-
Die Pharmazie Oct 2019In this study, micelles were designed to deliver an antitumor agent and a fluorescent marker to a tumor site. The micelles simultaneously encapsulated epirubicin (EPI)...
In this study, micelles were designed to deliver an antitumor agent and a fluorescent marker to a tumor site. The micelles simultaneously encapsulated epirubicin (EPI) and polyethylene glycol (PEG)-modified graphene quantum dots (GQDs-PEG), and employed a PEG-polylactic acid block copolymer amphiphilic block polymer as a nanocarrier. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy were used to characterize the functional groups in the synthesized GQDs-PEG. A Malvern particle size meter and transmission electron microscopy were used to show that the particle size of the GQDs-PEG is approximately 2-9 nm, and that of the bifunctional EPI-loaded micelles (EPI-FIDCR) is 19.59±1.21 nm, with zeta potential at -22.87±0.85 mV. The EE% and DL% for EPI in EPI-FIDCR are 74.02±0.55 % and 3.78±0.28 %, respectively. The IC values of EPI-FIDCR and EPI solution (EPI-Free) for tumor cells were 7.03 μg/mL and 5.54 μg/mL, showing that EPI-FIDCR still maintained strong cytotoxicity. Fluorescence micrographs of HeLa cells incubated with GQDs-PEG and EPI-FIDCR for 6 h, respectively, show that only EPI-FIDCR could enter the cells. cellular uptake assays and an inhibition study indicated that EPI-FIDCR could deliver both EPI and GQDs-PEG into tumor cells, while maintaining an inhibitory effect similar to that of unencapsulated EPI. A pharmacokinetic study showed that EPI-FIDCR could persist in the circulation for a significant period of time. The AUC calculated for the EPI-FIDCR formulation was 159.5-fold compared with that of EPI-Free, based on its improved stability and prolonged blood circulation time. The EPI-FIDCR enables both fluorescence imaging and controlled drug-release, exhibits prolonged systematic circulation time and has potential for the treatment of cancer.
Topics: Antibiotics, Antineoplastic; Drug Carriers; Drug Delivery Systems; Epirubicin; HeLa Cells; Humans; Micelles; Particle Size; Polyethylene Glycols; Polymers; Quantum Dots; Spectroscopy, Fourier Transform Infrared
PubMed: 31685080
DOI: 10.1691/ph.2019/9059 -
Pharmacological Research Oct 2020Doxorubicin (DOX) continues to attract the interest of preclinical and clinical investigations despite its longer-than-50-year record of longevity. The clinical... (Review)
Review
Doxorubicin (DOX) continues to attract the interest of preclinical and clinical investigations despite its longer-than-50-year record of longevity. The clinical application of DOX can be regarded as a sort of double-edged sword. On one hand, anthracyclines play an indisputable key role in the treatment of tumors; on the other hand, their chronic administration leads to cardiomyopathy and congestive heart failure, which is usually refractory to common medications. Finding the ideal cardioprotective agents has always been the focus of oncologists and cardiologists. Researchers put a lot of energy into phytochemicals because they are often in line with the expected standards, that is, to improve DOX-induced cardiotoxicity without compromising the clinical efficacy or to even produce synergy. We summarized the previous efforts, briefly outlined the mechanism of DOX cardiotoxicity, and focused on exploring the protective effects and potential mechanisms of all phytochemical types that have been investigated under DOX-induced cardiotoxicity. Phytochemicals have been found to be potential cardioprotective agents with universal safety and effectiveness. As a resource repository of pharmacophores, phytochemicals deserve to be utilized as drug templates for further development and research in combating DOX-induced cardiotoxicity.
Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Cognition Disorders; Doxorubicin; Herbal Medicine; Humans; Neoplasms; Phytochemicals; Phytotherapy
PubMed: 32652197
DOI: 10.1016/j.phrs.2020.105062 -
Kardiologia Polska Dec 2020
Topics: Anthracyclines; Antibiotics, Antineoplastic; Heart; Heart Failure; Humans; Neoplasms
PubMed: 33021353
DOI: 10.33963/KP.15637 -
Journal of Materials Chemistry. B Jan 2020Here we describe the assembly and pH-driven operation of two nanocarriers based on non-functionalized (MCM-41) and carboxylate-functionalized (MCM-41-COOH) containers...
