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American Journal of Hematology Nov 2020Management of AML involves choosing between purely palliative care, standard therapy and investigational therapy ("clinical trial"). Even most older patients likely... (Review)
Review
Management of AML involves choosing between purely palliative care, standard therapy and investigational therapy ("clinical trial"). Even most older patients likely benefit from treatment. Based on randomized trials CPX 351, midostaurin, gemtuzumab ozogamicin, and venetoclax, the latter three when combined with other drugs, should now be considered standard therapy. Knowledge of the likely results with these therapies is essential in deciding whether to recommend them or participate in a clinical trial, possibly including these drugs. Hence here, in the context of established prognostic algorithms, we review results with the recently- approved drugs compared with their predecessors and describe other potential options. We discuss benefit/risk ratios underlying the decision to offer allogeneic transplant and emphasize the importance of measurable residual disease. When first seeing a newly-diagnosed patient physicians must decide whether to offer conventional treatment or investigational therapy, the latter preferably in the context of a clinical trial. As noted below, such trials have led to changes in what today is considered "conventional" therapy compared to even 1-2 years ago. In older patients decision making has often included inquiring whether specific anti-AML therapy should be offered at all, rather than focusing on a purely palliative approach emphasizing transfusion and antibiotic support, with involvement of a palliative care specialist.
Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Gemtuzumab; Leukemia, Myeloid, Acute; Randomized Controlled Trials as Topic; Risk Assessment; Staurosporine; Sulfonamides; United States
PubMed: 32833263
DOI: 10.1002/ajh.25975 -
International Journal of Nanomedicine 2022Most of the traditional nanocarriers of cancer therapeutic moieties present dose-related toxicities due to the uptake of chemotherapeutic agents in normal body cells....
BACKGROUND
Most of the traditional nanocarriers of cancer therapeutic moieties present dose-related toxicities due to the uptake of chemotherapeutic agents in normal body cells. The severe life-threatening effects of systemic chemotherapy are well documented. Doxorubicin, DOX is the most effective antineoplastic agent but with the least specific action that is responsible for severe cardiotoxicity and myelosuppression that necessitates careful monitoring while administering. Stimuli-sensitive/intelligent drug delivery systems, specifically those utilizing temperature as an external stimulus to activate the release of encapsulated drugs, have become a subject of recent research. Thus, it would be ideal to have a nanocarrier comprising safe excipients and controllable drug release capacity to deliver the drug at a particular site to minimize unwanted and toxic effects of chemotherapeutics. We have developed a simple temperature-responsive nanocarrier based on eutectic mixture of fatty acids. This study aimed to develop, physicochemically characterize and investigate the biological safety of eutectic mixture of fatty acids as a novel construct for temperature-responsive drug release potential.
METHODS
We have developed phase change material, PCM, based on a series of eutectic mixtures of fatty acids due to their unique and attractive physicochemical characteristics such as safety, stability, cost-effectiveness, and ease of availability. The reversible solid-liquid phase transition of PCM is responsible to hold firm or actively release the encapsulated drug. The eutectic mixtures of fatty acids (stearic acid and myristic acid) along with liquid lipid (oleic acid) were prepared to exhibit a tunable thermoresponsive platform. Doxorubicin-loaded lipid nanocarriers were successfully developed with combined hot melt encapsulation (HME) and sonication method and characterized to achieve enhanced permeability and retention (EPR) effect-based solid tumor targeting in response to exogenous temperature stimulus. The cytotoxicity against melanoma cell lines and in vivo safety studies in albino rats was also carried out.
RESULTS
Doxorubicin-loaded lipid nanocarriers have a narrow size distribution (94.59-219.3 nm), and a PDI (0.160-0.479) as demonstrated by photon correlation microscopy and excellent colloidal stability (Z.P value: -22.7 to -32.0) was developed. Transmission electron microscopy revealed their spherical morphology and characteristics of a monodispersed system. A biphasic drug release pattern with a triggered drug release at 41°C and 43°C and a sustained drug release was observed at 37°C. The thermoresponsive cytotoxic potential was demonstrated in B16F10 cancer cell lines. Hemolysis assay and acute toxicity studies with drug-free and doxorubicin lipid nanocarrier formulations provided evidence for their non-toxic nature.
CONCLUSION
We have successfully developed a temperature-responsive tunable platform with excellent biocompatibility and intelligent drug release potential. The formulation components being from natural sources present superior characteristics in terms of cost, compatibility with normal body cells, and adaptability to preparation methods. The reported preparation method is adapted to avoid complex chemical processes and the use of organic solvents. The lipid nanocarriers with tunable thermoresponsive characteristics are promising biocompatible drug delivery systems for improved localized delivery of chemotherapeutic agents.
