liposomes can influence the payload of encapsulated drug, stability of liposomes under physiological conditions, and release of drug at the target tissue. Accordingly, the US Food and Drug Administration and the European Medicines Agency have issued guidance for manufacturers of generic liposomal doxorubicin that is designed to ensure that more than 30 physicochemical parameters that influence its safety and efficacy should be similar in the generic and reference listed drugs.
OBJECTIVE
This study aims to describe the physicochemical characterization procedures used to ensure consistency between batches of generic liposomal doxorubicin and with the reference listed drug.
METHODS
A range of spectroscopic, chromatographic, and other physicochemical tests was used to compare relative concentrations of liposome components, liposome morphology, ratios of free/entrapped doxorubicin, stability, and in vitro doxorubicin release rates in physiologically and clinically relevant media.
RESULTS
The tests established that generic and reference liposomes contained similar concentrations of drug, lipids, and excipients and that their physical forms were also similar.
CONCLUSION
The results of the tests demonstrate the physicochemical equivalence of generic liposomal doxorubicin hydrochloride and the reference listed drug, Doxil®/Caelyx®. Biochemical and clinical equivalence must also be demonstrated to fully meet regulatory requirements for generic liposomal medicines, and these are the subjects of separate studies.
Topics: Antibiotics, Antineoplastic; Chemistry, Physical; Doxorubicin; Drug Liberation; Humans; Hydrogen-Ion Concentration; Particle Size; Polyethylene Glycols; Surface Properties
PubMed: 29173186
DOI: 10.2174/1871520617666171121124610 -
International Journal of Biological... May 2023In this study, octenyl succinic anhydride (OSA) starch with different folic acid (FA) grafting time was prepared and the degree of FA substitution at different grafting...
In this study, octenyl succinic anhydride (OSA) starch with different folic acid (FA) grafting time was prepared and the degree of FA substitution at different grafting time was determined. The results of XPS quantitatively reflected the surface elemental composition of OSA starch grafted with FA. FTIR spectra further confirmed the successful introduction of FA on OSA starch granules. SEM images showed that the surface roughness of OSA starch granules was more obvious with higher FA grafting time. The particle size, zeta potential, and swelling properties were determined to study the effect of FA on the structure of OSA starch. TGA indicated that FA effectively enhanced the thermal stability of OSA starch at high temperature. The crystalline form of the OSA starch gradually transformed from A type to a hybrid A and V-type with the progress of FA grafting reaction. In addition, the anti-digestive properties of OSA starch were enhanced after grafting FA. Using doxorubicin hydrochloride (DOX) as the model drug, the loading efficiency of OSA starch grafted with FA for DOX reached 87.71 %. These results provide novel insights into OSA starch grafted with FA as potential strategy for loading DOX.
Topics: Starch; Succinic Anhydrides; Doxorubicin; Particle Size
PubMed: 36870656
DOI: 10.1016/j.ijbiomac.2023.123907 -
European Journal of Pharmaceutical... Mar 2017To increase the encapsulation efficiency and oral absorption of doxorubicin hydrochloride (DOX), a novel drug delivery system of enoxaparin sodium-PLGA hybrid...
Development of novel self-assembled ES-PLGA hybrid nanoparticles for improving oral absorption of doxorubicin hydrochloride by P-gp inhibition: In vitro and in vivo evaluation.
To increase the encapsulation efficiency and oral absorption of doxorubicin hydrochloride (DOX), a novel drug delivery system of enoxaparin sodium-PLGA hybrid nanoparticles (EPNs) was successfully designed. By introducing the negative polymer of enoxaparin sodium (ES) to form an electrostatic complex with the cationic drug, DOX, the encapsulation efficiency (93.78%) of DOX was significantly improved. The X-ray diffraction (XRD) results revealed that the DOX-ES complex was in an amorphous form. An in vitro release (pH6.8 PBS) study showed the excellent sustained-release characteristics of DOX-loaded EPNs (DOX-EPNs). In addition, in situ intestinal perfusion and intestinal biodistribution experiments demonstrated the improved membrane permeability and intestinal wall bioadhesion of DOX-EPNs, and caveolin- and clathrin-mediated endocytosis pathways were the main mechanisms responsible. The cytotoxicity of DOX was significantly increased by EPNs in Caco-2 cells, compared with DOX-Sol. Confocal laser scanning microscope (CLSM) images confirmed that the amount of DOX-EPNs internalized by Caco-2 cells was higher than that of DOX-Sol showing that P-glycoprotein-mediated drug efflux was reduced by the introduction of EPNs. The qualitative detection of transcytosis demonstrated the ability of the nanoparticles (NPs) to cross Caco-2 cell monolayers. An in vivo toxicity experiment demonstrated that DOX-EPNs reduced cardiac and renal toxic effects and were biocompatible. An in vivo pharmacokinetics study showed that the AUC and t of DOX-EPNs were increased to 3.63-fold and 2.47-fold in comparison with DOX solution (DOX-Sol), respectively. All these results indicated that the novel EPNs were an excellent platform to improve the encapsulation efficiency of an aqueous solution of this antitumor drug and its oral bioavailability.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Antineoplastic Agents; Biocompatible Materials; Biological Availability; Caco-2 Cells; Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Delivery Systems; Humans; Lactic Acid; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Tissue Distribution; X-Ray Diffraction
PubMed: 27989702
DOI: 10.1016/j.ejps.2016.12.014 -
Nanoscale Jul 2016Drug resistance is the underlying cause for therapeutic failure in clinical cancer chemotherapy. A prodrug copolymer mPEG-PAsp(DIP-co-BZA-co-DOX) (PDBD) was synthesized...
