Adipotide isn't something your body makes - it's a manufactured drug built from two pieces stitched together: a targeting piece that finds blood vessels feeding white body fat, and a second piece that kills the cells it attaches to. The idea is simple: cut off the blood supply to fat tissue and the fat shrinks. It made headlines in 2011 after a study showed dramatic weight loss in obese monkeys, but no drug company has taken it into human trials, largely because the same animal studies showed signs of kidney stress. Products sold online under the name 'Adipotide' today are unregulated research chemicals with no human safety or dosing data behind them.
How strong is the evidence?
The real evidence on Adipotide is thin: one solid study in obese monkeys, one comparison study in obese mice, and a published scientific critique questioning why it worked at all. There are no human trials and none have ever been registered. Most of the 19 papers pulled for this compound are false matches - 'FTPP' is also the abbreviation for an unrelated heart-imaging tracer and shows up in completely unrelated chemistry and medical-policy papers. Once those are set aside, this is a preclinical, animal-only research compound.
Uses
What people use it for
Experimental obesity research (animals only)
Animal / labAdipotide has been tested as a possible obesity treatment in obese monkeys and obese mice. It has never been approved, and no human trials have been conducted or registered.
Research into targeting fat's blood supply
Animal / labScientists use Adipotide as a proof-of-concept tool to study whether destroying the blood vessels that feed fat tissue can treat obesity and the metabolic problems that come with it, like insulin resistance.
Potential benefits
What it may help with
Rapid weight loss in obese monkeys
Animal / labIn the key 2011 study, obese monkeys treated with Adipotide lost weight quickly. Scans (MRI and DEXA) confirmed a real drop in white body fat, not just water weight.
Studies:22072637Better insulin resistance
Animal / labThe same monkey study found improved insulin resistance after treatment, meaning the animals' bodies got better at managing blood sugar as they lost fat.
Studies:22072637Less fat buildup in the liver and muscle (in mice)
Animal / labIn obese mice, this general approach reduced fat that had spilled over into the liver and muscle, alongside lower leptin and higher adiponectin, two hormones tied to fat storage and metabolism. Notably, in this study a nanoparticle-packaged version outperformed plain Adipotide at the low dose tested, so this benefit is best credited to the overall targeting strategy rather than to Adipotide alone.
Studies:23871959
What to watch for
Side effects & risks
- Moderate
Kidney changes
At the doses researchers settled on as optimal, the monkey study reported predictable, reversible changes in kidney function (specifically in the small tubes of the kidney that reabsorb nutrients). This happened across three different monkey species and is the main reason this compound has stayed out of human testing.
Dosing
Dosing — what studies used
There is no established human dose for Adipotide - it has never been given to a person in a published study. The animal research that exists doesn't report exact dose numbers either: the monkey study describes using a dose-finding process to land on an 'experimentally determined optimal dose' for each species, without stating the actual amount in the abstract, and the mouse study only describes a 'low dose' without a number. Anyone using an 'Adipotide' product today is working with zero real dosing guidance.
Obese Old World monkeys (3 species) - the primary Adipotide study
Animal studyNot stated in the published abstract; researchers used a dose-escalation process to find each species' own 'optimal' dose
Not specified in the abstract · Not specified in the abstract · Not specified in the abstract
This is the main study behind Adipotide's reputation. Kidney changes occurred at the doses researchers had settled on as optimal, and were reversible.
Diet-induced obese mice - comparison study
Animal studyDescribed only as a 'low dose'; no specific amount given in the abstract
Not specified in the abstract · Not specified in the abstract · Systemic injection
This study mainly compared plain Adipotide against a nanoparticle-packaged version of the same targeting peptide; the nanoparticle version performed better at the low dose tested.
No dosing regimen has ever been tested in humans. Treat any dosing figures found outside the studies above (forums, vendor sites) as unverified guesses, not science.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Adipotide is built from two pieces glued together. The first piece is a homing device: it seeks out and sticks to a protein called prohibitin, which sits on the surface of blood vessels that feed white body fat. The second piece is a 'kill switch' peptide that triggers the cells it touches to self-destruct. Together, the idea is that Adipotide rides its homing piece straight to the blood vessels feeding fat tissue, then destroys those vessels. Without a blood supply, the fat tissue is starved and shrinks. That said, this exact explanation has been publicly challenged: one published critique argued the weight loss seen in the monkey study could instead be explained by the animals simply eating less after treatment, rather than by fat tissue losing its blood supply. So the real reason Adipotide works is still debated among scientists.