Here we describe the assembly and pH-driven operation of two nanocarriers based on non-functionalized (MCM-41) and carboxylate-functionalized (MCM-41-COOH) containers loaded with the anticancer drug doxorubicin (DOX) and capped by quaternary ammonium pillar[5]arene (P[5]A) nanogates. MCM-41 and MCM-41-COOH containers were synthesized and transmission and scanning electron microscopies showed nanoparticles with spherical morphology and dimensions of 85 ± 13 nm. The nanochannels of MCM-41 loaded with DOX were gated through the electrostatic interactions between P[5]A and the silanolate groups formed at the silica-water interface, yielding the MCM-41-DOX-P[5]A nanocarrier. The second nanocarrier was gated through the electrostatic interactions between the carboxylate groups mounted on the surface of MCM-41 and P[5]A, resulting in the MCM-41-COO-DOX-P[5]A nanocarrier. The DOX release profiles from both nanocarriers were investigated by UV-vis spectroscopy at different pH values (2.0, 5.5 and 7.4) and also in the presence of ions, such as citrate (19 mmol L) and Zn (1.2 and 50 mmol L) at 37 °C. MCM-41-COO-DOX-P[5]A can be turned on and off eight times through the formation and breaking of electrostatic interactions. In vitro studies show that MCM-41-COO-DOX-P[5]A can penetrate and release DOX in the nucleus of human breast adenocarcinoma MCF-7 cancer cells leading to a pronounced cytotoxic effect. Therefore, the fabricated nanocarrier based on a water-soluble cationic pillar[5]arene nanogate, which is reversibly opened and closed by electrostatic interactions, can be considered as a promising drug transport and delivery technique for future cancer therapy.
Topics: Antibiotics, Antineoplastic; Calixarenes; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Carriers; Drug Liberation; Drug Screening Assays, Antitumor; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Materials Testing; Nanoparticles; Particle Size; Porosity; Quaternary Ammonium Compounds; Silicon Dioxide; Structure-Activity Relationship; Surface Properties; Tumor Cells, Cultured
PubMed: 31867589
DOI: 10.1039/c9tb00946a -
European Journal of Pharmacology Nov 2020Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), an immunosuppressive drug approved for the prophylaxis of allograft rejection in... (Review)
Review
Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), an immunosuppressive drug approved for the prophylaxis of allograft rejection in transplant recipients. Recent advances in the role of the type II isoform of inosine-5'-monophosphate dehydrogenase (IMPDH2) in the tumorigenesis of various types of cancer have called for a second look of MPA, the first IMPDH2 inhibitor discovered a hundred years ago, to be repurposed as an anticancer agent. Over a half century, a number of in vitro and in vivo experiments have consistently shown anticancer activity of MPA against several cell lines obtained from different malignancies and murine models. However, a few clinical trials have been conducted to investigate its anticancer activity in humans, and most of which have shown unsatisfactory results. Understanding of available evidence and underlying mechanism of action is a key step to be done so as to facilitate further investigations of MPA to reach its full therapeutic potential as an anticancer agent. This article provides a comprehensive review of non-clinical and clinical evidence available to date, with the emphasis on the molecular mechanism of action in which MPA exerts its anticancer activities: induction of apoptosis, induction of cell cycle arrest, and alteration of tumor microenvironment. Future perspective for further development of MPA to be an anticancer agent is extensively discussed, with the aim of translating the anticancer property of MPA from bench to bedside.
Topics: Animals; Antibiotics, Antineoplastic; Humans; IMP Dehydrogenase; Mycophenolic Acid; Neoplasms
PubMed: 32949604
DOI: 10.1016/j.ejphar.2020.173580 -
Journal of Biomedical Materials... Nov 2020Doxorubicin shows good anticancer activity, but poor pharmacokinetic property and high organ toxicity restrict its clinical application. The synthesized phenylboronic...
