Delivery System For Cancer Treatment Research Articles

Attenuated polyethylene glycol immunogenicity and overcoming accelerated blood clearance of a fully PEGylated dendrimer

Polyethylene glycol (PEG) is a popular biocompatible polymer and PEGylated nanoparticles passively accumulate in tumor tissues because of their enhanced permeability and retention effects. Recently, the anti-PEG immunity of PEGylated nanoparticles has become an issue that needs to be solved for their clinical applications. Dendrimers are highly branched and well-defined polymers with many terminal groups, which act as potent drug carriers. In this study, we examined the pharmacokinetics, biodistribution, anti-PEG immunity, and tumor accumulation of a fully PEGylated polyamidoamine (PAMAM) dendrimer after the first and second injections and compared them to those of a PEGylated liposome with the same lipid component as Doxil®. The PEGylated dendrimer showed greater blood circulation than that of the PEGylated liposome after the first and second injections in rats. In mice injected with the PEGylated dendrimer, much less anti-PEG immunoglobulin M (IgM) was generated than that in mice injected with the PEGylated liposome. The PEGylated dendrimer accumulated in the tumor after both the first and second injections. Our results indicated that the PEGylated dendrimer with a small size and high PEG density showed attenuated anti-PEG immunity and overcame the accelerated blood clearance phenomenon, which is useful for drug delivery systems for cancer treatment.

Fabrication of cisplatin-loaded core–shell Fe3O4@UiO-66-NH2 magnetic nanocomposite for potential drug delivery

In this study, we developed a biocompatible core–shell magnetic Fe3O4@UiO-66-NH2@CisPt nanocomposite loaded with cisplatin as a therapeutic agent for drug delivery and cancer treatment. The nanocomposite was synthesized using a step-by-step method resulting in the formation of two phases within the core–shell structure. Advanced analytical techniques, such as XRD, HR TEM, TEM, FTIR, and VSM, were used to thoroughly analyze the structural properties, morphology, magnetic characteristics, and atomic structure of the core–shell nanocomposite. Fe3O4@UiO-66-NH2@CisPt nanocomposite exhibits superparamagnetic behavior, which is advantageous for controlled drug delivery and release by applying an external magnetic field. This study presents a significant contribution to the development of effective drug delivery systems for cancer treatment.

Electrosprayable Levan-Coated Nanoclusters and Ultrasound-Responsive Drug Delivery for Cancer Therapy.

In this study, we synthesized levan shell hydrophobic silica nanoclusters encapsulating doxorubicin (L-HSi-Dox) and evaluated their potential as ultrasound-responsive drug delivery systems for cancer treatment. L-HSi-Dox nanoclusters were successfully fabricated by integrating a hydrophobic silica nanoparticle-doxorubicin complex as the core and an amphiphilic levan carbohydrate polymer as the shell by using an electrospray technique. Characterization analyses confirmed the stability, size, and composition of the nanoclusters. In particular, the nanoclusters exhibited a controlled release of Dox under aqueous conditions, demonstrating their potential as efficient drug carriers. The levanic groups of the nanoclusters enhanced the targeted delivery of Dox to specific cancer cells. Furthermore, the synergism between the nanoclusters and ultrasound effectively reduced cell viability and induced cell death, particularly in the GLUT5-overexpressing MDA-MB-231 cells. In a tumor xenograft mouse model, treatment with the nanoclusters and ultrasound significantly reduced the tumor volume and weight without affecting the body weight. Collectively, these results highlight the potential of the L-HSi-Dox nanoclusters and ultrasound as promising drug delivery systems with an enhanced therapeutic efficacy for biomedical applications.