Who should avoid it
- No one should use Adipotide outside of a supervised research setting - it has no human safety data at all
- Especially risky for anyone with existing kidney disease, given the kidney changes seen in animal studies
- Not appropriate during pregnancy or breastfeeding - never studied in this context
- Not a substitute for approved weight-loss treatments, which have actual human safety and dosing data behind them
Interactions to know
- No drug interaction data exists - Adipotide has never been tested in humans, alone or alongside other medications.
The papers that matter most
Key studies
The foundational Adipotide study: obese monkeys lost weight and had improved insulin resistance, but developed reversible kidney changes at the optimal doses tested - the finding that has kept this compound out of human trials.
A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys
In obese mice, a nanoparticle-packaged version of the same targeting strategy reduced weight, liver/muscle fat, and leptin more effectively than plain Adipotide at a low dose, suggesting delivery method matters a lot.
A comparative study between nanoparticle-targeted therapeutics and bioconjugates as obesity medication
A published critique arguing the monkey study's weight loss might be explained by reduced food intake rather than by Adipotide destroying the blood vessels of fat tissue - a genuine open question about how (or whether) the drug works as advertised.
Comment on 'a peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys'
Bottom line
Adipotide has real, dramatic-looking results in monkeys and mice, but it also caused kidney changes in those same animals and has never been given to a single human being in a published study. There's even open scientific debate about whether it works the way its makers claim. Until human trials exist, treat it as an unproven research chemical, not a weight-loss option.
Research papers
Studies we have on file for Adipotide. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
19 papers
PET imaging of mitochondrial function in acute doxorubicin-induced cardiotoxicity: a proof-of-principle study.
Mitochondrial dysfunction plays a key role in doxorubicin-induced cardiotoxicity (DIC). In this proof-of-principle study, we investigated whether PET mapping of cardiac membrane potential, an indicator of mitochondrial function, could detect an acute cardiotoxic effect of doxorubicin (DOX) in a large animal model. Eight Yucatan pigs were imaged dynamically with [18F](4-Fluorophenyl)triphenylphosphonium ([18F]FTPP+) PET/CT. Our experimental protocol included a control saline infusion into the left anterior descending coronary artery (LAD) followed by a DOX test infusion of either 1 mg/kg or 2 mg/kg during PET. We measured the change in total cardiac membrane potential (ΔΨT), a proxy for the mitochondrial membrane potential, ΔΨm, after the saline and DOX infusions. We observed a partial depolarization of the mitochondria following the DOX infusions, which occurred only in myocardial areas distal to the intracoronary catheter, thereby demonstrating a direct association between the exposure of the mitochondria to DOX and a change in ΔΨT. Furthermore, doubling the DOX dose caused a more severe depolarization of myocardium in the LAD territory distal to the infusion catheter. In conclusion, [18F]FTPP+ PET-based ΔΨT mapping can measure partial depolarization of myocardial mitochondria following intracoronary DOX infusion in a large animal model.
A comparative study between nanoparticle-targeted therapeutics and bioconjugates as obesity medication.
Antiangiogenesis has been the focus of a new strategy for the treatment of obesity. However, little is known regarding the issue of whether targeting angiogenesis by nanoparticle-targeted therapeutic is advantageous or not in debugging the co-morbidity associated with diet-induced obesity (DIO) and the metabolic syndrome. We report herein on the positive effect of prohibitin (an adipose vascular marker)-targeted nanoparticle (PTNP) encapsulated in a proapoptotic peptide [(D)(KLAKLAK)₂, KLA] on DIO and dysfunctional adipose tissue, a major mediator of the metabolic syndrome, as evidenced by ectopic fat deposition. The systemic injection of DIO mice with a low dose of KLA-PTNP, rather than a bioconjugate composed of the same targeting peptide and KLA (Adipotide) resulted in a reduction in body weight, as evidenced by a significant decrease in serum leptin levels, in parallel with an antiobesity effect on dysfunctional adipose cells, including adipocytes and macrophages. In addition, the KLA-PTNP treatment resulted in a reduction in ectopic fat deposits in liver and muscle with the lipolytic action of elevated serum adiponectin, with no detectable hepatoxicity. Notably, drug delivery via PTNP that had accumulated in obese fat via the enhanced permeability and retention effect was enhanced by multivalent active targeting and cytoplasmic delivery into adipose endothelial cells via escaping from endosomes/lysosomes. Thus, vascular-targeted nanotherapy has the potential to contribute to the control of adipose function and ectopic fat deposition associated with obesity and the metabolic syndrome.
