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1.
Drug Deliv ; 28(1): 2361-2372, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34747277

ABSTRACT

Although podophyllotoxin (POD) demonstrates high efficiency to inhibit various cancers, its clinic application is limited to poor bioavailability. Nanoparticles derived from homodimeric prodrugs with high drug loading potential are emerging as promising nanomedicines. However, complete intracellular drug release remains a major hindrance to the use of homodimeric prodrugs-based nanomedicine. We sought to develop a reactive oxygen species (ROS) responsive POD dimeric prodrug by incorporating vitamin K3 (VK3) and Pluronic F127 to synthesize a spheroid nanoparticle (PTV-NPs). PTV-NPs with high POD content could release drugs under the ROS enrichment microenvironment in cancer cells. The released VK3 could produce abundant ROS selectively in tumor cells catalyzed by the overexpressed NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme. In turn, the resultant high ROS concentration promoted the conversion of POD dimeric prodrug to POD monomer, thereby achieving the selective killing of cancer cells with weak system toxicity. In vitro and in vivo studies consistently confirmed that PTV-NPs exhibit high drug loading potential and upstanding bioavailability. They are also effectively internalized by tumor cells, induce abundant intracellular ROS generation, and have high tumor-specific cytotoxicity. This ROS-responsive dimeric prodrug nanoplatform characterized by selective self-amplification drug release may hold promise in the field of antitumor drug delivery.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Neoplasms/pathology , Podophyllotoxin/administration & dosage , Podophyllotoxin/pharmacology , Prodrugs/administration & dosage , Prodrugs/pharmacology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Drug Liberation , Drug Stability , Female , Humans , Hydrogen-Ion Concentration , Mice , Mice, Inbred BALB C , Mice, Nude , NAD(P)H Dehydrogenase (Quinone)/metabolism , NADP/metabolism , Nanoparticles/chemistry , Podophyllotoxin/pharmacokinetics , Poloxamer/chemistry , Polymers/chemistry , Prodrugs/pharmacokinetics , Reactive Oxygen Species/metabolism , Tumor Microenvironment/physiology , Vitamin K 3/chemistry , Xenograft Model Antitumor Assays
2.
Drug Deliv ; 27(1): 248-257, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32003255

ABSTRACT

Cancer is a kind of malignant diseases that threatens human health and the research application of anti-tumor drug therapeutics is growingly always been focused on. Many new compounds with great anticancer activity were synthesized but cannot be hard to be developed into clinical use due to its poor water solubility. Deoxypodophyllotoxin (DPT) is just an example. We develop lyophilized Deoxypodophyllotoxin (DPT) loaded polymeric micelles using methoxy polyethylene glycol-block-Poly (D, L-lactide) (mPEG-PLA). DPT-PM freeze-dried powder was successfully prepared using optimized formulation. mPEG-PLA was added to hydration media before hydrating as cryoprotectants. The freeze-dried powder exhibited white pie-solid without collapsing, and the particle size of DPT-PM reconstituted with water was about 20-35 nm. The entrapment efficiency of the reconstituted solution was 98%, which shows no differences with the micelles before lyophilization. In-vitro cytotoxicity and cellular uptake studies showed that DPT-PM has a higher degree of cytotoxicity comparing with DPT and mPEG-PLA micelles and uptake of mPEG-PLA was concentration and time-dependent. In vivo characterization of DPT-PM was done for pharmacokinetics behaviors, antitumor activity and safety. The obtained results showed significant improvement in plasma clearance bioavailability (p <0.05) and prolonged blood circulation time comparing with DPT-HP-ß-CD. Moreover, mPEG-PLA micelles had a better degree of anti-tumor efficacy, this was due to better accumulation of mPEG-PLA in tumor cell via enhanced permeability and retention (EPR) effect. Therefore, DPT-PM has great clinical value, and can be expected to be a novel antitumor preparation.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Drug Delivery Systems , Drugs, Chinese Herbal/administration & dosage , Nanoparticles , Podophyllotoxin/analogs & derivatives , Animals , Antineoplastic Agents, Phytogenic/pharmacokinetics , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Drugs, Chinese Herbal/pharmacokinetics , Drugs, Chinese Herbal/pharmacology , Freeze Drying , Humans , Male , Mice , Mice, Nude , Micelles , Neoplasms/drug therapy , Particle Size , Podophyllotoxin/administration & dosage , Podophyllotoxin/pharmacokinetics , Podophyllotoxin/pharmacology , Polyesters/chemistry , Polyethylene Glycols/chemistry , Time Factors , Tissue Distribution
3.
Nanotheranostics ; 4(1): 40-56, 2020.
Article in English | MEDLINE | ID: mdl-31911893

