Sustained Therapeutic Efficacy Research Articles

Novel biopolymer spray formulation for drug delivery in precision dentistry

Addressing the growing challenges of periodontal and peri-implant diseases, this study first reports a promising advancement in precision dentistry: an intricately formulated biopolymer spray designed for precise, localized drug delivery during tailored dental procedures. Poly (lactic-co-glycolic acid) (PLGA), recognized for its controlled release, biodegradability, and FDA-approved biocompatibility, forms the core of this formulation. Utilizing the double emulsion method, PLGA microparticles (PLGA-MPs) were loaded with dental antibiotics: sodium amoxicillin (AMX-Na), trihydrate amoxicillin (AMX-Tri), and metronidazole (Met). This antibiotic combination was thoughtfully selected to meet the distinctive requirements of the most impacting dental treatments. The newly developed biopolymer spray underwent thorough in-vitro analysis, revealing an optimized release curve for antibiotics over time, guaranteeing sustained therapeutic efficacy, and dose-dependent efficacy, accommodating personalized treatment approaches. The positive outcomes position the novel biopolymer spray formulation the leaders in advancing localized drug delivery during dental procedures. Moreover, the precise application and the tunable formulation meets the concept of precision medicine: in detail, this formulation represents a significant stride in dental therapeutics, significantly contributing to the predictability of dental implantology.

Controlled Release of Ceria and Ferric Oxide Nanoparticles via Collagen Hydrogel for Enhanced Osteoarthritis Therapy.

Osteoarthritis (OA), characterized by chronic inflammation and cartilage degeneration, significantly affects over 500 million people globally. Nanoparticles have emerged as promising treatments for OA; however, current strategies often employ a single type of nanoparticle targeting specific disease stages, limiting sustained therapeutic efficacy. In this study, a novel collagen hydrogel is introduced, thiol crosslinked collagen-cerium oxide-poly(D,L-lactic-co-glycolic acid) microspheres encapsulating nanoparticles (CSH-CeO2-pFe2O3), designed for the controlled release of cerium oxide (CeO2) and ferric oxide (Fe2O3) nanoparticles for comprehensive OA management. The sulfhydryl cross-linked collagen matrix embeds CeO2 nanoparticles and poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres encapsulating Fe2O3 nanoparticles. The CSH-CeO2-pFe2O3 hydrogel exhibits enhanced mechanical strength and remarkable injectability, along with a significant promotion of cell adhesion, proliferation, and chondrogenic differentiation. Notably, the hydrogel demonstrates intelligent responsiveness to high levels of reactive oxygen species, initiating the rapid release of CeO2 nanoparticles to address the intense inflammatory responses of early-stage OA, followed by the sustained release of Fe2O3 nanoparticles to facilitate cartilage regeneration during the proliferative phase. In a rat model with cartilage defects, the hydrogel significantly alleviates inflammation and enhances cartilage regeneration, holding substantial potential for effectively managing the pathologically complex OA.

Development and characterization of liposomal formulations containing sesquiterpene lactones for the treatment of chronic gout

Gout and hyperuricemia are characterized by high uric acid levels, and their treatment involves medications that have adverse effects. In this study, we evaluated oral liposomal formulations with eremantholide C and goyazensolide as a novel approach to reduce the toxicity associated with these substances while maintaining their anti-hyperuricemic activity. We characterized the formulations and evaluated them based on encapsulation efficiency and stability over 12 months and under simulated physiological environments. We determined the toxicity of the liposomal formulations in Caco-2 cells and the anti-hyperuricemic activity in rats. The formulations exhibited nanometric size, a narrow size distribution, and a negative zeta potential, indicating their stability and uniformity. The efficient encapsulation of the sesquiterpene lactones within the liposomes emphasizes their potential for sustained release and therapeutic efficacy. Stability evaluation revealed a small decrease in the eremantholide C concentration and a remarkable stability in the goyazensolide concentration. In Caco-2 cells, the liposomes did not exert toxicity, but did exhibit an antiproliferative effect. In vivo assays demonstrated that the liposomes reduced serum uric acid levels. Our study represents an advancement in gout and hyperuricemia treatment. The liposomal formulations effectively reduced the toxicity associated with the sesquiterpene lactones while maintaining their therapeutic effects.