Topics: Animals; Rats; Doxorubicin; Drug Liberation; Fatty Acids; Microscopy, Electron, Transmission; Neoplasms; Temperature
PubMed: 35656165
DOI: 10.2147/IJN.S359664 -
Journal of Clinical Oncology : Official... Aug 2020
Topics: Breast Neoplasms; Cisplatin; Cyclophosphamide; Doxorubicin; Germ Cells; Humans; Neoadjuvant Therapy
PubMed: 32516090
DOI: 10.1200/JCO.20.01190 -
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 -
International Journal of Molecular... May 2022The human gonadotropin releasing hormone (GnRH-I) and its sea lamprey analogue GnRH-III specifically bind to GnRH receptors on cancer cells and can be used as targeting...
The human gonadotropin releasing hormone (GnRH-I) and its sea lamprey analogue GnRH-III specifically bind to GnRH receptors on cancer cells and can be used as targeting moieties for targeted tumor therapy. Considering that the selective release of drugs in cancer cells is of high relevance, we were encouraged to develop cleavable, self-immolative GnRH-III-drug conjugates which consist of a -aminobenzyloxycarbonlyl (PABC) spacer between a cathepsin B-cleavable dipeptide (Val-Ala, Val-Cit) and the classical anticancer drugs daunorubicin (Dau) and paclitaxel (PTX). Alongside these compounds, non-cleavable GnRH-III-drug conjugates were also synthesized, and all compounds were analyzed for their antiproliferative activity. The cleavable GnRH-III bioconjugates revealed a growth inhibitory effect on GnRH receptor-expressing A2780 ovarian cancer cells, while their activity was reduced on Panc-1 pancreatic cancer cells exhibiting a lower GnRH receptor level. Moreover, the antiproliferative activity of the non-cleavable counterparts was strongly reduced. Additionally, the efficient cleavage of the Val-Ala linker and the subsequent release of the drugs could be verified by lysosomal degradation studies, while radioligand binding studies ensured that the GnRH-III-drug conjugates bound to the GnRH receptor with high affinity. Our results underline the high value of GnRH-III-based homing devices and the application of cathepsin B-cleavable linker systems for the development of small molecule drug conjugates (SMDCs).
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cathepsin B; Cell Line, Tumor; Daunorubicin; Female; Gonadotropin-Releasing Hormone; Humans; Molecular Targeted Therapy; Ovarian Neoplasms; Paclitaxel; Petromyzon; Pyrrolidonecarboxylic Acid; Receptors, LHRH
PubMed: 35563462
DOI: 10.3390/ijms23095071 -
ACS Applied Materials & Interfaces Apr 2023Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An...
Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An easily scalable, sustainable, and cost-effective manufacturing strategy and long-term stability for storage are crucial for successful translation. Here, we report a system and method to instantly formulate NF achieved with a nanoscale polyelectrolyte coacervate-like system, consisting of anionic pseudopeptide poly(l-lysine isophthalamide) derivatives, polyethylenimine, and doxorubicin (Dox) via simple "mix-and-go" addition of precursor solutions in seconds. The coacervate-like nanosystem shows enhanced intracellular delivery of Dox to patient-derived multidrug-resistant (MDR) cells in 3D tumor spheroids. The results demonstrate the feasibility of an instant drug formulation using a coacervate-like nanosystem. We envisage that this technique can be widely utilized in the nanomedicine field to bypass the special requirement of large-scale production and elongated shelf life of nanomaterials.
Topics: Humans; Feasibility Studies; Doxorubicin; Neoplasms; Nanostructures; Drug Carriers; Nanoparticles; Cell Line, Tumor; Drug Delivery Systems
PubMed: 36976817
DOI: 10.1021/acsami.2c21586 -
MBio Oct 2022Exposure of immunosuppressed individuals to the opportunistic fungal pathogen Aspergillus fumigatus may result in invasive pulmonary aspergillosis (IPA), which can lead...