Drug resistance is the underlying cause for therapeutic failure in clinical cancer chemotherapy. A prodrug copolymer mPEG-PAsp(DIP-co-BZA-co-DOX) (PDBD) was synthesized and assembled into a nanoscale vesicle comprising a PEG corona, a reduction and pH dual-sensitive hydrophobic membrane and an aqueous lumen encapsulating doxorubicin hydrochloride (DOX·HCl) and arsenite (As). The dual stimulation-sensitive design of the vesicle gave rise to rapid release of the physically entrapped DOX·HCl and arsenite inside acidic lysosomes, and chemically conjugated DOX inside the cytosol with high glutathione (GSH) concentration. In the optimized concentration range, arsenite previously recognized as a promising anticancer agent from traditional Chinese medicine can down-regulate the expressions of anti-apoptotic and multidrug resistance proteins to sensitize cancer cells to chemotherapy. Consequently, the DOX-As-co-loaded vesicle demonstrated potent anticancer activity. Compared to the only DOX-loaded vesicle, the DOX-As-co-loaded one induced more than twice the apoptotic ratio of MCF-7/ADR breast cancer cells at a low As concentration (0.5 μM), due to the synergistic effects of DOX and As. The drug loading strategy integrating chemical conjugation and physical encapsulation in stimulation-sensitive carriers enabled efficient drug loading in the formulation.
Topics: Apoptosis; Arsenites; Doxorubicin; Drug Carriers; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Polyethylene Glycols; Prodrugs
PubMed: 26731009
DOI: 10.1039/c5nr07868g -
International Journal of Pharmaceutics Jul 2022In this study, a biodegradable multifunctional photothermal drug delivery nanoparticles (MPH NPs) using curcumin (Cur) as the ligand coated with hyaluronic acid (HA) was...
In this study, a biodegradable multifunctional photothermal drug delivery nanoparticles (MPH NPs) using curcumin (Cur) as the ligand coated with hyaluronic acid (HA) was successfully prepared, which could simultaneously deliver Cur and doxorubicin hydrochloride (DOX·HCl) to overcome the common drug resistance in cancer cells. Polydopamine (PDA) as a protective shell prevents premature degradation of Cur in physiological environment and enables it to play effective medicinal value. MPH NPs can specifically recognize CD44 receptors on the surface of cancer cells for tumor targeting, with the damage of the partially released DOX to the superficial tumor cells, and then the positively charged Cur released may gradually penetrate into the cells through electron interaction to improve the problem of low permeability. In vitro cell experiments showed that hydrophobic/hydrophilic drugs co-loaded MPDH (MPH loaded with DOX·HCl) could enter the cancer cells through the endocytosis mediated by clathrin / caveolin, and the inhibition rate of MPDH on HeLa cells reached 79.28 % irradiation under 808 nm laser. MPH were composed of safe materials that have been proven to be biodegradable in human body, which avoided the disadvantages that NPs were difficult to discharge and caused damage to normal organs during long-term use.
Topics: Cell Line, Tumor; Curcumin; Doxorubicin; Drug Liberation; HeLa Cells; Humans; Indoles; Nanoparticles; Pharmaceutical Preparations; Phototherapy; Photothermal Therapy; Polymers; Precision Medicine; Theranostic Nanomedicine
PubMed: 35710074
DOI: 10.1016/j.ijpharm.2022.121912 -
Molecular Pharmaceutics Aug 2021Breast cancer is one of the most common malignant tumors in women. The existence of multiple breast cancer subtypes often leads to chemotherapy failure or the...