ABSTRACT

The hydrophobicity and high potency of many therapeutic agents makes them difficult to use effectively in clinical practice. This work focuses on conjugating phospholipid tails (2T) onto podophyllotoxin (P) and its analogue (N) using a linker and characterizing the effects of their incorporation into lipid-based drug delivery vehicles for triggered ultrasound delivery. Differential Scanning Calorimetry results show that successfully synthesized lipophilic prodrugs, 2T-P (~28 % yield) and 2T-N(~26 % yield), incorporate within the lipid membranes of liposomes. As a result of this, increased stability and incorporation are observed in 2T-P and 2T-N in comparison to the parent compounds P and N. Molecular dynamic simulation results support that prodrugs remain within the lipid membrane over a relevant range of concentrations. 2T-N's (IC50: 20 nM) biological activity was retained in HeLa cells (cervical cancer), whereas 2T-P's (IC50: ~4 µM) suffered, presumably due to steric hindrance. Proof-of-concept studies using ultrasound in vitro microbubble and nanodroplet delivery vehicles establish that these prodrugs are capable of localized drug delivery. This study provides useful information about the synthesis of double tail analogues of insoluble chemotherapeutic agents to facilitate incorporation into drug delivery vehicles. The phospholipid attachment strategy presented here could be applied to other well suited drugs such as gemcitabine, commonly known for its treatment of pancreatic cancer.


Subject(s)
Antineoplastic Agents/chemistry , Drug Delivery Systems/methods , Liposomes/chemistry , Prodrugs/chemistry , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cell Survival/drug effects , HeLa Cells , Humans , Liposomes/administration & dosage , Liposomes/pharmacokinetics , Microbubbles , Phospholipids/administration & dosage , Phospholipids/chemistry , Phospholipids/pharmacokinetics , Podophyllotoxin/administration & dosage , Podophyllotoxin/chemistry , Podophyllotoxin/pharmacokinetics , Prodrugs/administration & dosage , Prodrugs/pharmacokinetics , Theranostic Nanomedicine , Ultrasonic Waves
4.
Invest New Drugs ; 37(4): 693-701, 2019 08.
Article in English | MEDLINE | ID: mdl-30547316

ABSTRACT

Purpose To determine the maximum tolerated dose (MTD) of F14512, a topoisomerase II inhibitor designed to target cancer cells through the polyamine transport system, (three-hour daily infusion given for 3 consecutive days every 3 weeks) in platinum-refractory or resistant ovarian cancer. Other objectives were safety, pharmacokinetics (PK), PK/pharmacodynamics relationship, and efficacy. Methods This was an open-label, dose-escalation, multicenter phase I study. Results Eleven patients were enrolled and were treated at dose levels (DLs) of 10 and 5 mg/m2/day. All patients received the 3 injections per cycle as per study protocol (median, 1 cycle (Ferlay et al. Int J Cancer 136:E359-386, 2015; Siegel et al. CA Cancer J Clin 65:5-29, 2015; Oronsky et al. Med Oncol 34:103, 2017; Barret et al. Cancer Res 68:9845-9853, 2008; Ballot et al. Apoptosis 17:364-376, 2012; Brel et al. Biochem Pharmacol 82:1843-1852, 2011; Gentry et al. Biochemistry 50:3240-3249, 2011; Kruczynski et al. Investig New Drugs 29:9-21, 2011; Chelouah et al. PLoS One 6:e23597, 2011)) with no dose reductions. At DL 10 mg/m2/day, 6 dose-limiting toxicities (DLTs) were reported (3/4 evaluable patients: 2 grade 3 febrile neutropenia, 1 grade 4 neutropenia lasting at least 7 days, 1 grade 3 nausea, 1 decreased appetite, and 1 grade 3 asthenia). At dose 5 mg/m2/day, 2 DLTs were reported (2/6 treated patients: 2 grade 3 febrile neutropenia). Both DLs were defined as MTD. Stable disease was reported as best overall response in 2 (40%) patients having both received 9 cycles, one at each DL. 90.9% of patients experienced grade 4 neutropenia, but for only one (9.1%) it was reported as a serious adverse event. Conclusion Although there was some encouraging efficacy signal, grade 4 neutropenia led to complications and it was decided to stop the study. A DL below 5 mg/m2/day was not tested as this would not allow reaching the minimum serum concentration needed for the pharmacological activity of the drug.


Subject(s)
Ovarian Neoplasms/drug therapy , Podophyllotoxin/analogs & derivatives , Topoisomerase II Inhibitors/administration & dosage , Aged , Drug Resistance, Neoplasm , Female , Humans , Middle Aged , Neutropenia/chemically induced , Ovarian Neoplasms/metabolism , Platinum Compounds/therapeutic use , Podophyllotoxin/administration & dosage , Podophyllotoxin/pharmacokinetics , Polyamines , Topoisomerase II Inhibitors/pharmacokinetics , Treatment Outcome
5.
Drug Metab Dispos ; 46(6): 897-907, 2018 06.
Article in English | MEDLINE | ID: mdl-29618575