Nanocatalytic Anti‐Tumor Immune Regulation

AbstractImmunotherapy has brought a new dawn for human being to defeat cancer. Although existing immunotherapy regimens (CAR‐T, etc.) have made breakthroughs in the treatments of hematological cancer and few solid tumors such as melanoma, the therapeutic efficacy on most solid tumors is still far from being satisfactory. In recent years, the researches on tumor immunotherapy based on nanocatalytic materials are under rapid development, and significant progresses have been made. Nanocatalytic medicine has been demonstrated to be capable of overcoming the limitations of current clinicnal treatments by using toxic chemodrugs, and exhibits highly attractive advantages over traditional therapies, such as the enhanced and sustained therapeutic efficacy based on the durable catalytic activity, remarkably reduced harmful side‐effects without using traditional toxic chemodrugs, and so on. Most recently, nanocatalytic medicine has been introduced in the immune‐regulation for disease treatments, especially, in the immunoactivation for tumor therapies. This article presents the most recent progresses in immune‐response activations by nanocatalytic medicine‐initiated chemical reactions for tumor immunotherapy, and elucidates the mechanism of nanocatalytic medicines in regulating anti‐tumor immunity. By reviewing the current research progress in the emerging field, this review will further highlight the great potential and broad prospects of nanocatalysis‐based anti‐tumor immune‐therapeutics.

Nanomaterials in Medicine: Understanding Cellular Uptake, Localization, and Retention for Enhanced Disease Diagnosis and Therapy.

Nanomaterials (NMs) have emerged as promising tools for disease diagnosis and therapy due to their unique physicochemical properties. To maximize the effectiveness and design of NMs-based medical applications, it is essential to comprehend the complex mechanisms of cellular uptake, subcellular localization, and cellular retention. This review illuminates the various pathways that NMs take to get from the extracellular environment to certain intracellular compartments by investigating the various mechanisms that underlie their interaction with cells. The cellular uptake of NMs involves complex interactions with cell membranes, encompassing endocytosis, phagocytosis, and other active transport mechanisms. Unique uptake patterns across cell types highlight the necessity for customized NMs designs. After internalization, NMs move through a variety of intracellular routes that affect where they are located subcellularly. Understanding these pathways is pivotal for enhancing the targeted delivery of therapeutic agents and imaging probes. Furthermore, the cellular retention of NMs plays a critical role in sustained therapeutic efficacy and long-term imaging capabilities. Factors influencing cellular retention include nanoparticle size, surface chemistry, and the cellular microenvironment. Strategies for prolonging cellular retention are discussed, including surface modifications and encapsulation techniques. In conclusion, a comprehensive understanding of the mechanisms governing cellular uptake, subcellular localization, and cellular retention of NMs is essential for advancing their application in disease diagnosis and therapy. This review provides insights into the intricate interplay between NMs and biological systems, offering a foundation for the rational design of next-generation nanomedicines.

PH-temperature Responsive Hydrogel-Mediated Delivery of Exendin-4 Encapsulated Chitosan Nanospheres for Sustained Therapeutic Efficacy in Type 2 Diabetes Mellitus.

Type 2 Diabetes Mellitus (T2D) is a chronic, obesity-related, and inflammatory disorder characterize by insulin resistance, inadequate insulin secretion, hyperglycemia, and excessive glucagon secretion. Exendin-4 (EX), a clinically established antidiabetic medication that acts as a glucagon-like peptide-1 receptor agonist, is effective in lowering glucose levels and stimulating insulin secretion while significantly reducing hunger. However, the requirement for multiple daily injections due to EX's short half-life is a significant limitation in its clinical application, leading to high treatment costs and patient inconvenience. To address this issue, an injectable hydrogel system is developed that can provide sustained EX release at the injection site, reducing the need for daily injections. In this study, the electrospray technique is examine to form EX@CS nanospheres by electrostatic interaction between cationic chitosan (CS) and negatively charged EX. These nanospheres are uniformly dispersed in a pH-temperature responsive pentablock copolymer, which forms micelles and undergoes sol-to-gel transition at physiological conditions. Following injection, the hydrogel gradually degraded, exhibiting excellent biocompatibility. The EX@CS nanospheres are subsequently released, maintaining therapeutic levels for over 72h compared to free EX solution. The findings demonstrate that the pH-temperature responsive hydrogel system containing EX@CS nanospheres can be a promising platform for the treatment of T2D.

Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity

BackgroundAlthough immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may...

Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity

Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.

