-
Cancer Chemotherapy and Pharmacology Sep 2018To compare the pharmacokinetic bioequivalence and safety of a generic pegylated liposomal doxorubicin formulation (SPIL DXR hydrochloride liposome injection) with that... (Randomized Controlled Trial)
Randomized Controlled Trial
Two multicenter Phase I randomized trials to compare the bioequivalence and safety of a generic doxorubicin hydrochloride liposome injection with Doxil or Caelyx in advanced ovarian cancer.
PURPOSE
To compare the pharmacokinetic bioequivalence and safety of a generic pegylated liposomal doxorubicin formulation (SPIL DXR hydrochloride liposome injection) with that of the reference products, Caelyx or Doxil.
METHODS
Two open-label, two-way reference crossover studies were conducted in patients with ovarian cancer. C, AUC, and AUC, V, and Cl for total, free, and encapsulated DXR were evaluated in 18 blood samples taken pre-dose (t = 0), at increasing time intervals over the following 14 days. A washout period of 28 days was observed before crossing over.
RESULTS
Studies 1 and 2 were completed by 24/29 and 41/60 patients, respectively. Pharmacokinetic data from 24 patients from each study established bioequivalence for free DXR in study 2, and for total and encapsulated DXR in both studies. Data from 29 and 54 patients, respectively, were included in the safety evaluation. Of these, 37 patients experienced 81 post-dose adverse events (40 related to the test product and 41 related to the reference product). In study 1, four patients were withdrawn owing to adverse events. Eleven patients experienced serious adverse events and one death occurred in study 2.
CONCLUSIONS
Bioequivalence between the test and the reference products was established for total and encapsulated DXR in both studies, and for free DXR in the study with the larger sample size (study 2). There were no significant differences between the safety profiles of the generic formulation and the reference products. No correlation was found between drug level and adverse events.
TRIAL REGISTRATION
Study 1 was registered retrospectively; registration number is NCT03055143, dated February 15, 2017. Study 2 registration number is NCT00862355, dated March 13, 2009.
Topics: Adolescent; Adult; Aged; Cross-Over Studies; Doxorubicin; Drugs, Generic; Female; Humans; Middle Aged; Ovarian Neoplasms; Polyethylene Glycols; Therapeutic Equivalency; Treatment Outcome; Young Adult
PubMed: 29995186
DOI: 10.1007/s00280-018-3643-3 -
Biomaterials Science Nov 2020Drug resistance and side effects are the two main problems of chemotherapy. In order to address these big challenges, p-PB@d-SiO, which has the ability to co-deliver...
Drug resistance and side effects are the two main problems of chemotherapy. In order to address these big challenges, p-PB@d-SiO, which has the ability to co-deliver both the hydrophobic drug doxorubicin hydrochloride (DOX) and the hydrophilic drug ibuprofen (IBU), is constructed to achieve synergistic treatment. The drug-loaded nanoparticle consists of porous Prussian blue (p-PB) as the core and dendrimer-like SiO (d-SiO) as the shell, which is further thiolated and coated with polyethylene glycol thiol (HS-PEG) to form the "Dual-Key-and-Lock" drug carrier p-PB@d-SiO-SS-PEG. The locked drugs can only be released in the presence of cooperative triggers, i.e., a high glutathione concentration (the first key) and an acidic environment (the second key). The "dual key"-triggered release is much more significant in cancer lesions than in normal tissues, reducing side effects. Furthermore, cell viability experiments highlight the superior therapeutic efficacy of the dual-drug-loaded nanoparticles compared with the single-drug systems (60%, 73% and 86% vs. 56%, 68%, and 76% at 100, 200 and 500 μg mL, respectively). In vitro and in vivo experiments demonstrate the potential application of p-PB@d-SiO-SS-PEG for dual-mode fluorescence and magnetic-resonance-imaging-guided chemo-photothermal therapy. The "Dual-Key-and-Lock" drug carrier system exhibits the "1 + 1 > 2" effect, demonstrating its excellent performance in synergy therapy for improved therapeutic efficiency and thereby reducing conventional drug resistance and side effects.
Topics: Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Liberation; Hyperthermia, Induced; Nanoparticles; Phototherapy; Photothermal Therapy; Silicon Dioxide
PubMed: 33001076
DOI: 10.1039/d0bm01400a -
Current Drug Delivery Aug 2022Liposomes have been widely used in drug delivery systems because the encapsulation of liposomes changes the biological distribution profile and improves the therapeutic...