Exposure of immunosuppressed individuals to the opportunistic fungal pathogen Aspergillus fumigatus may result in invasive pulmonary aspergillosis (IPA), which can lead to the development of cerebral aspergillosis (CA), a highly lethal infection localized in the central nervous system (CNS). There are no experimental models of CA that effectively mimic human disease, resulting in a considerable knowledge gap regarding mechanisms of neurological pathogenicity and neuroimmune responses during infection. In this report, immunosuppressed mice (via acute, high-dose corticosteroid administration) challenged with A. fumigatus resting conidia intranasally, followed a day later by a 70-fold lower inoculum of pre-swollen conidia intravenously (IN + IV + steroid), demonstrated increased weight loss, signs of severe clinical disease, increased fungal burden in the brain, and significant reduction in survival compared to immunosuppressed mice challenged intranasally only (IN + steroid) or non-immunosuppressed mice challenged both intranasally and intravenously (IN + IV). The IN + IV + steroid group demonstrated significant decreases in monocytes, eosinophils, dendritic cells (DCs), and invasive natural killer T (iNKT) cells, but not neutrophils or γδ T cells, in the brain compared to the IN + IV group. Likewise, the IN + IV + steroid group had significantly lower levels of interleukin (IL)-1β, IL-6, IL-17A, CC motif chemokine ligand 3 (CCL3), CXC chemokine ligand 10 (CXCL10), and vascular endothelial growth factor (VEGF) in the brain compared to the IN + IV group. IN + IV + steroid was superior to both IN + IV + chemotherapy (cytarabine + daunorubicin) and IN + IV + neutropenia for the development of CA. In conclusion, we have developed a well-defined, physiologically relevant model of disseminated CA in corticosteroid-induced immunosuppressed mice with a primary pulmonary infection. This model will serve to advance understanding of disease mechanisms, identify immunopathogenic processes, and help define the protective neuroinflammatory response to CA. Invasive fungal infections (IFIs) result in significant mortality in immunosuppressed individuals. Of these, invasive pulmonary aspergillosis (IPA), caused by the opportunistic mold Aspergillus fumigatus, is the most lethal. Lethality in IPA is due to two main factors: destruction of the lung leading to compromised pulmonary function, and dissemination of the organism to extrapulmonary organs. Of these, the CNS is the most common site of dissemination. However, very little is known regarding the pathogenesis of or immune response during cerebral aspergillosis, which is directly due to the lack of an animal model that incorporates immunosuppression, lung infection, and consistent dissemination to the CNS/brain. In this report, we have developed a new experimental animal model of CA which includes the above parameters and characterized the neuroimmune response. We further compared this disseminated CA model to two additional immunosuppressive strategies. Overall, this model of disseminated CA following IPA in an immunosuppressed host provides a novel platform for studying the efficacy of antifungal drugs and immunotherapies for improving disease outcomes.
Topics: Mice; Humans; Animals; Invasive Pulmonary Aspergillosis; Interleukin-17; Vascular Endothelial Growth Factor A; Antifungal Agents; Ligands; Interleukin-6; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Lung; Adrenal Cortex Hormones; Pneumonia; Steroids; Chemokines, CXC; Cytarabine; Daunorubicin; Chemokines
PubMed: 36040029
DOI: 10.1128/mbio.02254-22 -
Drug Delivery Dec 2020Proliferative vitreoretinopathy (PVR) is a significant threat for vision recovery from retinal detachment or ocular trauma. Currently, no approved pharmacological...
Proliferative vitreoretinopathy (PVR) is a significant threat for vision recovery from retinal detachment or ocular trauma. Currently, no approved pharmacological intervention to prevent PVR. Daunorubicin (DNR) and dexamethasone (DEX) were sequentially loaded into oxidized porous silicon (pSiO) particles by covalent conjugation. The DNR + DEX-loaded particles, and control particles loaded with DNR only and DEX only were incubated with RPE-populated collagen for daily gel surface quantitation. Toxicity was monitored by ophthalmic examinations and histological evaluation 21 days after injection. At 3rd week following intravitreal injection, a localized retinal detachment (RD) was created by subretinal injection of Healon in all pretreated eyes in addition to 3 non-interventional control eyes. 10 µg of bromodeoxyuridine (BrdU) was injected into the vitreous 4 h before sacrifice on day 3 after RD induction. Retinal sections were stained for glial fibrillary green protein (GFAP) and BrdU to identify activated glial cells and retinal cell proliferation. The studies demonstrated that all three pSiO particle types were well tolerated in vivo. DNR alone and DNR + DEX combination formulations demonstrated equally strong suppression on gel contraction (least square mean area of the gel: control = 1.71 vs. 30DNR = 1.85 or 30/40Dual = 1.83, < .05). Eyes pretreated with pSiO-DNR + DEX exhibited the least GFAP activation (least square mean intensity mm: Dual = 4.03, DNR = 7.76, Dex = 16.23, control = 29.11, < .05) and BrdU expression (Mean number of BrdU positive cells per mm of retina: Dual = 2.77, DNR = 4.58, Dex = 4.01, control = 6.16, < .05). The synergistic effect of a sustained release pSiO-DNR/DEX showed promise for the prevention of PVR development while reducing the necessary therapeutic concentration of each drug.
Topics: Animals; Daunorubicin; Delayed-Action Preparations; Dexamethasone; Drug Delivery Systems; Intravitreal Injections; Porosity; Rabbits; Retina; Retinal Detachment; Silicon; Vitreoretinopathy, Proliferative; Vitreous Body
PubMed: 33100053
DOI: 10.1080/10717544.2020.1833382 -
Molecules (Basel, Switzerland) Apr 2022(Spreng.) A.J. Vega & Dematt. (syn.: Less) is popularly known as "assa-peixe" and its leaves are used in folk medicine mainly to treat respiratory diseases. In this...