Doxorubicin shows good anticancer activity, but poor pharmacokinetic property and high organ toxicity restrict its clinical application. The synthesized phenylboronic acid-modified F127-chitosan conjugate was used to prepare doxorubicin-loaded micelles through dialysis method. The physicochemical properties of the doxorubicin-loaded micelles were characterized. These micelles were further evaluated for in vitro release/cytotoxicity, in vivo activity/biosafety, and pharmacokinetic studies. in vitro release experiment demonstrated that the release of doxorubicin from drug-loaded micelles was pH-dependent. in vitro cytotoxic study showed that the introduction of phenylboronic acid resulted in lower IC against B16 cells than that in non-modified F127-chitosan micelles group, and the doxorubicin-loaded micelles displayed lower in vitro activity against B16, A549, and HT-29 cells than free doxorubicin did. However, in vivo experiments confirmed that the doxorubicin-loaded micelles were safe for mouse main organs, obviously improved pharmacokinetic parameters of doxorubicin in rat and achieved comparable inhibition of tumor growth with no animal death in B16-bearing mice models throughout the experiment when compared with free doxorubicin. The phenylboronic acid-sialic acid interaction and pH-sensitive drug release might play important roles in increased tumor targeting and therapeutic effect of the doxorubicin-loaded micelles.
Topics: A549 Cells; Animals; Antibiotics, Antineoplastic; Boronic Acids; Cell Line, Tumor; Cell Survival; Chitosan; Doxorubicin; Drug Delivery Systems; Drug Liberation; HT29 Cells; Humans; Melanoma, Experimental; Mice; Micelles; Oligosaccharides; Particle Size; Rats; Rats, Sprague-Dawley
PubMed: 32583518
DOI: 10.1002/jbm.b.34670 -
Journal of Natural Products May 2020Eight new polyhydroxanthones, penicixanthones A-H (-), including four monomers (-) and four dimers (-), were isolated from solid cultures of SC0070. Their structures...
Eight new polyhydroxanthones, penicixanthones A-H (-), including four monomers (-) and four dimers (-), were isolated from solid cultures of SC0070. Their structures were elucidated by extensive spectroscopic analysis, X-ray single-crystal diffraction, and theoretical computations of ECD spectra. Penicixanthone B () has a hexahydroxanthone structure featuring an unusual oxygen bridge between C-6 and C-8a. Penicixanthone D () is distinct from other penicixanthones in stereochemistry, and its biosynthetic mechanism was proposed based on theoretical simulations for the reaction pathway of C-10a epimerization. Penicixanthone G () exhibited the most potent cytotoxicity (IC: 0.3-0.6 μM) when tested against human carcinoma A549, HeLa, and HepG2 cells, whereas it was nontoxic to the normal Vero cells (IC > 50 μM). It also displayed the strongest antibacterial activity (MIC: 0.4 μg/mL) against both and the methicillin-resistant strain MRSA.
Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Bacteria; Cell Line, Tumor; Circular Dichroism; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Fermentation; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Structure; Staphylococcus aureus; Talaromyces; X-Ray Diffraction; Xanthines
PubMed: 32293887
DOI: 10.1021/acs.jnatprod.9b01071 -
Pharmaceutical Nanotechnology 2020Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first...
BACKGROUND
Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDA-approved PEG-liposomes of DOX for the treatment of over 600,000 cancer patients, and it can overcome doxorubicin-induced cardiomyopathy and other side effects and prolong life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment.
OBJECTIVE
We intended to prepare a novel DOX liposome that was prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical application.
METHODS
DOX liposomes were prepared using the combination of thin-film dispersion ultrasonic method and ammonium sulfate gradient method and the factors that influenced formulation quality were optimized. After formulation, particle size, entrapment efficiency, drug loading, stability, and pharmacokinetics were determined.