ABSTRACT

Antitumor evaluation in tumor-bearing mouse is time- and energy-consuming. We aimed to investigate whether in vivo antitumor efficacy could be predicted on the basis of in vitro pharmacodynamics using deoxypodophyllotoxin (DPT), an antitumor candidate in development, as a model compound. Proliferation kinetics of monolayer-cultivated NCI-H460 cells under various DPT concentrations were quantitatively investigated and expressed as calibration curves. Koch two-phase natural growth model combined with sigmoid Emax model, i.e., dM/dt = 2λ0λ1M/(λ1 + 2λ0M) - Emax C γ /(EC50γ + C γ )·M, was introduced to describe cell proliferation (M) against time under DPT treatment (C). Estimated in vitro pharmacodynamic parameters were: EC50, 8.97 nM; Emax , 0.820 day-1, and γ, 7.13. A physiologically based pharmacokinetic model including tumor compartment was introduced to predict DPT disposition in plasma, tumor tissue, and main normal tissues of NCI-H460 tumor-bearing mice following a single dose. The in vivo pharmacodynamic model and parameters were assumed the same as the in vitro ones, and linked with simulated tumor pharmacokinetic profiles by a physiologically based pharmacokinetic (PBPK) model to build a PBPK-pharmacodynamic (PBPK-PD) model. After natural growth parameters (λ0 and λ1) were estimated, the objective in this study was to predict with the PBPK-PD model the tumor growth in NCI-H460 tumor-bearing mice during multidose DPT treatment, a use of the model similar to what others have reported. In our work, the model was successfully applied to predict tumor growth in SGC-7901 tumor-bearing mice. The resulting data indicated that in vivo antitumor efficacy might be predicted on the basis of in vitro cytotoxic assays via a PBPK-PD model approach. We demonstrated that the approach is reasonable and applicable and may facilitate and accelerate anticancer candidate screening and dose regimen design in the drug discovery process.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Podophyllotoxin/analogs & derivatives , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Drugs, Chinese Herbal , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Biological , Podophyllotoxin/pharmacokinetics , Podophyllotoxin/pharmacology , Xenograft Model Antitumor Assays/methods
6.
Int J Nanomedicine ; 12: 7963-7977, 2017.
Article in English | MEDLINE | ID: mdl-29133981

ABSTRACT

To achieve enhanced physical stability of poly(ethylene glycol)-poly(d,l-lactide) polymeric micelles (PEG-PDLLA PMs), a mixture of methoxy PEG-PDLLA-polyglutamate (mPEG-PDLLA-PLG) and mPEG-PDLLA-poly(l-lysine) (mPEG-PDLLA-PLL) copolymers was applied to self-assembled stable micelles with polyion-stabilized cores. Prior to micelle preparation, the synthetic copolymers were characterized by 1H-nuclear magnetic resonance (NMR) and infrared spectroscopy (IR), and their molecular weights were calculated by 1H-NMR and gel permeation chromatography (GPC). Dialysis was used to prepare PMs with deoxypodophyllotoxin (DPT). Transmission electron microscopy (TEM) images showed that DPT polyion complex micelles (DPT-PCMs) were spherical, with uniform distribution and particle sizes of 36.3±0.8 nm. In addition, compared with nonpeptide-modified DPT-PMs, the stability of DPT-PCMs was significantly improved under various temperatures. In the meantime, the pH sensitivity induced by charged peptides allowed them to have a stronger antitumor effect and a pH-triggered release profile. As a result, the dynamic characteristic of DPT-PCM was retained, and high biocompatibility of DPT-PCM was observed in an in vivo study. These results indicated that the interaction of anionic and cationic charged polyionic segments could be an effective strategy to control drug release and to improve the stability of polymer-based nanocarriers.


Subject(s)
Drug Carriers/chemistry , Podophyllotoxin/analogs & derivatives , Polyglutamic Acid/chemistry , Polylysine/chemistry , Animals , Drug Carriers/administration & dosage , Drug Liberation , Drugs, Chinese Herbal , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Male , Micelles , Molecular Weight , Particle Size , Podophyllotoxin/administration & dosage , Podophyllotoxin/pharmacokinetics , Polyesters/chemistry , Polyethylene Glycols/chemistry , Proton Magnetic Resonance Spectroscopy , Rabbits , Rats, Sprague-Dawley , Static Electricity , Temperature
7.
Biomaterials ; 137: 11-22, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28528299

ABSTRACT

Treatment options for metastatic and multidrug resistant (MDR) tumors are limited, and most of the chemotherapeutic drugs exhibit low efficacy against MDR cancers. An anti-tubulin agent podophyllotoxin (PPT) displays high potency against MDR tumor cells. However, due to its poor solubility and non-specificity, PPT cannot be used systemically. We have developed a self-assembling nanoparticle dosage form for PPT (named Celludo) by covalently conjugating PPT and polyethylene glycol (PEG) to acetylated carboxymethyl cellulose (CMC-Ac) via ester linkages. Celludo displayed extended blood circulation with an 18-fold prolonged half-life (t1/2), 9000-fold higher area under the curve (AUC), and 1000-fold reduced clearance compared to free PPT. Tumor delivery was 500-fold higher in the Cellduo group compared to free PPT. Against the lung metastatic model of EMT6-AR1, Celludo showed selective localization in the metastatic nodules and increased the median survival to 20 d compared to 6-8 d with docetaxel and PPT treatment. In the intraperitoneal metastatic model of human ovarian NCI-ADR/RES tumor, Celludo prolonged the median survival from 50 d to 70 d, whereas the standard therapy PEGylated liposomal doxorubicin showed no effect. No major toxicity was detected with the Celludo treatment. These results demonstrate that Celludo is effective against metastatic and MDR tumors.