Fatty Liver/Adipose Tissue Dual-Targeting Nanoparticles with Heme Oxygenase-1 Inducer for Amelioration of Obesity, Obesity-Induced Type 2 Diabetes, and Steatohepatitis.
Persistent uptake of high-calorie diets induces the storage of excessive lipid in visceral adipose tissue. Lipids secreted from obese adipose tissue are accumulated in peripheral tissues such as the liver, pancreas, and muscle, and impair insulin sensitivity causing type 2 diabetes mellitus (T2DM). Furthermore, the accumulation of inflammatory cytokines and lipids in the liver induces apoptosis and fibrogenesis, and ultimately causes nonalcoholic steatohepatitis (NASH). To modulate obese tissue environments, it is challenged to selectively deliver inducers of heme oxygenase-1 (HO-1) to adipose tissue with the aid of a prohibitin targeting drug delivery system. Prohibitin binding peptide (PBP), an oligopeptide targeting prohibitin rich in adipose tissue, is conjugated on the surface of Hemin- or CoPP-loaded poly(lactide-co-glycolide) nanoparticles (PBP-NPs). PBP-NPs efficiently differentiate lipid storing white adipocytes into energy-generating brown adipocytes in T2DM and NASH models. In addition, PBP-NPs are found to target prohibitin overexpressed fatty liver in the NASH model and inhibit hepatic uptake of circulating lipids. Furthermore, PBP-NPs switch phenotypes of inflammatory macrophages in damaged organs and lower inflammation. Taken together, dual-targeted induction of HO-1 in fatty adipose and liver tissues is proven to be a promising therapeutic strategy to ameliorate obesity, insulin resistance, and steatohepatitis by lowering lipids and cytokines.
A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys.
Obesity, defined as body mass index greater than 30, is a leading cause of morbidity and mortality and a financial burden worldwide. Despite significant efforts in the past decade, very few drugs have been successfully developed for the treatment of obese patients. Biological differences between rodents and primates are a major hurdle for translation of anti-obesity strategies either discovered or developed in rodents into effective human therapeutics. Here, we evaluate the ligand-directed peptidomimetic CKGGRAKDC-GG-(D)(KLAKLAK)(2) (henceforth termed adipotide) in obese Old World monkeys. Treatment with adipotide induced targeted apoptosis within blood vessels of white adipose tissue and resulted in rapid weight loss and improved insulin resistance in obese monkeys. Magnetic resonance imaging and dual-energy x-ray absorptiometry confirmed a marked reduction in white adipose tissue. At experimentally determined optimal doses, monkeys from three different species displayed predictable and reversible changes in renal proximal tubule function. Together, these data in primates establish adipotide as a prototype in a new class of candidate drugs that may be useful for treating obesity in humans.
Fluorinated High-Valent Sn(IV) Porphyrins Show Remarkable Photodynamic Activity in Cancer Cells.
In recent years, Sn(IV) porphyrins have proven to be excellent choice as photosensitizers for photodynamic therapy. This work reports the synthesis, characterization and photodynamic activity of four high-valent fluorinated Sn(IV) porphyrins having different numbers of F-atoms in the peripheral of meso-phenyl groups viz. (Dichloro)meso-tetrakis(4-fluorophenylporphyrinato)stannic(IV), [Sn(IV)FTPP(Cl)2] or Sn1; (Dichloro)meso-tetrakis(2,4-difluorophenylporphyrinato)stannic(IV), [Sn(IV)2,4-FTPP(Cl)2] or Sn2; (Dichloro)meso-tetrakis(2,6-difluorophenylporphyrinato)stannic(IV), [Sn(IV)2,6-FTPP(Cl)2] or Sn3 and (Dichloro)meso-tetrakis(4-trifluoromethylphenylporphyrinato)stannic(IV), [Sn(IV)CF3TPP(Cl)2] or Sn4. The solid-state structure of Sn1 has been determined by single crystal X-ray diffraction analysis. The increasing number of F-atoms attached to the meso-phenyl positions of the porphyrin framework results in increase of their lipophilicity, singlet oxygen quantum yield (ΦΔ) and photocytotoxicity in A549 (human lung adenocarcinoma cells), MCF-7 and MDA-MB-231 (human breast adenocarcinoma) cells. Sn4 predominantly localize in the mitochondria of A549 cells. The light-induced cell death by the Sn(IV) porphyrins in A549 cells occur primarily via apoptosis.