(Spreng.) A.J. Vega & Dematt. (syn.: Less) is popularly known as "assa-peixe" and its leaves are used in folk medicine mainly to treat respiratory diseases. In this study, we evaluated the cytogenotoxic and anticytogenotoxic potential of the leaf aqueous extract (LAE) and its -butanol fraction (BF) in the presence or absence of doxorubicin (DXR) (pre-, co-, and post-treatments) on a murine model for 24 h or 120 h. The micronucleus test (MN) and the comet assay were used to assess the cytogenotoxic and anticytogenotoxic potential of LAE and BF (250, 500, and 1000 mg/kg) administered via gavage to Swiss Webster mice. The chemical profiles of LAE and BF were assessed by liquid chromatography coupled to mass spectrometry, and their metabolites were putatively identified. Lastly, the possible biological activities related to the (anti) cytogenotoxicity of the compounds were predicted using the PASS online webserver. The in vivo results showed that different doses of LAE and BF did not present cytotoxic activity; however, the MN test revealed a slight mutagenic activity for the 24 h treatments. Moderate genotoxic effects were demonstrated for all treatments in the comet assay. Regarding anticytotoxicity and antimutagenicity, LAE and BF presented a high cytoprotective potential against DXR toxic effects. In the co-treatment, LAE reduced the DXR genotoxicity by ~27%, and -BF did not demonstrate antigenotoxic potential. In contrast, an antigenotoxic effect was observed for both LAE and -BF in the pre- and post-treatments, reducing DXR genotoxicity by ~41% and ~47%, respectively. Chemical analysis of LAE and BF showed the presence of eight phenolic compounds, including seven chlorogenic acids and a flavonoid. The PASS online tool predicted antimutagenic, anticancer, antineoplastic, chemoprotective, antioxidant, and radical scavenging activities for all constituents identified in LAE and -BF. leaves presented a protective effect against DXR cytogenotoxicity. In general, LAE and -BF showed a greater antigenotoxic potential in the pre- and post-treatments. The metabolites putatively identified in LAE and -BF exhibited antioxidant and chemoprotective potential according to computational prediction analysis. Altogether, our results highlight the potential application of to protect against toxic manifestations induced by DXR.
Topics: Animals; Antioxidants; Asteraceae; DNA Damage; Doxorubicin; Gas Chromatography-Mass Spectrometry; Mice; Micronucleus Tests; Phytochemicals; Plant Extracts; Plant Leaves
PubMed: 35458751
DOI: 10.3390/molecules27082553 -
International Journal of Molecular... Jul 2022In this work, we report the fabrication and functional demonstration of a kind of dually responsive nanoparticles (NPs) as a potential drug delivery vector. The pH...
In this work, we report the fabrication and functional demonstration of a kind of dually responsive nanoparticles (NPs) as a potential drug delivery vector. The pH value, corresponding to the acidic microenvironment at the tumor site, and mannitol, to the extracellular trigger agent, were employed as the dually responsive factors. The function of dual responses was achieved by breaking the dynamic covalent bonds between phenylboronic acid (PBA) groups and diols at low pH value (pH 5.0) and/or under the administration of mannitol, which triggered the decomposition of the complex NPs and the concomitant release of anticancer drug of doxorubicin (DOX) loaded inside the NPs. The NPs were composed of modified chitosan (PQCS) with quaternary ammonium and PBA groups on the side chains, heparin (Hep), and poly(vinyl alcohol) (PVA), in which quaternary ammonium groups offer the positive charge for the cell-internalization of NPs, PBA groups serve for the formation of dynamic bonds in responding to pH change and mannitol addition, PVA furnishes the NPs with diol groups for the interaction with PBA groups and the formation of dynamic NPS, and Hep plays the roles of reducing the cytotoxicity of highly positively-charged chitosan and forming of complex NPs for DOX up-loading. A three-step fabrication process of drug-loaded NPs was described, and the characterization results were comprehensively demonstrated. The sustained drug release from the drug-loaded NPs displayed obvious pH and mannitol dependence. More specifically, the cumulative DOX release was increased more than 1.5-fold at pH 5.0 with 20 mg mL mannitol. Furthermore, the nanoparticles were manifested with effective antitumor efficient and apparently enhanced cytotoxicity in response to the acidic pH value and/or mannitol.
Topics: Ammonium Compounds; Chitosan; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogen-Ion Concentration; Mannitol; Nanoparticles
PubMed: 35806347
DOI: 10.3390/ijms23137342