Subject(s)
Antineoplastic Agents/therapeutic use , Nanoparticles/chemistry , Ovarian Neoplasms/drug therapy , Podophyllotoxin/therapeutic use , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Carboxymethylcellulose Sodium/chemistry , Cell Line, Tumor , Delayed-Action Preparations , Drug Liberation , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Mice, Inbred BALB C , Ovarian Neoplasms/pathology , Podophyllotoxin/administration & dosage , Podophyllotoxin/pharmacokinetics , Polyethylene Glycols/chemistry
8.
Nan Fang Yi Ke Da Xue Xue Bao ; 36(9): 1237-1241, 2016 08 20.
Article in Chinese | MEDLINE | ID: mdl-27687657

ABSTRACT

OBJECTIVE: To assess the distribution and systemic toxicity of podophyllotoxin-loaded nanostructured lipid carriers (POD-NLC) after topical application on the cervical mucosa in Tibet minipigs. METHODS: Twelve Tibet mini-pigs were randomized into test group and control group to receive topical application of 0.5% POD-NLC and 0.5% POD tincture, respectively, on the cervical mucosa. Cervical mucosal irritation, targeted distribution and systemic absorption of POD were observed at different time points within 24 h after the drug application. RESULTS: No local inflammation reaction was observed in the test group, while serious local irritations (swelling, blisters, blood blisters, erosion and ulceration) occurred in the control group. The fluorescence intensity of POD in the mucosal tissue reached the peak level at 4 h after drug application in the control group, while the POD fluorescence intensity increased slowly and reached the peak level at 16 h in the test group. The peak blood POD concentration occurred at 6 h after POD-NLC application in the test group (14.28∓0.33 ng/mL), as compared to 4 h in the control group (42.46∓0.32 ng/mL). At all the time points within 24 h, blood POD concentration remained significantly lower in the test group than in the control group (P<0.05), and the area under curve of blood POD concentration in the control group was 1.38-fold greater than that in the test group. CONCLUSION: POD-NLC allows sustained release of POD and achieves a higher POD concentration in the mucosal tissue without causing local irritation or obvious systemic toxicity in Tibet minipigs.


Subject(s)
Cervix Uteri/metabolism , Drug Carriers/pharmacokinetics , Mucous Membrane/metabolism , Podophyllotoxin/pharmacokinetics , Animals , Female , Lipids/chemistry , Nanostructures/chemistry , Particle Size , Swine , Swine, Miniature , Tibet
9.
Clin Cancer Res ; 21(23): 5314-23, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26169968

ABSTRACT

PURPOSE: F14512 is a new topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells and increases topoisomerase II poisoning. F14512 is currently in a phase I/II clinical trial in patients with acute myeloid leukemia. The aim of this study was to investigate F14512 potential in a new clinical indication. Because of the many similarities between human and dog lymphomas, we sought to determine the tolerance, efficacy, pharmacokinetic/pharmacodynamic (PK/PD) relationship of F14512 in this indication, and potential biomarkers that could be translated into human trials. EXPERIMENTAL DESIGN: Twenty-three dogs with stage III-IV naturally occurring lymphomas were enrolled in the phase I dose-escalation trial, which consisted of three cycles of F14512 i.v. injections. Endpoints included safety and therapeutic efficacy. Serial blood samples and tumor biopsies were obtained for PK/PD and biomarker studies. RESULTS: Five dose levels were evaluated to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematologic toxicity. F14512 induced an early decrease of tumoral lymph node cells, and a high response rate of 91% (21/23) with 10 complete responses, 11 partial responses, 1 stable disease, and 1 progressive disease. Phosphorylation of histone H2AX was studied as a potential PD biomarker of F14512. CONCLUSIONS: This trial demonstrated that F14512 can be safely administered to dogs with lymphoma resulting in strong therapeutic efficacy. Additional evaluation of F14512 is needed to compare its efficacy with standards of care in dogs, and to translate biomarker and efficacy findings into clinical trials in humans.