INTRODUCTION
Liposomes have been widely used in drug delivery systems because the encapsulation of liposomes changes the biological distribution profile and improves the therapeutic indices of various drugs. Thermosensitive liposomes have been proven to be a precise and effective method for cancer therapy in many preclinical studies. However, the lack of specific targeting ability to cancer cells limited their application in safe and efficient chemotherapy.
METHODS
In the present study, an ovarian targeting ligand namely WSGFPGVWGASVK (WSG) screened by phage display in vivo was grafted on the thermosensitive phospholipids to prepare the liposomes targeting ovarian cancer cells. WSG was first grafted onto the hydrophilic terminal of DSPEPEG2000 molecules, and then the WSG modified thermosensitive liposomes (WSG-Lipo) were prepared by thin-film hydration method. Doxorubicin hydrochloride (DOX) was used as a model drug to investigate the drug release behavior of liposomes at different temperatures. The specificity of liposomes to SKOV-3 cells was studied by cell uptake in vitro.
RESULTS
The WSG-Lipo-DOX could release more DOX at 42°C than at 37°C, showing stronger specificity to SKOV-3 cells and thus selectively inhibiting SKOV-3 cells activity in vitro.
CONCLUSION
The active targeting liposome showed potential in improving the specificity of thermosensitive liposomes and would be applied in the chemotherapy combined with a thermotherapy.
Topics: Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Female; Humans; Liposomes; Ovarian Neoplasms
PubMed: 35319368
DOI: 10.2174/1567201819666220321110812 -
Molecules (Basel, Switzerland) Jul 2018A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was...
A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was synthesized and coupled to doxorubicin using -(3-dimethylaminopropyl)-'-ethylcarbodiimide hydrochloride (EDC)/sulfo⁻NHS coupling. The doxorubicin conjugate was characterized using ¹H NMR and LC-MS and subsequently reacted under conditions of ROS formation (Cu/H₂O₂) resulting in successful and rapid thioacetal oxidative cleavage, which was monitored using ¹H NMR.
Topics: Doxorubicin; Magnetic Resonance Spectroscopy; Molecular Structure; Nanoparticles; Oxidation-Reduction; Peptides; Quantum Dots; Reactive Oxygen Species
PubMed: 30037071
DOI: 10.3390/molecules23071809 -
Langmuir : the ACS Journal of Surfaces... Mar 2021Hollow mesoporous silica nanoparticles (HMSNs) served as nanocarriers for transporting doxorubicin hydrochloride (DOX) and indocyanine green (ICG) and were incorporated...
Hollow mesoporous silica nanoparticles (HMSNs) served as nanocarriers for transporting doxorubicin hydrochloride (DOX) and indocyanine green (ICG) and were incorporated into a pH-sensitive targeted drug delivery system (DDS). Boronate ester bonds were employed to link HMSNs and dopamine-modified hyaluronic acid (DA-HA), which acted as both the "gatekeeper" and targeting agents (HMSNs-B-HA). Well-dispersed HMSNs-B-HA with a diameter of about 170 nm was successfully constructed. The conclusion was drawn from the in vitro drug release experiment that ICG and DOX (ID) co-loaded nanoparticles (ID@HMSNs-B-HA) with high drug loading efficiency could sustain drug release under acidic conditions. More importantly, in vitro cell experiments perfectly showed that ID@HMSNs-B-HA could well inhibit murine mammary carcinoma (4T1) cells via chemotherapy combined with photodynamic therapy and accurately target 4 T1 cells. In summary, all test results sufficiently demonstrated that the prepared ID@HMSNs-B-HA was a promising nano-DDS for cancer photodynamic combined with chemotherapy.
Topics: Animals; Doxorubicin; Drug Delivery Systems; Hyaluronic Acid; Hydrogen-Ion Concentration; Mice; Nanoparticles; Neoplasms; Photochemotherapy; Porosity; Silicon Dioxide
PubMed: 33586432
DOI: 10.1021/acs.langmuir.0c03250 -
Journal of Pharmaceutical Sciences Dec 2021With the deepening of tumor targeting research, the application of intelligent responsive drug carriers in the field of controlled drug release has become more and more...