Breast cancer is one of the most common malignant tumors in women. The existence of multiple breast cancer subtypes often leads to chemotherapy failure or the development of drug resistance. In recent years, photodynamic therapy has been proven to enhance the sensitivity of tumors to chemotherapeutic drugs. Porphyrin-based metal-organic framework (MOF) materials could simultaneously be used as carriers for chemotherapy and photosensitizers in photodynamic therapy. In this paper, doxorubicin hydrochloride (DOX) was loaded in porphyrin MOFs, and the mechanism of the synergistic effect of the DOX carriers and photodynamic therapy on breast cancer was investigated. In vitro and in vivo experiments have shown that MOFs could prolong the residence time of DOX in tumor tissues and promote the endocytosis of DOX by tumor cells. In addition, adjuvant treatment with photodynamic therapy can promote breast cancer tumors to resensitize to DOX and synergistically enhance the chemotherapy effect of DOX. Therefore, this study can provide effective development ideas for reversing drug resistance during breast cancer chemotherapy and improving the therapeutic effect of chemotherapy on breast cancer.
Topics: Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Cell Survival; Disease Models, Animal; Doxorubicin; Drug Liberation; Endocytosis; Female; Humans; MCF-7 Cells; Metal Nanoparticles; Metal-Organic Frameworks; Mice; Mice, Inbred BALB C; Nanoparticle Drug Delivery System; Photochemotherapy; Photosensitizing Agents; Porphyrins; Tissue Distribution; Treatment Outcome; Tumor Burden
PubMed: 34213912
DOI: 10.1021/acs.molpharmaceut.1c00249 -
Biomedical Materials (Bristol, England) Jun 2023This work aimed to establish a simple and feasible method to obtain silk fibroin nanoparticles (SFNPs) with uniform particles size, and then modify the SFNPs with...
This work aimed to establish a simple and feasible method to obtain silk fibroin nanoparticles (SFNPs) with uniform particles size, and then modify the SFNPs with nanobody (Nb) 11C12 targeting the proximal membrane end of carcinoembryonic antigen on the surface of colorectal cancer (CRC) cells. The regenerated silk fibroin (SF) was isolated using ultrafiltration tubes with a 50 kDa molecular weight cut-off, and the retention fraction (named as SF > 50 kDa) was further self-assembled into SFNPs by ethanol induction. Scanning electron microscope (SEM) and high-resolution transmission electron microscop showed that the SFNPs with uniform particles size were formed. Due to electrostatic adsorption and pH responsiveness, SFNPs have been proved to effectively load and release the anticancer drug doxorubicin hydrochloride (DOX) (DOX@SFNPs). Further, targeting molecule Nb 11C12 was used to modify these nanoparticles, constituting the targeted outer layer of the drug delivery system (DOX@SFNPs-11C12), achieving precise localization to cancer cells. The release amount of DOX observed fromdrug release profiles increased as follows: pH 7.4 < pH 6.8 < pH 5.4, demonstrating that the DOX release could be accelerated in a weakly acidic environment.cytotoxicity experiments displayed that SFNPs-11C12 nanoparticles exhibited good safety and biocompatibility. Drug-loaded nanoparticles, DOX@SFNPs-11C12, led to higher LoVo cells apoptosis compared to DOX@SFNPs. Fluorescence spectrophotometer characterization and confocal laser scanning microscopy further showed that the internalization of DOX was highest in the DOX@SFNPs-11C12, certifying that the introduced targeting molecule enhanced the uptake of drug delivery system by LoVo cells. This study provides a simple and operational approach to developing an optimized SFNPs drug delivery system modified by targeting Nb, which can be a good candidate for CRC therapy.
Topics: Humans; Fibroins; Carcinoembryonic Antigen; Antineoplastic Agents; Nanoparticles; Doxorubicin; Drug Delivery Systems; Colorectal Neoplasms; Hydrogen-Ion Concentration
PubMed: 37321227
DOI: 10.1088/1748-605X/acdeba -
Nanomedicine (London, England) Aug 2018To meet the requirements on both delivery stability during blood circulation and fast intracellular release for water-soluble chemotherapeutics encapsulated in...
AIM
To meet the requirements on both delivery stability during blood circulation and fast intracellular release for water-soluble chemotherapeutics encapsulated in polymersomes.
MATERIALS & METHODS
A shell photo-crosslinked and esterase-sensitive polymersome (C-PEAMP-D) was constructed based on amphiphilic polyphosphazene PEAMP containing 2-aminoethyl methacrylate.
RESULTS
The leakage of doxorubicin hydrochloride (DOX·HCl) was significantly inhibited from 42.27 to 26.64% in 10 h and the accelerated intracellular DOX·HCl release occurred responsively to the esterase at high concentration in cancer cells. Consequently, C-PEAMP-D achieved better antitumor efficiency when compared with free DOX·HCl and uncrosslinked PEAMP vesicle.
CONCLUSION
We provided a strategy to conquer drug leakage in systemic circulation and trigger enzyme-sensitive drug release inside cancer cells for improving oncotherapy outcome of water-soluble chemotherapeutics.
Topics: Animals; Doxorubicin; Drug Carriers; Female; HeLa Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Organophosphorus Compounds; Polymers; Uterine Cervical Neoplasms; Water; Xenograft Model Antitumor Assays
PubMed: 30188247
DOI: 10.2217/nnm-2018-0048