Subject(s)
Antineoplastic Agents/pharmacology , Dog Diseases/drug therapy , Lymphoma/veterinary , Podophyllotoxin/analogs & derivatives , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Biomarkers , Cell Line, Tumor , Dog Diseases/metabolism , Dog Diseases/pathology , Dogs , Drug Evaluation, Preclinical , Female , Histones/metabolism , Humans , Male , Neoplasm Staging , Podophyllotoxin/adverse effects , Podophyllotoxin/pharmacokinetics , Podophyllotoxin/pharmacology , Topoisomerase II Inhibitors/adverse effects , Topoisomerase II Inhibitors/pharmacokinetics , Topoisomerase II Inhibitors/pharmacology , Treatment Outcome
10.
Med Oncol ; 32(4): 129, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25794491

ABSTRACT

AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Podophyllotoxin/analogs & derivatives , Receptor, IGF Type 1/metabolism , Adenocarcinoma/secondary , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/secondary , Carcinoma, Squamous Cell/secondary , Cohort Studies , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Follow-Up Studies , Humans , Lung Neoplasms/pathology , Lymphatic Metastasis , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Pilot Projects , Podophyllotoxin/pharmacokinetics , Podophyllotoxin/therapeutic use , Prognosis , Tissue Distribution , Gemcitabine
11.
J Biomed Nanotechnol ; 10(8): 1627-34, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25016662

ABSTRACT

The purpose of this work was to develop a novel picropodophyllin-loaded micelle-like nanoparticle with a biodegradable amphiphilic star-shaped polycaprolactone-polyethyleneglycol copolymer (S-PCL-PEG). S-PCL-PEG was synthesized using star-shaped polycaprolactone (S-PCL) as a hydrophobic block and monomethoxy polyethyleneglycol (PEG) as a hydrophilic block and characterized by 1H-NMR. It was confirmed by the pyrene fluorescence probe method that the obtained S-PCL-PEG could form micelles through self-assembly in aqueous media. In addition, picropodophyllin (PPP), a hydrophobic anticancer drug, could be entrapped in the hydrophobic inner core of the micelles using the thin film hydration method, forming PPP-loaded micelle-like nanoparticles (PPP-NPs). PPP-NPs had a high encapsulation efficiency of greater than 90%, an average size of 90-110 nm with a symmetrical monodisperse distribution and a zeta potential of -18 mV. Additionally, in vitro release tests showed that approximately 70% of the drug was released from PPP-NPs into PBS (pH 7.4) containing 0.2% Tween 80 at 37 degrees C for 96 h, and the drug release data fit well to the Higuchi equation. Furthermore, an in vitro tumor cell growth inhibition assay showed that the IC50 values of the PPP solution and PPP-NPs against SMMC7721 liver cancer cell lines were 0.4 microg/ml and 0.2 microg/ml respectively, which indicated that the cytotoxicity of PPP-NPs against tumor cells was greater than that of the PPP solution. In conclusion, S-PCL-PEG micelle-like nanoparticles loaded with PPP have a promising future for administration by injection.


Subject(s)
Micelles , Nanoparticles/chemistry , Podophyllotoxin/analogs & derivatives , Polyesters/chemistry , Polyethylene Glycols/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Humans , Particle Size , Podophyllotoxin/chemistry , Podophyllotoxin/pharmacokinetics , Podophyllotoxin/pharmacology
12.
J Pharm Biomed Anal ; 88: 410-5, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24176745

ABSTRACT

A rapid and sensitive liquid chromatography/tandem mass spectrometry method was developed and validated for the quantification of deoxypodophyllotoxin (DPT) concentration in rat plasma with diazepam as internal standard (IS). DPT and IS were extracted with ethyl acetate, and the chromatographic separation was accomplished by using a Waters Symmetry C18 analytical column (2.1mm×150mm, 5µm) with a mobile phase consisting of acetonitrile and deionized water (70:30, v:v) containing 0.1% formic acid at a flow rate of 0.2mL/min. Multiple Reaction Monitoring (MRM), using electrospray ionization in positive ion mode, was employed to quantitatively detect DPT and IS. The monitored transitions were set at m/z 399.05-231.00 and m/z 285.00-154.00 for DPT and IS, respectively. The calibration curve was linear over the concentration range of 7.8-1000ng/mL (R(2)≥0.9999). The intra- and inter-day precision values were less than 7%. Similarly, the mean intra- and inter-day accuracy were found to be within -2.8% to 1.9% of the interval, with all samples locating within general assay acceptability criteria for QC samples according to FDA guidelines. This method was further and successfully applied in the pharmacokinetics study of DPT in rat.


Subject(s)
Podophyllotoxin/analogs & derivatives , Animals , Area Under Curve , Calibration , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Chromatography, Liquid , Drugs, Chinese Herbal , Female , Male , Plant Extracts/chemistry , Plants, Medicinal/chemistry , Podophyllotoxin/blood , Podophyllotoxin/pharmacokinetics , Rats , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry
13.
Biol Trace Elem Res ; 147(1-3): 408-17, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22351100