With the deepening of tumor targeting research, the application of intelligent responsive drug carriers in the field of controlled drug release has become more and more extensive, and multiple responsive nano drug carriers have attracted greater attention. In this paper, nanoparticles with gold nanorods (GNR) as the core, mesoporous silica (mSiO) doped with hydroxyapatite (HAP) as the inorganic hybrid shell and physically loaded with doxorubicin hydrochloride (DOX·HCl) are prepared (DOX/GNR/mSiO/HAP, DNPs). DNPs nanoparticles have a typical core-shell structure. The gold nanorods as the core have extremely high light-to-heat conversion efficiency. Under the irradiation of near-infrared light, light can be converted into heat. The inorganic hybrid shell is a drug reservoir. The excellent photothermal response of gold nanorods combined with the excellent pH response of hydroxyapatite can obtain slow and sustained release of chemotherapeutic drugs. In vivo and in vitro anti-tumor cell activity study show that the DNPs in the laser showed stronger cytotoxicity than the other groups. Compared to chemotherapy and phototherapy alone, DNPs selectively accumulate in the tumor through the enhanced penetration and retention (EPR) effects. and have the unified function of hyperthermia and chemotherapy, and have significant inhibitory effect on tumor growth. Therefore, this study provides a new idea for the study of the combination of multiple therapeutic methods in the treatment of cancer.
Topics: Cell Line, Tumor; Doxorubicin; Drug Liberation; Gold; Hyperthermia, Induced; Nanoparticles; Phototherapy; Photothermal Therapy
PubMed: 34480929
DOI: 10.1016/j.xphs.2021.08.034 -
Nanomedicine (London, England) May 2017In this study, the effects of liposome characteristics on oral absorption of doxorubicin, as a hydrophilic low-permeability drug, were investigated.
AIM
In this study, the effects of liposome characteristics on oral absorption of doxorubicin, as a hydrophilic low-permeability drug, were investigated.
MATERIALS & METHODS
Different doxorubicin-loaded liposomes were prepared, characterized and orally administered to 18 groups of rats. Plasma concentrations of doxorubicin and its aglycone metabolite were measured, and Caco-2 uptake and transport of optimum liposomes were investigated.
RESULTS
After studying different factors, a fourfold increase in oral bioavailability was achieved with the non-PEGylated, 120-nm-sized positively charged rigid liposomes (lipid to drug ratio = 10). The extent of drug's first-pass metabolism as well as endocytosis of nanoparticles were markedly affected by liposomal formulation.
CONCLUSION
Oral absorption is highly dependent on liposomal properties, and optimum formulations are effective for low-permeability drugs.
Topics: Administration, Oral; Animals; Antibiotics, Antineoplastic; Biological Availability; Caco-2 Cells; Doxorubicin; Humans; Liposomes; Male; Rats; Rats, Sprague-Dawley
PubMed: 28447868
DOI: 10.2217/nnm-2017-0007 -
ACS Biomaterials Science & Engineering Dec 2020We developed four types of -phenylene-bridged periodic mesoporous organosilica NPs (-P PMO NPs) with tailored physical parameters including size, morphology, porosity,...
We developed four types of -phenylene-bridged periodic mesoporous organosilica NPs (-P PMO NPs) with tailored physical parameters including size, morphology, porosity, and surface area using a new polymer-scaffolding approach. The particles have been formulated to facilitate the codelivery of small-molecule hydrophobic/hydrophilic cargos such as model anticancer drugs (i.e., doxorubicin hydrochloride (DOX) and -benzylguanine) and model fluorescent dyes (i.e., rhodamine 6G and Nile red). -P PMO NPs were synthesized via a cetyltrimethylammonium bromide (CTAB)-directed sol-gel process using two different organic solvents and in the presence of polymeric scaffolding constituents that led to morphologically distinct PMO NPs despite using the same organosilane precursors. After the formulation process, the polymeric scaffolding agent was conveniently washed away from the PMO NPs. Extensive analyses were used to characterize the physicochemical attributes of the PMO NPs such as their chemical composition, morphologies, etc. Spherical and rod-shaped PMOs of diameters ranging between 79 and 342 nm, surface areas between 770 and 1060 m/g, and pore volumes between 0.79 and 1.37 cm/g were prepared using the polymer-scaffolding approach. The performance of these materials toward drug-loading capacity, cytotoxicity, and cancer cell internalization was evaluated. Interestingly, the designed particles exhibited significantly high payloads of drugs and dyes (up to 78 and 94%, respectively). Cellular studies also demonstrated exceptional biocompatibility and marked internalization into both human breast cancer MCF-7 and glioblastoma U-87 MG cells. Further, DOX also possessed a noticeable release from particles and accumulation in cell nuclei with increased incubation time in vitro. Ultimately, this work validates the controlled design and synthesis of PMO NPs using a polymer-scaffolding approach and highlights the potential of these materials as excellent delivery systems for combination therapy with high loading capability to improve the therapeutic index for cancers.