A Review on Phytochemical Characterization of Kwatha–Ayurvedic Polyherbal Formulation

A paradigm shifts from the conventional approach of a single drug-based system to polyherbal formulations is recently observed in the modern pharmaceutical industry. The rising demand has led to a decrease in the quality and efficacy of herbal medicines. In order to ensure the sustained demand and therapeutic efficacy, it is vitally important to devise proper methods of standardization from the raw drugs to finished polyherbal formulations. However, there is no consensus regarding how these herbal medicines should be standardized. The phytochemical standardization by multiple markerbased fingerprint profiling along with preliminary screening and quantification of marker compounds can assure the reproducibility of the activity of the polyherbal formulations to an extent. The clinically pertinent scientific data to support the asserted synergistic therapeutic effects of Ayurvedic poylyherbal formulations is inadequate. In this review, we discuss the phytochemical standardization and pharmacological studies of kwatha, a major form of herbal remedies in Ayurvedic pharmacology, and the underlying concept of synergism. Kwatha (decoction) is the backbone of self-administered herbal preparations in India. Since the majority of the active principles of plants are water-soluble, herbal decoctions that are usually prepared in water formulate the potent and effective Ayurvedic medicines.

Structural optimization of HPMA copolymer-based dexamethasone prodrug for improved treatment of inflammatory arthritis

Despite their notorious adverse effects, glucocorticoids (GC, potent anti-inflammatory drugs) are used extensively in clinical management of rheumatoid arthritis (RA) and other chronic inflammatory diseases. To achieve a sustained therapeutic efficacy and reduced toxicities, macromolecular GC prodrugs have been developed with promising outcomes for the treatment of RA. Fine-tuning the activation kinetics of these prodrugs may further improve their therapeutic efficacy and minimize the off-target adverse effects. To assess the feasibility of this strategy, five different dexamethasone (Dex, a potent GC)-containing monomers with distinctively different linker chemistries were designed, synthesized, and copolymerized with N-(2-hydroxypropyl) methacrylamide (HPMA) to obtain 5 macromolecular Dex prodrugs. Their Dex releasing rates were analyzed in vitro and shown to display a wide spectrum of activation kinetics. Their therapeutic efficacy and preliminary toxicology profiles were assessed and compared in vivo in an adjuvant-induced arthritis (AA) rat model in order to identify the ideal prodrug design for the most effective and safe treatment of inflammatory arthritis. The in vivo data demonstrated that the C3 hydrazone linker-containing prodrug design was the most effective in preserving joint structural integrity. The results from this study suggest that the design and screening of different activation mechanisms may help to identify macromolecular prodrugs with the most potent therapeutic efficacy and safety for the management of inflammatory arthritis.

Effects of shell thickness of hollow poly(lactic acid) nanoparticles on sustained drug delivery for pharmacological treatment of glaucoma

Structural designing of carriers with extended drug release profiles is critically important for achieving long-acting drug delivery systems toward efficient managements of chronic diseases. Here, we present a strategy to exploit the effects of the shell thickness of hollow poly(lactic acid) nanoparticles (HPLA NPs) in sustained glaucoma therapy. Formulations based on pilocarpine-loaded HPLA NPs with tailorable shell thickness ranging from 10 to 100 nm were shown to be highly compatible with human lens epithelial cells in vitro and with rabbit eyes in vivo. Specifically, shell thickness regulated the release of pilocarpine, with thick shells (~70 to 100 nm) providing sustained drug release performance but limited drug-loading efficiency, whereas ultrathin shells (~10 nm) induced the opposite effects. Remarkably, moderately thick shells (~40 nm) showed the most effective release profile of pilocarpine (above the therapeutic levels of ~10 µg/mL for over 56 days). In a rabbit model of glaucoma, single intracameral administration of an HPLA NP-based formulation with shell thickness of ~40 nm sustainably alleviated ocular hypertension for over 56 days, consequently protecting the structural integrity of the corneal endothelium, preserving the electrophysiological functions of the retina, and attenuating retinal and optic nerve degeneration in progressively glaucomatous eyes. The findings therefore implied a promising use of shell thickness effects in the development of long-acting drug delivery systems for pharmacological treatment of chronic ocular diseases. Statement of SignificanceOwing to their large surface areas and modifiable structures, nanoparticles have been considered as a promising platform for drug delivery; however, achieving drug nanocarrier systems with reduced burst release and sustained therapeutic efficacy remains challenges. This work presents the first report on rational design of hollow poly(lactic acid) nanocarriers for tailoring the structure-property-function relationships toward effective treatment of glaucoma. The shell thickness of the hollow nanocarriers is demonstrated to have influential impacts on pilocarpine encapsulation efficiency and release profile, indicating that the most sustained delivery performance (maintaining the release of pilocarpine above therapeutic level over 56 days) can be obtained for the polymeric nanoparticles with moderate shell thickness of ~40 nm.