Reversible On-Off Switching of Excitation-Wavelength-Dependent Emission of a Phosphorescent Soft Salt Based on Platinum(II) Complexes.
Excitation-wavelength-dependent (Ex-De) emission materials show excellent potential in diverse advanced photonic areas. Of significant importance is the on-demand regulation of the Ex-De luminescence behavior of these materials, which is previously unprecedented. In this study, we report on a platinum(II) complex-based phosphorescent soft salt S1 ([Pt(tpp)(ed)]+[Pt(ftpp)(CN)2]- (where ttp = 2-(4-(trifluoromethyl)phenyl)pyridine, ed = ethane-1,2-diamine, and ftpp = 2-(4-fluoro-3-(trifluoromethyl)phenyl)pyridine)) with Ex-De photoluminescence (PL) property. UV-visible absorption and PL spectra of S1 were recorded in DMSO-H2O mixture (1 × 10-3 M) with various H2O fractions to investigate its ground and excited states. Interestingly, the PL spectra of S1 powder show that its maximum emission peak is red-shifted from 595 to 644 nm upon excitation at different wavelengths from 360 to 520 nm, accompanied by an obvious emission color change from yellow-orange to red. Furthermore, confocal laser scanning fluorescence microscopy was employed to determine the PL property of self-assembled uniform S1 nanostructure, and the result shows that the Ex-De emission behavior is absent. On the basis of these results, we conclude the various Pt(II)···Pt(II) distances that exist are the major factor responsible for the properties of the Ex-De PL of S1 powder. Thus, for the first time, reversible on-off switching of Ex-De PL of S1 was achieved by manipulating its Pt(II)···Pt(II) distances through mechanical stress and vapor fuming. Finally, we demonstrate the high-level anticounterfeiting applications via on-demand multicolor displays.
Evaluation of (4-[18F]Fluorophenyl)triphenylphosphonium ion. A potential myocardial blood flow agent for PET.
The lipophilic cationic compound, (4-[¹⁸F]fluorophenyl)triphenylphosphonium ion (¹⁸F-FTPP) was synthesized and evaluated as a potential positron emission tomography (PET) myocardial perfusion agent. ¹⁸F-FTPP was prepared from (4-nitrophenyl)triphenylphosphonium nitrate and ammonium [¹⁸F]fluoride by nucleophilic aromatic substitution and was purified by high performance liquid chromatography before use. Biodistribution studies were performed in rats at 5, 30, 60 min (five rats per time point). Three rats were evaluated by microPET imaging after injection of ¹⁸F-FTPP. In addition, microPET imaging in rabbits (three) was performed before and after occlusion of the left anterior descending (LAD) artery with ¹³NH₃ (111 MBq) and ¹⁸F-FTPP (74 MBq). Biodistribution data in rats showed rapid blood clearance and high levels of accumulation in the heart; 75:1 heart-to-blood ratio at 30 min. Uptake of radioactivity in the heart was 1.64% ID/G, 1.51% ID/g, and 1.57% ID/g at 5, 30, and 60 min. At 5, 30, and 60 min, lung activity was 0.69% ID/g, 0.03% ID/g, and 0.38% ID/g, and liver uptake was 0.34% ID/g, 0.18% ID/g, and 0.17% ID/g. Heart-to-lung ratios at 5, 30, and 60 min were 2, 5, and 4. Bone accumulation was minimal. MicroPET imaging in both rats and rabbits after injection of ¹⁸F-FTPP demonstrated an initial spike of activity in the myocardium corresponding to blood flow followed by a plateau after 1 min. Region of interest analysis of microPET images of normal and LAD-occluded rabbits with ¹³NH₃ and ¹⁸F-FTPP indicated similar distributions of the two tracers in both normal and altered blood flow regions. The excellent heart-to-blood ratio of ¹⁸F-FTPP and its correlation with ¹³NH₃ distribution in normal and LAD-occluded rabbits suggest that this radiopharmaceutical may have potential as a PET agent for characterizing mitochondrial damage and/or myocardial blood flow.
Fitness-to-practise policies in Australian medical schools--are they fit for purpose?