RESULTS
DOX liposomes were near-spherical morphology with the average size of 90 nm and polydispersity index (PDI) of less than 0.30. The drug loading was up to 7.5%, and the entrapment efficiency was over 80%. The pharmacokinetic studies showed that free DOX could be easily removed and the blood concentration of free DOX group was significantly lower than that of DOX liposomes, which indicated that the novel DOX liposome had a certain sustainedrelease effect.
CONCLUSION
In summary, DOX liposome is economical and easy-prepared with prolonged circulation time. Lay Summary: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDAapproved PEG-liposomes of DOX to treat over 600.000 cancer patients, overcoming doxorubicin- induced cardiomyopathy and other side effects and prolonging life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. We intend to prepare a novel DOX liposome prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical use. The novel DOX liposome is economical and easy-prepared with prolonged circulation time.
Topics: Animals; Antibiotics, Antineoplastic; Delayed-Action Preparations; Doxorubicin; Drug Compounding; Drug Liberation; Drug Stability; Injections, Intravenous; Lecithins; Liposomes; Male; Particle Size; Polyethylene Glycols; Rats, Sprague-Dawley; Stearates; Technology, Pharmaceutical
PubMed: 32787769
DOI: 10.2174/2211738508666200813141454 -
Advanced Drug Delivery Reviews Nov 2021We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be... (Review)
Review
We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be utilized in human clinical trials. This class of compounds is designed to carry a payload of a cytotoxic agent and adequately circulate in order to accumulate at a tumor that is being heated. At the target the carrier is activated by heat and releases its contents at high concentrations. We summarize the preclinical and clinical experience of LTLD including its successes and challenges in the development process.
Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Drug Delivery Systems; Drug Development; Drug Liberation; Humans; Hyperthermia; Hyperthermia, Induced; Polyethylene Glycols
PubMed: 34555486
DOI: 10.1016/j.addr.2021.113985 -
BMC Cancer Nov 2020The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients....
BACKGROUND
The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients. However, the treatment and prognosis of STS and breast cancer are quite different, and reference to breast cancer data alone may not reflect the efficacy of doxorubicin treatment in STS. This study, thus, aimed to review and analyze clinical data of STS patients treated with a high cumulative doxorubicin dose, to provide a reference for treatment selection and clinical trial design.
METHODS
We retrospectively collected and analyzed clinical data of patients with advanced STS who received doxorubicin-based chemotherapy from January 2016 to January 2020. The patients were divided into a standard-dose group (who received ≤6 cycles of doxorubicin after the initial diagnosis) and an over-dose group (who were re-administered doxorubicin [doxorubicin-rechallenge] after receiving 6 cycles of doxorubicin therapy discontinuously). Patient characteristics, cumulative doxorubicin dose, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), cardiotoxicity incidence, and treatment effectiveness were evaluated in both groups.
RESULTS
A total of 170 patients with advanced STS were recruited (146 in the standard-dose group and 24 in the over-dose group). The average cumulative doxorubicin dose was 364.04 ± 63.81 mg/m2 in the standard-dose group and 714.38 ± 210.09 mg/m2 in the over-dose group. The ORR, DCR, and median PFS were 15.07, 58.9%, and 6 (95% confidence interval [CI]: 5.8-6.5) months in the standard-dose group and 16.67, 66.67%, and 4 (95%CI: 2.0-5.8) months in the over-dose group, respectively. Symptomatic heart failure occurred in five patients (3.42%) of the standard-dose group and in one patient (4.17%) of the over-dose group. In these patients with cardiotoxicity, doxorubicin was discontinued, and all of them died of uncontrolled tumor growth. No drug-related deaths occurred.
CONCLUSIONS
The continuation of or rechallenge with doxorubicin beyond the recommended cumulative dose could be a promising therapeutic option in the treatment of chemotherapy-sensitive advanced sarcomas. Further evaluation is necessary in prospective trials.
Topics: Antibiotics, Antineoplastic; Doxorubicin; Female; Humans; Male; Sarcoma
PubMed: 33228579
DOI: 10.1186/s12885-020-07663-x