ABSTRACT

Bulk fabrication of ordered hollow structural particles (HSPs) with large surface area and high biocompatibility simultaneously is critical for the practical application of HSPs in biosensing and drug delivery. In this article, we describe a smart approach for batch synthesis of calcium carbonate nanotubes (CCNTs) based on supported liquid membrane (SLM) with large surface area, excellent structural stability, prominent biocompatibility, and acid degradability. The products were characterized by transmission electron micrograph, X-ray diffraction, Fourier transform infrared spectra, UV-vis spectroscopy, zeta potential, and particle size distribution. The results showed that the tube-like structure facilitated podophyllotoxin (PPT) diffusion into the cavity of hollow structure, and the drug loading and encapsulation efficiency of CCNTs for PPT are as high as 38.5 and 64.4 wt.%, respectively. In vitro drug release study showed that PPT was released from the CCNTs in a pH-controlled and time-dependent manner. The treatment of HEK 293T and SGC 7901 cells demonstrated that PPT-loaded CCNTs were less toxic to normal cells and more effective in antitumor potency compared with free drugs. In addition, PPT-loaded CCNTs also enhanced the apoptotic process on tumor cells compared with the free drugs. This study not only provides a new kind of biocompatible and pH-sensitive nanomaterial as the feasible drug container and carrier but more importantly establishes a facile approach to synthesize novel hollow structural particles on a large scale based on SLM technology.


Subject(s)
Antineoplastic Agents/administration & dosage , Calcium Carbonate/chemistry , Drug Delivery Systems/methods , Nanotubes/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Calcium Carbonate/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Diffusion/drug effects , Dose-Response Relationship, Drug , Flow Cytometry , HEK293 Cells , Humans , Hydrogen-Ion Concentration , Microscopy, Electron, Transmission , Nanotubes/ultrastructure , Particle Size , Podophyllotoxin/administration & dosage , Podophyllotoxin/pharmacokinetics , Spectrophotometry , Spectroscopy, Fourier Transform Infrared , Time Factors , X-Ray Diffraction
14.
J Chromatogr B Analyt Technol Biomed Life Sci ; 879(5-6): 326-34, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21251888

ABSTRACT

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of the new anticancer agent picropodophyllin (AXL1717) and its isomer podophyllotoxin levels in human serum has been developed. Monitoring of hexylamine adducts rather than proton adducts was used to optimize sensitivity. The chromatography system was an Acquity BEH C18, 2.1 mm × 50 mm 1.7 µm column with gradient elution (mobile phase A: 2.5 mM hexylamine and 5 mM formic acid in Milli-Q water and mobile phase B: methanol). The retention times were 1.4 min for picropodophyllin, 1.5 min for podophyllotoxin and 1.9 min for internal standard deoxypodophyllotoxin. The isomers were base-line separated. The analytes were detected after electrospray ionization in positive mode with selected reaction monitoring (SRM) with ion transitions m/z 516→102 for picropodophyllin and podophyllotoxin and m/z 500→102 for internal standard. The sample preparation was protein precipitation with acetonitrile (1:3) containing internal standard followed by dilution of the supernatant with mobile phase A (1:1). The limit of quantification (LOQ) was 0.01 µmol/L for picropodophyllin and podophyllotoxin. The limit of detection (LOD) at 3 times the signal to noise (S/N) was estimated below 0.001 µmol/L for picropodophyllin and podophyllotoxin. The quantification range of the method was between 0.01 µmol/L and 5 µmol/L for both isomers. The accuracy was within ±15% of the theoretical value for both picropodophyllin and podophyllotoxin and inter-assay precision did not exceed ±15%, except for the 0.016 µmol/L level of podophyllotoxin, which was 18%. The selectivity of the method was verified by analysis of two different product ions for each analyte and by analysis for interference of seven different batches of blank human serum. The combined recovery and matrix effects were about 83% for picropodophyllin and podophyllotoxin. The new LC-MS/MS method showed sufficient sensitivity and selectivity for determination of picropodophyllin and its isomer podophyllotoxin levels in human serum from subjects receiving therapeutic doses of AXL1717.


Subject(s)
Amines/chemistry , Chromatography, Liquid/methods , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/blood , Spectrometry, Mass, Electrospray Ionization/methods , Adult , Aged, 80 and over , Animals , Drug Stability , Drugs, Chinese Herbal , Female , Humans , Least-Squares Analysis , Male , Mice , Podophyllotoxin/analysis , Podophyllotoxin/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Swine , Tandem Mass Spectrometry
15.
Nan Fang Yi Ke Da Xue Xue Bao ; 30(6): 1256-9, 1267, 2010 Jun.
Article in Chinese | MEDLINE | ID: mdl-20584651

ABSTRACT

OBJECTIVE: To develop and validate a sensitive method for quantitative analysis of podophyllotoxin in blood and dermal microdialysis samples of rats based on liquid chromatography-tandem mass spectrometry (UFLC-MS-MS). METHODS: The microdialysis samples were prepared by liquid-liquid extraction using ethyl acetate with etoposide as the internal standard (IS). Podophyllotoxin was separated with an Agilent ZORBAX XDB-C18 column (2.1 mmx50 mm, 3.5 microm). The mobile phase consisted of acetonitrile: 10 mmol/L ammonium acetate (40:60, V/V) at a flow rate of 0.3 ml/min and the analysis was performed at the ambient temperature. The UFLC-MS/MS system was operated in the mode of multiple reaction monitoring using the electrospray ionization technique in positive mode. RESULTS: Podophyllotoxin and etoposide responses were optimized at the transitions m/z 432.7-->397.3 and 589.5-->229.5, respectively. Calibration curves were linear over the range 2.0-1000 ng/ml. The lowest limits of quantification and detection values were 2.0 ng/ml and 0.7 ng/ml, respectively. The inter- and intra-day precision and accuracy were both less than 15%. CONCLUSION: This selective and sensitive method can be used to quantity podophyllotoxin in the blood and dermal microdialysates of rats.