The role of aromatic ring number in phenolic compound-conjugated chitosan injectables for sustained therapeutic antiglaucoma efficacy

The development of long-lasting therapeutic drug delivery system is greatly desired for effective treatment of glaucoma, a chronic and multifactorial disease. Herein, the roles of aromatic ring number in phenolic compound-conjugated chitosan injectables are exploited for achieving an advanced drug carrier with potent anti-inflammatory and anti-oxidant properties. Low and high number of aromatic rings can induce deleterious impacts on the pharmaceutical applications of injectables, whereas the compound with a moderate ring number is proved as the most efficient agent for boosting drug delivery performances and endowing the chitosan injectables with therapeutic properties. Kaempferol–conjugated injectable formulation reveals a remarkable effectiveness for intracameral pilocarpine administration, which can alleviate progressive glaucoma via simultaneously exerting multiple pharmacological activities to suppress ocular hypertension, inflammation, and oxidative stress. These findings provide a significant advance in understanding structure-property relationship of the phenolic compound-conjugated chitosan injectables as long-lasting therapeutic drug delivery systems for medical management of glaucoma.

Abstract 270: Loss of S100A1 Protein Negatively Impacts Glucose Metabolism and Energy Homeostasis in Cardiomyocytes

Introduction: As a true metabolic omnivore, the heart is able to utilize different substrates for energy production. In the hypertrophied and early failing state, cardiac muscle leans towards glucose as a major carbon substrate to meet its energetic demand. Given that S100A1 gene therapy reverses the compromised energetic balance of the failing heart, we were interested in determining the specific role of the EF-hand calcium sensor S1001A1 in cardiomyocyte energy metabolism. Methods and results: To study metabolic changes in response to different carbon substrates, we used neonatal rat ventricular cardiomyocytes (NRVMs), which were subjected to electrical stimulation (2Hz) in culture and adenoviral-mediated anti-S100A1 shRNA silencing or scr-shRNA, and either fed with glucose, oleate or lactate only for 24hrs. Of note, lack of S100A1 expression only impaired energy metabolism of cardiomyocytes in response to glucose as reflected by a significantly decreased ATP content and subsequently enhanced AMP/ATP and p-AMPK/AMPK ratios with consecutive elevated p-ACC/ACC and Glut4 protein levels. In contrast, energy metabolism appeared to remain normal in response to oleate in S100A1-deprived cells. Targeted metabolomics yielded a tremendous decrease in glucose-6-phosphate levels as the first key step in glucose metabolism despite enhanced AMPK activation in glucose-fed S100A1-defiecient cardiomyocytes. Conclusion: Our novel in vitro data indicate that S100A1 protein may be crucial for cardiomyocytes to meet their energetic demand when glucose is the major substrate. Since the latter becomes the preferred substrate for functionally compromised heart over fatty acids, lack of S100A1 expression - as a result of fetal gene reprogramming - most likely impairs the ability of the heart to sufficiently utilize glucose to meet its energetic demand. These data shed new mechanistic light on the sustained therapeutic efficacy of S100A1 gene therapy of heart failure where S100A1 may be a key factor enabling the heart to sufficiently use glucose to reverse its compromised energetic state. Further studies answering these pressing questions are underway for an informed design of a best-case patient enrollment scenario for a first-in-men clinical study.

Sustained Therapeutic Efficacy of Humanized Anti-CD19 Chimeric Antigen Receptors (CAR)-T in Relapsed/Refractory Acute Lymphoblastic Leukemia