To describe current use and possible effects of Australian medical school fitness-to-practise policies (FTPPs), and to define and benchmark FTPP best practice. A questionnaire-based study of Australian medical schools was conducted in August 2009. Use of FTPPs by medical schools; criteria used in FTPPs; remediation processes; numbers of students excluded for professional misconduct, reasons for exclusion, and year of study at time of exclusion. The questionnaire was completed by 15 of 19 medical schools to which it was sent, and 12 schools reported using an FTPP. There was wide variation in the FTPP criteria used by individual schools, and use of an FTPP appeared to be independent of medical student registration with state medical boards and type of course entry. There were no apparent differences in medical student exclusion rates between schools with FTPPs and those without. The most common reason for exclusion was persistent inappropriate attitude or behaviour, including poor attendance, and most exclusions occurred by the third year of study. Most Australian medical schools use FTPPs, but these policies are variable and lack proven effectiveness. The variations in the numbers of students excluded by the different medical schools for unprofessional behaviour suggest discrepancies in the medical schools' abilities to detect and manage students with problems in this area. Previous calls to develop a nationally consistent approach to the management of poorly behaving students should be addressed.
Saturation-Tolerant Prescribed Control for Nonlinear Systems With Unknown Control Directions and External Disturbances.
In this article, saturation-tolerant prescribed control (SPC) is investigated for a class of multiinput-multioutput (MIMO) nonlinear systems. The key challenge lies in how to guarantee both input and performance constraints simultaneously for nonlinear systems especially under external disturbance and unknown control directions. We propose concise finite-time tunnel prescribed performance (FTPP) for better tracking performance, which features tight allowable set and user-specified settling time. To comprehensively tackle the conflict between the above two constraints, an auxiliary system is designed to explore their interconnections instead of neglecting their contradictions. By introducing its generated signals into FTPP, the obtained saturation-tolerant prescribed performance (SPP) has the ability to degrade or recover the performance boundaries in the light of different saturation conditions. Consequently, the developed SPC, together with nonlinear disturbance observer (NDO), can effectively improve the robustness and reduce the conservatism against external disturbances, input, and performance constraints. Finally, comparative simulations are presented to showcase these theoretical findings.
Prohibitin: targeting peptide coupled to ovarian cancer, luteinization and TGF-β pathways.
Ovarian epithelial tumor (OET) is a silent disease of late diagnosis and poor prognosis. Currently treatment options are limited and patient response to treatment is difficult to predict so there is a serious need to delineate the real pathogenesis to predict tumour prognosis. Prohibitin (PHB) is an evolutionarily protein that regulates the cell cycle. TGF-β has been shown to be a positive and negative regulator of cellular proliferation and differentiation. The present study provides an overview on the role played by PHB1, TGF-β and LH in ovarian cancer. The study was conducted on 60 patients with ovarian tumors (benign, borderline and malignant) and 20 healthy volunteers. LH and TGF-β serum levels were measured by ELISA. Expression of prohibitin and LHR-mRNA were assessed by IHC and TaqMan® real time gene expression assay, respectively. Serum levels of LH and TGF-β were significantly decreased among borderline and malignant groups. There was significant over-expression of LHRmRNA in malignant group. Prohibitin expression was significantly increased in malignant ovarian tissue. Strong negative correlations were found between LHR mRNA expression and serum LH levels, and between IHC score of prohibitin and serum levels of LH among patients with borderline ovarian tumors. Steady decline of LH and TGF-B serum levels, from benign cystadenoma to borderline tumor to carcinoma, suggests their inhibitory role against OET cell growth. Increased PHB1 expression in OET suggests its proliferative activity that can be regulated by luteinisation and/or TGF-β. Furthermore increased LHR mRNA tissue expression can provide hope for using LH in treatment of some types of ovarian cancers.
A novel "three-dimensional-printed individual guide template-assisted percutaneous vertebroplasty" for osteoporotic vertebral compression fracture: a prospective, controlled study.