Topics: Doxorubicin; Humans; Nanoparticles; Nanostructures; Neoplasms; Organosilicon Compounds; Polymers
PubMed: 33320612
DOI: 10.1021/acsbiomaterials.0c01082 -
ACS Applied Bio Materials Aug 2023The development of a multifunctional cancer diagnosis and treatment platform offers excellent prospects for the effective eradication of malignant solid tumors. Herein,...
The development of a multifunctional cancer diagnosis and treatment platform offers excellent prospects for the effective eradication of malignant solid tumors. Herein, a doxorubicin hydrochloride (DOX)-loaded tannic acid (TA)-coated liquid metal (LM) multifunctional nanoprobe was synthesized and applied as a highly efficient platform for the photoacoustic (PA) imaging-guided photothermal/chemotherapy of tumor. The multifunctional nanoprobes exhibited strong near-infrared absorption, a remarkable photothermal conversion efficiency (PCE) of 55%, and high DOX loading capacity. Combined with the large intrinsic thermal expansion coefficient of LM, highly efficient PA imaging and effective drug release were realized. The LM-based multifunctional nanoprobes were specifically adsorbed into the cancer cells and tumor tissues via glycoengineering biorthogonal chemistry. The and photothermal/chemo-anticancer activity confirmed their promising potential in cancer treatment. The subcutaneous breast tumor-bearing mice completely recovered in 5 days under light illumination with clear PA imaging presentation, which showed better antitumor outcomes than single-mode chemotherapy or photothermal therapy (PTT), while keeping side effects at a minimum. Such an LM-based PA imaging-guided photothermal/chemotherapy strategy provided a valuable platform for resistant cancer precise treatment and intelligent biomedicine.
Topics: Animals; Mice; Photoacoustic Techniques; Combined Modality Therapy; Neoplasms; Doxorubicin
PubMed: 37432729
DOI: 10.1021/acsabm.3c00348 -
Carbohydrate Polymers Feb 2021Herein, lactoferrin (Lf)/phenylboronic acid (PBA)-functionalized hyaluronic acid nanogels crosslinked with disulfide-bond crosslinker was developed as a...
Herein, lactoferrin (Lf)/phenylboronic acid (PBA)-functionalized hyaluronic acid nanogels crosslinked with disulfide-bond crosslinker was developed as a reduction-sensitive dual-targeting glioma therapeutic platform for doxorubicin hydrochloride (DOX) delivery (Lf-DOX/PBNG). Spherical Lf-DOX/PBNG with optimized physicochemical properties was obtained, and it could rapidly release the encapsulated DOX under high glutathione concentration. Moreover, enhanced cytotoxicity, superior cellular uptake efficiency, and significantly improved brain permeability of Lf-DOX/PBNG were observed in cytological studies compared with those of DOX solution, DOX-loaded PBA functionalized nanogels (DOX/PBNG), and Lf modified DOX-loaded nanogels (Lf-DOX/NG). The pharmacokinetic study exhibited that the area under the curve of DOX/PBNG, Lf-DOX/NG, and Lf-DOX/PBNG increased by 8.12, 4.20 and 4.32 times compared with that of DOX solution, respectively. The brain accumulation of Lf-DOX/PBNG was verified in biodistribution study to be 12.37 and 4.67 times of DOX solution and DOX/PBNG, respectively. These findings suggest that Lf-DOX/PBNG is an excellent candidate for achieving effective glioma targeting.
Topics: Animals; Antibiotics, Antineoplastic; Boronic Acids; Brain; Brain Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Carriers; Glioma; Hyaluronic Acid; Lactoferrin; Mice; Mice, Inbred ICR; Nanogels; Particle Size; Rats, Sprague-Dawley; Tissue Distribution; Rats
PubMed: 33278970
DOI: 10.1016/j.carbpol.2020.117194