Subject(s)
Microdialysis/methods , Podophyllotoxin/blood , Podophyllotoxin/pharmacokinetics , Skin/metabolism , Tandem Mass Spectrometry/methods , Animals , Chromatography, Liquid/methods , Rats , Sensitivity and Specificity
16.
Zhonghua Zhong Liu Za Zhi ; 32(2): 103-6, 2010 Feb.
Article in Chinese | MEDLINE | ID: mdl-20403239

ABSTRACT

OBJECTIVE: The objective of this study was to compare the biodistribution and PET imaging of (11)C-PDT and (18)F-FDG in a mouse model of lung adenocarcinoma, and to evaluate the value of (11)C-PDT as a new tracer for PET imaging of lung cancer. METHODS: Twenty four lung adenocarcinoma-bearing mice were randomly divided into two groups, 12 each. The mice received (11)C-PDT or (18)F-FDG injection i.v. respectively. The biodistribution of (11)C-PDT or (18)F-FDG in the mice was measured with a well-gamma detector at 60 min after injection. The PET imagings of mice were performed using either of the two tracers. RESULTS: Considerable uptake of the both radioactive tracers in the tumors was observed. The tumor uptake of (11)C-PDT [(0.65 +/- 0.20)%ID/g] was significantly lower than that of (18)F-FDG [(7.44 +/- 1.56)%ID/g, P < 0.01]. In the (11)C-PDT group, the highest uptake was observed in the liver, kidney and blood in a successively declining order, while the highest uptake of (18)F-FDG was seen in a order of heart, tumor and kidneys. The tumor/muscle ratio of (11)C-PDT uptake was relatively high (2.02 +/- 0.56), but still lower than that of (18)F-FDG (2.95 +/- 0.49, P < 0.01). All values of other tumor/organ ratios (T/NT) of (11)C-PDT uptake were < 2. High radioactive uptake was showed in the tumor and abdominal organs on PET images in the tumor-bearing mice injected with (11)C-PDT, and (18)F-FDG uptake was showed in the heart, tumor and abdominal organs. The tumor PET images with (11)C-PDT and (18)F-FDG were all clear. CONCLUSION: The uptake of (11)C-PDT in lung cancer is higher than that in muscle tissues, and pulmonary cancers can be detected by PET imaging. (11)C-PDT may be a promising PET tracer for lung cancers.


Subject(s)
Adenocarcinoma/metabolism , Carbon Radioisotopes/pharmacokinetics , Fluorodeoxyglucose F18/pharmacokinetics , Lung Neoplasms/metabolism , Podophyllotoxin/pharmacokinetics , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/pathology , Animals , Cell Line, Tumor , Kidney/diagnostic imaging , Kidney/metabolism , Liver/diagnostic imaging , Liver/metabolism , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Mice , Myocardium/metabolism , Positron-Emission Tomography , Tissue Distribution
17.
Int J Pharm ; 388(1-2): 223-30, 2010 Mar 30.
Article in English | MEDLINE | ID: mdl-20045452

ABSTRACT

In this research, we intercalated anti-tumor drug podophyllotoxin (PPT) into layered double hydroxides (LDHs) and investigated the in vitro cytotoxicity to tumor cells, the cellular uptake and in vivo anti-tumor inhibition of PPT-LDH. The nanohybrids were prepared by a two-step method with the size of 80-90nm and the zeta potential of 20.3mV. The in vitro cytotoxicity experiment indicated that PPT-LDH nanoparticles show better anti-tumor efficacy than PPT and are more readily taken up by Hela cells. PPT-LDH shows a long-term suppression effect on the tumor growth, and enhances the apoptotic process of tumor cells. The in vivo tests reveal that delivery of PPT via LDH nanoparticles is more efficient, but the mice toxicity of PPT in PPT-LDH hybrids is reduced in comparison with PPT alone. Pharmacokinetics study displays a prolonged circulation time and an increased bioavailability of PPT-LDH than PPT. These observations imply that LDH nanoparticles are the potential carrier of anti-tumor drugs in a range of new therapeutic applications.