Conventional percutaneous vertebroplasty (PVP) are mainly guided by C-arm fluoroscopy, and it usually leads to excessive X-ray radiation exposure to patients, surgeons, and anesthetists. Moreover, multi-time fluoroscope may prolong the operation time. 3D-printed template could help minimize fluoroscopy shot times and fluoroscopy dosage during operation, and shorten operation time. We perform this study to compare the efficacy and accuracy of PVP assisted by "three-dimensional printed individual guide template" versus conventional PVP. Patients who suffered acute painful single segment osteoporotic vertebral compression fracture(OVCF) needed operative treatment were randomly assigned into three-dimensional printing individual guide template-assisted percutaneous vertebroplasty group (group A) or conventional PVP guided by C-arm fluoroscopy group (group B) at a 1:1 ratio. Fluoroscopy times for puncture points (FTPP), total radiation dosages (TRD), total fluoroscopy time (TFT), and total operation time (TOT) were recorded as the main evaluation factors to evaluate the two operation procedures. A total of 36 acute painful single segment OVCF patients were successfully operated on, and each group has 18 patients. None of the patients presented symptomatic complications. The surgical success rate in group A was 94.4%(17/18), one patient in the group A was failed and then operated by conventional procedure. FTPP (1.8 ± 0.8 in group A vs 5.2 ± 1.9 in group B, P < 0.05), TRD (4.9 ± 0.9 mGy vs 7.9 ± 1.6 mGy, P < 0.05), TFT (16.7 ± 2.9 vs 26.6 ± 5.3, P < 0.05), and total operation time (19.4 ± 2.4 min vs 27.8 ± 4.0 min, P < 0.05) were presented statistically difference in the two groups. The incidence of cement leakage occurred in group A (3/18, 16.7%) was less than that occurred in group B (7/18, 38.9%) (P > 0.05). Compared with the conventional PVP, "three-dimensional-printed individual guide template-assisted PVP" could minimize fluoroscopy shot times during operation and fluoroscopy dosage, shorten operation time, and is a more precise and feasible operation method. The present study was registered with the Chinese Clinical Trial Registry (ChiCTR) ( http://www.chictr.org.cn ), and its registration no. is ChiCTR1900024283.
The effects on length of stay of introducing a fast track patient pathway for myocardial infarction: a before and after evaluation.
The aim was to assess whether the implementation of a fast-track patient pathway (FTPP) at an invasive treatment ward (ITW) could reduce the length of hospital stay (LOHS), among patients with non-ST Elevation Myocardial Infarction (NSTEMI). A before-and-after study was carried out, based on historical data from a total of 202 patients with NSTEMI admitted to a coronary ITW during two inclusion periods each lasting 100 days (Period I, 2004, no fast track, 95 consecutive patients; Period II, 2005, fast track implemented, 107 consecutive patients). Patients were followed during 180 days as concerns the total LOHS. A total of 33 patients passed through the FTPP. Their mean total LOHS was significantly shorter (3.3 days reduction; 95% CI 1.7, 5.5 days) as compared with all Period II patients. In total, Period II patients, however, spent significantly more days (mean, 1.7 days more; 95% CI 0.2, 3.3 days) in hospital than Period I patients. Thus, the implementation of FTPP reduced the mean LOHS for patients selected for the FTPP, but the mean LOHS for other patients rose and so the overall mean LOHS turned out to be significantly prolonged. The implementation of FTPP appears a complicated matter; changing one component has consequences for the wider health-care system.
Mn(III) porphyrins as photosensitizers: structural, photophysical and anticancer studies.
Herein, we synthesized, characterized and explored the photo-triggered anticancer activity of five Mn(III) porphyrins Mn1-Mn5, viz. (diaqua)meso-(tetraphenylporphyrinato)manganese(III) propionate, [Mn(III)TPP(H2O)2]+(C3H5O2-) or Mn1; (diaqua)meso-tetrakis(4-methylphenylporphyrinato)manganese(III) propionate, [Mn(III)TMeP(H2O)2]+(C3H5O2-) or Mn2; (diaqua)meso-tetrakis(4-methoxyphenylporphyrinato)manganese(III) propionate, [Mn(III)TMP(H2O)2]+(C3H5O2-) or Mn3; (diaqua)meso-tetrakis(4-fluorophenylporphyrinato)manganese(III) propionate, [Mn(III)FTPP(H2O)2]+(C3H5O2-) or Mn4 and (diaqua)meso-tetrakis(4-chlorophenylporphyrinato)manganese(III) propionate, [Mn(III)ClTPP(H2O)2]+(C3H5O2-) or Mn5, which remain virtually unexplored as photodynamic therapy (PDT) agents like other paramagnetic metalloporphyrins. These Mn(III) porphyrins, bearing different para-substituents on their meso-phenyl rings and two water molecules as axial ligands, were characterized using spectroscopic techniques and structurally through single-crystal X-ray diffraction, revealing an octahedral MnN4O2 geometry. Binding studies demonstrated a strong affinity of the metalloporphyrins for human serum albumin (HSA), indicating their potential for biological applications. The visible light-assisted generation of reactive oxygen species (ROS) by these Mn(III) porphyrins was confirmed via 1,3-diphenylisobenzofuran (DPBF) titration, identifying singlet oxygen (1O2) as one of the primary ROS. Photoredox activity under visible light, displayed by the Mn(III) porphyrins in the presence of ascorbic acid involving +3 and +2 oxidation states of manganese, further underscores the photochemotherapeutic potential of Mn1-Mn5. The ROS generation ability was further validated intracellularly in HeLa cells using Mn4 with the help of 2',7'-dichlorofluorescein diacetate (DCFDA) assay under visible light irradiation (λ = 400-700 nm). Furthermore, among the five Mn(III) porphyrin complexes (Mn1-Mn5) evaluated for photo-triggered anticancer activity using MTT assays, Mn4 exhibited superior photocytotoxicity, with a half-maximal inhibitory concentration (IC50) of 4.93 ± 0.7 μM against HeLa cancer cells under visible light irradiation and negligible dark toxicity (IC50 > 50 μM). These results suggest that both type-I and type-II ROS generation pathways contribute to the observed photocytotoxicity. This study highlights the potential of paramagnetic metalloporphyrins, particularly Mn(III) porphyrins, in anticancer application by demonstrating their effectiveness as photosensitizers for photodynamic cancer therapy.