Anti-Netrin-1 decorated nanoparticles combined with chemotherapy for the treatment of triple-negative breast cancer

Nanoparticle's success as drug delivery systems for cancer treatment has been achieved through passive targeting mechanisms. However, tumor heterogeneity and rapid drug clearance limit the treatment efficacy. Improved outcomes and selective drug release can be achieved by grafting ligands at the surface of nanocarriers that bind molecules overexpressed in the tumor microenvironment (TME). In this work, we developed a docetaxel-loaded nanoemulsions (NEs) binding an anti-netrin-1 monoclonal antibody (NP137) to selectively target the netrin-1 protein overexpressed in many different tumors. The goal is to refine a combined approach utilizing NP137 and docetaxel as an improved tumor-targeting chemotherapeutic agent for addressing triple-negative breast cancer (TNBC). Several factors have been considered for the optimization of the active targeted drug delivery system via the click-chemistry conjugation, as the impact of PEGylated surfactant that stabilize the NEs shell on conjugation efficiency, cytocompatibility with EMT6 cell line and colloidal stability over time of NEs. Results showed that a 660 Da PEG chain length contributed to NEs colloidal stability, had no impact on cell viability or on the antibody binding ability for its ligand after surface conjugation. Docetaxel was encapsulated into the oily core of NEs, with an encapsulation efficiency of 70 %. To validate our treatment strategy in vivo, the 4T1 murine breast cancer model was used. As a result, the comparison of active-targeted and non-targeted NEs revealed that only active-targeted NE could decrease the tumor growth rate.

Polymer Conjugate as the New Promising Drug Delivery System for Combination Therapy against Cancer

Abstract: This review highlights the advantages of combination therapy using polymer conjugates as drug delivery systems for cancer treatment. In this review, the specific structures and materials of polymer conjugates, as well as the different types of combination chemotherapy strategies, are discussed. Specific targeting strategies, such as monoclonal antibody therapy and small molecule ligands, are also explored. Additionally, self-assembled polymer micelles and overcoming multidrug resistance are described as potential strategies for combination therapy. The assessment of combinational therapeutic efficacy and the challenges associated with polymer conjugates are also addressed. The future outlook aims to overcome these challenges and improve the effectiveness of drug delivery systems for combination therapy. The conclusion emphasizes the potential of polymer conjugates in combination therapy while acknowledging the need for further research and development in this field.

Size-dependent effects of niosomes on the penetration of methotrexate in skin layers

BackgroundNiosomes hold promise as drug delivery systems for cancer treatment, with niosome size impacting stability, biodistribution, and effectiveness. This study optimized methotrexate (MTX)-loaded niosome formulation by studying the effects of components and processing conditions on size. The niosomes formulation was made by the thin-film hydration technique.ResultsThe optimized formulation (NIO 17) with a 6:2:2 ratio of span 60, soya PC, and cholesterol achieved 55.05% methotrexate encapsulation, particle size 597.2 nm, PDI 0.49, and zeta potential − 23.3 mV. The compatibility of methotrexate with lipids was confirmed via Fourier transform infrared spectroscopy, and transmission electron microscopy revealed spherical, well-dispersed vesicles. Differential scanning calorimetry indicated methotrexate conversion or entrapment within vesicles. In vitro release exhibited a sustained pattern with an initial burst. NIO 17 showed potent anti-cancer activity against B16-F10 cells (GI50: 38.7176 μg/mL). Ex vivo studies suggest tailoring niosome size (597.2–982.3 nm) to target specific skin depths (0–38 μm) for enhanced localized drug delivery.ConclusionsThis study demonstrates the potential of methotrexate-loaded niosomes as a novel cancer therapy approach, highlighting the potent anti-cancer activity and transdermal delivery potential of NIO 17. Further research is necessary to explore its clinical translation.Graphical abstract

Integrating natural compounds and nanoparticle-based drug delivery systems: A novel strategy for enhanced efficacy and selectivity in cancer therapy.