Subject(s)
Antineoplastic Agents/pharmacology , Hydroxides/chemistry , Neoplasms, Experimental/drug therapy , Podophyllotoxin/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Biological Availability , Chemistry, Pharmaceutical/methods , Female , HeLa Cells , Humans , Mice , Mice, Nude , Nanoparticles , Neoplasm Transplantation , Podophyllotoxin/administration & dosage , Podophyllotoxin/pharmacokinetics , Time Factors
18.
Leuk Res ; 34(10): 1383-9, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20096930

ABSTRACT

The polyamine transport system (PTS), hyperactive in cancer cells, can constitute a gate to deliver F14512, a novel spermine epipodophyllotoxin conjugate recently selected for clinical development in AML phase I. We investigated in vitro the high antiproliferative effect of F14512 against 13 leukemia cell lines, and demonstrated a statistically significant correlation with the level of PTS activity, using a novel fluorescent marker F96982. This labelling protocol was then adapted for clinical applications for blood, bone marrow and AML samples with CD45 gating. Within the patient samples, the PTS activity varied significantly in AML cells, as compared to normal lymphocytes. In conclusion, the identification of PTS-positive AML with F98982 probe offers new perspectives to select patients prone to respond to F14512.


Subject(s)
Biogenic Polyamines/metabolism , Fluorescent Dyes/metabolism , Leukemia, Myeloid, Acute/drug therapy , Oxadiazoles/metabolism , Podophyllotoxin/analogs & derivatives , Spermine/analogs & derivatives , Animals , Antigens, CD34/analysis , Biological Transport , CHO Cells , Cell Line, Tumor , Cricetinae , Cricetulus , Flow Cytometry , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Podophyllotoxin/pharmacokinetics , Podophyllotoxin/therapeutic use , Spermine/metabolism
19.
J Mater Sci Mater Med ; 19(3): 1197-202, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17701296

ABSTRACT

The aim of this study was to construct PPT-LDH nanohybrids and compare their tumor inhibition effects with that of free PPT. Anticancer drug podophyllotoxin (PPT) was encapsulated in the galleries of Mg-Al layered double hydroxides (LDHs) by a two-step approach. Tyrosine (Tyr) was first incorporated into the interlayer space by co-precipitation with LDH, prop-opening the layers of Mg-Al/LDH and creating an interlayer environment inviting drug molecules. PPT was subsequently intercalated into the resulting material lamella by an ion exchange process. The intermediate and final products, which can be termed drug-inorganic nanocomposites, have been characterized by powder X-ray diffraction (XRD), UV-VIS spectrophotometer, transmission electron microscopy (TEM) and in cell culture. Our results demonstrate that the interlayer spacing distance of the PPT-LDH nanohybrids (34% w/w of drug/material) is 18.2 A. LDHs do not harm normal cells (293T) based on toxicity tests. Ex-vivo anticancer experiments reveal that the PPT-LDH nanohybrids have higher tumor suppression effects than intercalated PPT. We conclude that the higher tumor inhibition effects of PPT-LDH hybrids result from the inorganic drug delivery vehicle, LDHs.


Subject(s)
Hydroxides/chemistry , Pharmaceutical Vehicles/chemical synthesis , Podophyllotoxin/administration & dosage , Antineoplastic Agents/administration & dosage , Cell Proliferation/drug effects , Cells, Cultured , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Humans , Nanostructures/chemistry , Pharmaceutical Vehicles/chemistry , Podophyllotoxin/pharmacokinetics , Treatment Outcome
20.
Rapid Commun Mass Spectrom ; 22(1): 52-8, 2008.
Article in English | MEDLINE | ID: mdl-18050240

ABSTRACT

The in vitro metabolism of deoxypodophyllotoxin (DPT), a medicinal herbal product isolated from Anthriscus sylvestris (Apiaceae), was investigated in rats and human microsomes and human recombinant cDNA-expressed CYPs. The incubation of DPT with pooled human microsomes in the presence of NADPH generated five metabolites while its incubation with dexamethasone (Dex)-induced rat liver resulted in seven metabolites (M1-M7) with major metabolic reactions including mono-hydroxylation, O-demethylation and demethylenation. Reasonable structures of the seven metabolites of DPT could be proposed, based on the electrospray tandem mass spectra. Chemical inhibition by ketoconazole and metabolism studies with human recombinant cDNA-expressed CYPs indicated that CYP 3A4 and 2C19 are the major CYP isozymes in the metabolism of DPT in human liver microsomes.


Subject(s)
Insecticides/analysis , Microsomes, Liver/chemistry , Podophyllotoxin/analogs & derivatives , Animals , Biotransformation , Chromatography, High Pressure Liquid , Cytochromes/analysis , Cytochromes/antagonists & inhibitors , Cytochromes/metabolism , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Drugs, Chinese Herbal , Enzyme Inhibitors/pharmacology , Humans , In Vitro Techniques , Insecticides/pharmacokinetics , Isoenzymes/analysis , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Male , Microsomes, Liver/metabolism , Podophyllotoxin/analysis , Podophyllotoxin/pharmacokinetics , Protons , Rats , Rats, Sprague-Dawley , Recombinant Proteins/metabolism , Tandem Mass Spectrometry
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