A new strategy to screen molecular imaging probe uptake in cell culture without radiolabeling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Numerous new molecular targets for diseases are rapidly being identified and validated in the postgenomic era, urging scientists to explore novel techniques for accelerating molecular probe development. In this study, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was investigated as a potential tool for high-throughput screening and characterization of molecular imaging probes. Specifically, MALDI-TOF-MS was used to screen a small library of phosphonium cations for their ability to accumulate in cells. C6 cells incubated with phosphonium cations at room temperature were collected and lysed for experiments. Calibration curves for the internal standard, methyltriphenyl phosphonium, and for tetraphenylphosphonium bromide (TPP) and other phosphonium cations were first established. The time course of TPP uptake by C6 cells was then quantified using both MALDI-TOF-MS and liquid scintillation counting with (3)H-TPP. In addition, MALDI-TOF-MS was used to screen a library of 8 phosphonium cations and subsequently rank their ability to penetrate membranes and accumulate in cells. Finally, the accumulation of 4-fluorophenyltriphenyl phosphonium (FTPP) in the membrane potential-modulated cells was also measured by MALDI-TOF-MS. MALDI-TOF-MS spectra clearly revealed that TPP was easily identified from cell lysates even as early as 10 min after incubation and that levels as low as 0.11 fmol of TPP per cell could be detected, suggesting the high sensitivity of this technique. The time course of TPP influx determined by both MALDI-TOF-MS and radioactivity counting showed no statistically significant difference (P > 0.05 for all time points). These data validated MALDI-TOF-MS as an alternative approach for accurately measuring uptake of phosphonium cations by cells. TPP and FTPP demonstrated greater accumulation in cells than did the other cations evaluated in this study. Furthermore, uptake profiles suggested that FTPP preserves the membrane potential-dependent uptake property of TPP in cell cultures. Taken together, these data justify further synthesis and evaluation of (18)F-FTPP as a molecular probe for imaging mitochondrial dysfunction. These results demonstrate that MALDI-TOF-MS is a powerful analytic tool for rapid screening and characterization of phosphonium cations as molecular probes. This technique can potentially be applied to the evaluation of other imaging probes or drugs and thus may facilitate their rational design and development.
Comment on "a peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys".
A study reporting that a peptidomimetic adipotide reduces weight loss in obese monkeys by inducing apoptosis of blood vessels surrounding white adipose tissue may instead reflect a direct effect of adipotide on food consumption.
In vivo 3D myocardial membrane potential mapping in humans using PET/MRI.