Background: Immunogenicity derived from the murine scFv, a major molecular design of CAR, may limit the persistence of CAR-T cells, resulting in high relapase rate in cured relapsed/refractory acute lymphoblastic leukemia (r/r ALL) patients after successful treatment. In this study, we aimed to develop a humanized anti-CD19 scFv CAR-T (hCAR-T) and treated patients with r/r ALL. Methods: In this one-arm, open-labelled phaseⅠ/Ⅱ study, we infused the T cells modified with hCAR-T to patients with r/r ALL. Long term followup for response and safety to treatment were evaluated. Findings: Eleven patients with r/r ALL were recruited in this study. Nine patients were response-evaluable and all achieved CR at three months; Seven patients remain CR till now and five have been in CR for over 12 months without further treatment. Long persistence of hCAR-T cells was observed in the most of patients. Among these patients, three of them with high and rapidly progressive tumour burden (median 90%) experienced grade 3-4 of CRS. These severe CRS were successfully controlled by earlier use of tocilizumab, glucocorticoid and plasma exchange (PE). Interpretation: T cells expressing the humanized anti-CD19 scFv CAR exhibited the sustained therapeutic efficacy in treatment of r/r ALL. Low replase rate was assocated with long persistence of CAR-T cells. The severe CRS could be controlled by tocilizumab, glucocorticoid and plasma exchange (PE). Clinical Trial Number: The study was registered at Clinicaltrials.gov (NCT02349698). Funding Statement: This work was supported by National Key Research and Development Program (2016YFC1303405), National Natural Science Foundation of China 81520108025), Clinical Research Project of the Southwest Hospital (SWH2016ZDCX1005, SWH2016LCZD-02), Chongqing Precision Biotech Co., Ltd. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was approved by the Ethics Committee of the Southwest Hospital of Third Military Medical University (Chongqing, China). It was performed according to the principles of the Declaration of Helsinki. All patients or their guardians provided written informed consent before they were recruited in this study.

Treatment duration affects cytoprotective efficacy of positive allosteric modulation of α7 nAChRs after focal ischemia in rats.

To minimize irreversible brain injury after acute ischemic stroke (AIS), the time to treatment (i.e., treatment delay) should be minimized. However, thus far, all cytoprotective clinical trials have failed. Analysis of literature identified short treatment durations (≤72 h) as a common motif among completed cytoprotective clinical trials. Here, we argue that short cytoprotective regimens even if given early after AIS may only slow down the evolution of ischemic brain injury and fail to deliver sustained long-term solutions leading to relapses that may be misinterpreted for conceptual failure of cytoprotection. In this randomized blinded study, we used young adult male rats subjected to transient 90 min suture middle cerebral artery occlusion (MCAO) and treated with acute vs. sub-chronic regimens of PNU120596, a prototypical positive allosteric modulator of α7 nicotinic acetylcholine receptors with anti-inflammatory cytoprotective properties to test the hypothesis that insufficient treatment durations may reduce therapeutic benefits of otherwise efficacious cytoprotectants after AIS. A single acute treatment 90 min after MCAO significantly reduced brain injury and neurological deficits 24 h later, but these effects vanished 72 h after MCAO. These relapses were avoided by utilizing sub-chronic treatments. Thus, extending treatment duration augments therapeutic efficacy of PNU120596 after MCAO. Furthermore, sub-chronic treatments could offset the negative effects of prolonged treatment delays in cases where the acute treatment window after MCAO was left unexploited. We conclude that a combination of short treatment delays and prolonged treatment durations may be required to maximize therapeutic effects of PNU120596, reduce relapses and ensure sustained therapeutic efficacy after AIS. Similar concepts may hold for other cytoprotectants including those that failed in clinical trials.

Design, in vitro/in vivo evaluation of meclizine HCl-loaded floating microspheres targeting pregnancy-related nausea and vomiting

The aim of this study was to investigate whether floating microspheres prepared from polymer blends of hydroxypropyl methylcellulose in combination with either Eudragit S100 or Eudragit RS100 could improve the systemic bioavailability of the antiemetic drug; meclizine HCl (MCZ). Floating microspheres containing MCZ were prepared by emulsion solvent evaporation method. The influence of different polymer blend compositions on various formulation parameters and in vitro release characteristics of the prepared microspheres was investigated. In addition, the in vivo pharmacokinetic profile of an optimized formula was evaluated. The mean particle size of prepared microspheres ranged from 290 to 383 μm. The percent drug entrapment efficiency varied between 51.9 ± 0.3% to 91.6 ± 0.7%. The formulated microspheres exhibited excellent floating ability. In vitro release profiles of floating microspheres indicated a rapid initial release followed by a sustained drug release for up to 24 h. The pharmacokinetic data affirmed the sustained effect of the optimized formula as indicated by the prolonged tmax, compared to the plain drug. Furthermore, the optimized formula showed higher relative bioavailability (154.25%), compared to the plain drug. These results suggest that MCZ floating microspheres might represent potential alternative to conventional MCZ oral formulations, with a higher and sustained therapeutic efficacy.