Cancer remains a leading cause of death worldwide, necessitating the development of innovative and more effective treatment strategies. Conventional cancer treatments often suffer from limitations such as systemic toxicity, poor pharmacokinetics, and drug resistance. Recently, there has been growing attention to utilizing natural compounds derived from various sources as possible cancer therapeutics. Natural compounds have demonstrated diverse bioactive properties, including antioxidant, anti-inflammatory, and antitumor effects, making them attractive candidates for cancer treatment. However, their limited solubility and bioavailability present challenges for effective delivery to cancer cells. To overcome these limitations, researchers have turned to nanotechnology-based drug delivery systems. Nanoparticles, with their small size and unique properties, can encapsulate therapeutic agents and offer benefits such as improved solubility, prolonged drug release, enhanced cellular uptake, and targeted delivery. Functionalizing nanoparticles with specific ligands further enhances their precision in recognizing and binding to cancer cells. Combining natural compounds with nanotechnology holds great promise in achieving efficient and safe cancer treatments by enhancing bioavailability, pharmacokinetics, and selectivity toward cancer cells. This review article provides an overview of the advancements in utilizing natural substances and nanotechnology-based drug delivery systems for cancer treatment. It discusses the benefits and drawbacks of various types of nanoparticles, as well as the characteristics of natural compounds that make them appealing for cancer therapy. Additionally, current research on natural substances and nanoparticles in preclinical and clinical settings is highlighted. Finally, the challenges and future perspectives in developing natural compound-nanoparticle-based cancer therapies are discussed.

CARBON DOTS: Bioimaging and Anticancer Drug Delivery.

Cancer, responsible for approximately 10 million lives annually, urgently requires innovative treatments, as well as solutions to mitigate the limitations of traditional chemotherapy, such as long-term adverse side effects and multidrug resistance. This review focuses on Carbon Dots (CDs), an emergent class of nanoparticles (NPs) with remarkable physicochemical and biological properties, and their burgeoning applications in bioimaging and as nanocarriers in drug delivery systems for cancer treatment. The review initiates with an overview of NPs as nanocarriers, followed by an in-depth look into the biological barriers that could affect their distribution, from barriers to administration, to intracellular trafficking. It further explores CDs' synthesis, including both bottom-up and top-down approaches, and their notable biocompatibility, supported by a selection of in vitro, in vivo, and ex vivo studies. Special attention is given to CDs' role in bioimaging, highlighting their optical properties. The discussion extends to their emerging significance as drug carriers, particularly in the delivery of doxorubicin and other anticancer agents, underscoring recent advancements and challenges in this field. Finally, we showcase examples of other promising bioapplications of CDs, emergent owing to the NPs flexible design. As research on CDs evolves, we envisage key challenges, as well as the potential of CD-based systems in bioimaging and cancer therapy.

Exploring the vast potentials and probable limitations of novel and nanostructured implantable drug delivery systems for cancer treatment.

Conventional cancer chemotherapy regimens, albeit successful to some extent, suffer from some significant drawbacks, such as high-dose requirements, limited bioavailability, low therapeutic indices, emergence of multiple drug resistance, off-target distribution, and adverse effects. The main goal of developing implantable drug delivery systems (IDDS) is to address these challenges and maintain anti-cancer drugs directly at the intended sites of therapeutic action while minimizing inevitable side effects. IDDS possess numerous advantages over conventional drug delivery, including controlled drug release patterns, one-time drug administration, as well as loading and stabilizing poorly water-soluble chemotherapy drugs. Here, we summarized conventional and novel (three-dimensional (3D) printing and microfluidic) preparation techniques of different IDDS, including nanofibers, films, hydrogels, wafers, sponges, and osmotic pumps. These systems could be designed with high biocompatibility and biodegradability features using a wide variety of natural and synthetic polymers. We also reviewed the published data on these systems in cancer therapy with a particular focus on their release behavior. Various release profiles could be attained in IDDS, which enable predictable, adjustable, and sustained drug releases. Furthermore, multi-step or stimuli-responsive drug release could be obtained in these systems. The studies mentioned in this article have proven the effectiveness of IDDS for treating different cancer types with high prevalence, including breast cancer, and aggressive cancer types, such as glioblastoma and liver cancer. Additionally, the challenges in applying IDDS for efficacious cancer therapy and their potential future developments are also discussed. Considering the high potential of IDDS for further advancements, such as programmable release and degradation features, further clinical trials are needed to ensure their efficiency. The overall goal of this review is to expand our understanding of the behavior of commonly investigated IDDS and to identify the barriers that should be addressed in the pursuit of more efficient therapies for cancer. See also the graphical abstract(Fig. 1).