The mitochondrial membrane potential is a key biophysical parameter of mitochondrial function, which can be useful for the diagnosis and treatment monitoring of various cardiac diseases. We present a non-invasive PET/MR imaging method for 3D myocardial membrane potential mapping in humans. An in vivo PET/MR imaging study was performed in three healthy subjects (1 male and 2 females; 48 ± 29 years old) under a study protocol approved by the local Institutional Review Board (IRB). Written informed consent was obtained from all subjects before participation in the study. The [18F](4-Fluorophenyl)triphenylphosphonium ([18F]-FTPP+) PET tracer was administered using a bolus-plus-infusion protocol (bolus activity of 301.2 ± 7.6 MBq, infusion activity of 90.0 ± 4.9 MBq), where an infusion of 120 min was started shortly after the bolus injection (time of infusion, TOI). Dynamic cardiac PET/MR imaging was performed approximately 20 min after the TOI and continued for 100 min. The extracellular volume fraction mapping was performed via cardiac MR with a free-breathing, 3D cardiac T1 mapping sequence before and after the contrast agent injection (gadoterate meglumine, 0.1 mmol/kg). A linear tangent space alignment (LTSA) model-based method was used to reconstruct high-frame-rate dynamic images from sparsely sampled (k,t)-space data for T1. PET motion correction was performed using two steps of rigid image registration in a multi-resolution fashion, followed by a non-rigid image registration with B-spline transform. The tissue membrane potential was calculated using a kinetic model based on the Nernst equation with myocardial tracer concentration, tracer volume of distribution, and extracellular volume fraction measurements. Fully 3D membrane potential maps were successfully estimated from all three subjects. The estimated whole-heart membrane potentials were - 144.7 ± 3.5 mV, - 160.7 ± 5.3 mV, and - 165.8 ± 3.1 mV for each subject. The proposed method allows 3D myocardial membrane potential mapping in humans in vivo.
Waypoints tracking for USVs employing fixed-time prescribed performance fuzzy inverse optimal control with marine experiment.
This paper presents a fixed-time control framework for underactuated Unmanned Surface Vehicles (USVs) to track waypoint trajectories under large initial position errors. A Fixed-Time Prescribed Performance (FTPP) guidance law is designed to ensure predefined tracking accuracy. Considering that the Hamilton-Jacobi-Bellman (HJB) equation cannot be directly solved, an optimal control output is derived through a fuzzy inverse optimization approach, while ensuring fixed-time stability. Although fixed-time stability theory ensures that the steady-state time is independent of the initial condition, satisfactory convergence remains difficult to achieve under large position errors. To address this issue, a Dynamic Virtual Guiding Ship (DVGS) mechanism is introduced to replace the original reference trajectory. Finally, the effectiveness and feasibility of the proposed approach are validated through numerical simulations and sea experiments with a 4.9-meter underactuated USV.
Organelle-Directed Staudinger Reaction Enabling Fluorescence-on Resolution of Mitochondrial Electropotentials via a Self-Immolative Charge Reversal Probe.
Organelles often feature parameters pertinent to functions and yet responsive to biochemical stress. The electropotential across the mitochondrial membrane (ΔΨm) is a crucial mediator of cell fates. Herein we report a bioorthogonal reaction enabled fluorescence-on probing of ΔΨm alterations featuring anionic fluorescein-triphenylphosphonium diad (F-TPP), which is released via intramitochondria Staudinger reaction triggered self-immolation of o-azidomethylbenzoylated F-TPP. Compared to classical cationic mitochondria-specific dyes, F-TPP is hydrophilic and negatively charged. Effectively discerning ΔΨm changes upon diverse stress inducers, the organelle-directed bioorthogonal imaging strategy offers unprecedented choices to probe mitochondrial biology with functional molecules that are otherwise inaccessible via physiological organelle-probe affinity.
96-well plate-to-plate gravity fluorous solid-phase extraction (F-SPE) for solution-phase library purification.
Large particle size (125_210 microm) fluorous silica gel bonded with a -SiCH2CH2C8F17 stationary phase has been employed for gravity-driven fluorous solid-phase extraction (F-SPE) on two types of 96-well plates. A 1 or 0.75 g portion of fluorous silica is packed to each well of the 3.5-mL Ex-Blok and the 2.2-mL deep-well filtration plates, respectively. Up to 50 mg of reaction mixture is loaded and then eluted with a fluorophobic solvent (DMSO, DMF, or 85:15 DMF-H2O). Products collected in 96-well receiving plates are directly concentrated on a GeneVac vacuum centrifuge. This simple and highly efficient plate-to-plate F-SPE technique has been demonstrated in the purification of four 96-compound libraries produced by scavenging reactions with 1-(perfluoroctyl)propyl isatoic anhydride (F-IA), amide coupling reactions with 2-chloro-4,6-bis[(perfluorooctyl)propyloxy]-1,3,5-triazine (F-CDMT) or 2,4-dichloro-6-(perfluorooctyl)propyloxy-1,3,5-triazine (F-DCT), and Mitsunobu reactions with fluorous diethyl azodicarboxylate (F-DEAD) and triphenylphosphine (F-TPP). Approximately 80% of products in each library have greater than 85% purity after F-SPE without conducting chromatography.
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