Sustained therapeutic efficacy of budesonide-loaded chitosan swellable microparticles after lung delivery: Influence of in vitro release, treatment interval and dose

Sustained drug delivery to the respiratory tract is highly desirable for local treatment of chronic lung diseases. In this context, a correlation of in vitro drug release with in vivo efficacy data is essential to accelerate the application of sustained drug delivery system for inhalation into the clinical setting.In this study, budesonide was incorporated into distinct chitosan-based swellable microparticles, which were characterized, and the in vitro drug release behavior determined. The particles were then given to an allergic asthma animal model as single and successive administrations, and the therapeutic response was determined by measuring cell counts, IL-4 and IL-5 levels in bronchoalveolar lavage fluid, IL-4 and IL-5 mRNA in the lung and by histopathologic examination of lung tissues. After a single administration, the time-dependent therapeutic effect of the swellable microparticles was correlated with the in vitro release behavior, which lasted for 12 or 18 h depending on the molecular weight of the chitosan. After seven days of successive treatment, the number of eosinophils decreased further and IL-4 and IL-5 mRNA expression in the lung tissue was more greatly inhibited. Moreover, the chitosan-based swellable microparticles allowed longer administration intervals (every two days), which decreased the required dose for effectiveness by 50%.These results demonstrate that chitosan-based swellable microparticles can sustain the therapeutic effect of budesonide in the respiratory tract which in principal can be applied to other drugs for the treatment of local lung diseases.

Reinforcement of polymeric nanoassemblies for ultra-high drug loadings, modulation of stiffness and release kinetics, and sustained therapeutic efficacy.

The optimization of current polymeric nanoparticle therapies is restricted by low drug loadings and limited tunability of core properties. To overcome these shortcomings, a novel self-association approach is utilized to fabricate a dual-loaded poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX) conjugate nanoparticle (NP) in which the physical entrapment of free paclitaxel (PTX) affords unprecedented ultra-high drug loadings >100 wt%, modulation of mechanical stiffness, and tunable release kinetics. Despite high incorporation of free PTX (up to 50 wt%), the dual-loaded PGC-PTX nanocarriers (i.e., PGC-PTX + PTX NPs) exhibit controlled and sustained drug release over 15 days, without burst release effects. Importantly, optimization of drug/material efficiency concomitantly affords improved in vitro efficacy. In vivo, PGC-PTX + PTX NPs are safely administered at doses exceeding the median lethal dose of standard PTX, while a single high dose significantly extends survival relative to weekly PTX administrations in a murine model of peritoneal carcinomatosis.

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells.

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34+ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. Mol Cancer Ther; 16(8); 1497-510. ©2017 AACR.

Long term sustained therapeutic effects of percutaneous posterior tibial nerve stimulation treatment of neurogenic overactive bladder in multiple sclerosis patients: 12-months results.

The aim of this study is to determine the sustained therapeutic efficacy and treatment intervals for PTNS in NOAB with MS, offering periodic additional treatments during 1 year in patients who completed an initial course of 12 consecutive weekly sessions. A total of 34 patients enrolled to the PTNS treatment and 21 patients completed the 1 year PTNS treatment with a tapering protocol of 6, 9, and 12 months of therapy, respectively. After 12 weeks of therapy, PTNS was applied at 14 day intervals for 3 months, 21 day intervals for 3 months, and 28 day intervals for 3 months. The patients completed a 3-day voiding diary at 3rd, 6th, 9th, and 12th month. The patients requested to complete validated questionnaires (ICIQ-SF, OAB-V8, OAB-q SF) were carried out within 3-month intervals thereafter during their enrolment in the study. A total of 21 patients were enrolled in the study. Of these 5 (23.8%) were men and 16 (76.2%) women. The improvements for all voiding diary parameters were significant in the 6th, 9th, and 12th months when compared with baseline. Mean values between baseline and 12 month parameters suggested that daytime frequency decreased by 5.4 voids daily, urge incontinence decreased by 3.4 episodes daily, urgency episodes decreased by 7.4 episodes daily, nocturia decreased by 2.6 voids, and voided volume improved by a mean of 72.1 cc. These results have demonstrated NOAB symptom improvement in MS patients can be achieved with 12 weekly PTNS treatments which show excellent durability over 12 months. Neurourol. Urodynam. 36:104-110, 2017. © 2015 Wiley Periodicals, Inc.