CD-44 active cystamine-bridged hyaluronic acid-polydopamine nanoparticles for chemo-photothermal cancer therapy

The development of targeted drug delivery systems for cancer treatment has been a topic of great interest in recent years. We developed redox-responsive, NIR-activated, cystamine-bridged hyaluronan-polydopamine (Cys-HA-PDA) nanoparticles (NPs) loaded with doxorubicin (Dox) that bind to CD44 receptors on cancer cells and exhibit enhanced anticancer efficacy due to a chemo-photothermal effect under redox conditions. Synthesized Cys-HA-PDA NPs at 200 µg/mL concentration produced a temperature of 59.5 ℃ at 2 W/cm2, which destroyed tumor cells. The presence of disulfide bonds in Cys-HA-PDA NPs resulted in self-degradability in the cytosol of cancer cells. Furthermore, electrostatic interactions and pi-pi stacking allowed Dox to be successfully encapsulated in Cys-HA-PDA nanoparticles; calculated maximum drug loading and encapsulation efficiency were 21.6% and 88.3%, respectively. The anticancer activity of Dox-loaded NPs on HepG2 cancer cells was increased under NIR laser light (800 nm, 2 W/cm2). Furthermore, interaction with CD44 receptor enhanced the intracellular uptake of Dox-loaded Cys-HA-PDA NPs by HepG2 cells. Overall, the study shows that the use of redox-responsive nanoparticles for CD44-targeted drug delivery is a promising anticancer strategy.

Capric Acid and Myristic Acid Permeability Enhancers in Curved Liposome Membranes.

Liposomes are considered as advanced drug delivery systems for cancer treatment. A generation of pH-sensitive liposomes is being developed that use fatty acids (FAs) as a trigger for drug release in tumor tissues. However, FAs are also known to enhance permeability, and it is unclear whether FAs in liposomes may cause drug leakage or premature drug release. The passive permeability of the drug through the membrane of the liposome is thus a crucial factor for timely drug delivery. To investigate how the curvature and lipid composition of liposomes affect their passive permeability, coarse-grained molecular dynamics were performed. The permeability was determined with a counting method. Flat bilayers and three liposomes with varying diameters were studied, which had varying lipid compositions of dipalmitoylphosphatidylcholine, cholesterol, and deprotonated or neutral saturated FAs. The investigated permeants were water and two other small permeants, which have different free energy profiles (solubility) across the membrane. First, for the curvature effect, our results showed that curvature increases the water permeability by reducing the membrane thickness. The permeability increase for water is about a factor of 1.7 for the most curved membranes. However, a high curvature decreases permeability for permeants with free energy profiles that are a mix of wells and barriers in the headgroup region of the membrane. Importantly, the type of experimental setup is expected to play a dominant role in the permeability value, i.e., whether permeants are escaping or entering the liposomes. Second, for the composition effect, FAs decrease both the area per lipid (APL) and the membrane thickness, resulting in permeability increases of up to 55%. Cholesterol has a similar effect on the APL but has the opposite impact on membrane thickness and permeability. Therefore, FAs and cholesterol have opposing effects on permeability, with cholesterol's effect being slightly stronger in our simulated bilayers. As all permeability values were well within a factor of 2, and with liposomes usually being larger and less curved in experimental applications, it can be concluded that the passive drug release from a pH-sensitive liposome does not seem to be significantly affected by the presence of FAs.

Smartphone-based iontophoresis transdermal drug delivery system for cancer treatment

Cancer is a leading cause of the death worldwide. However, the conventional cancer therapy still suffers from several limitations, such as systemic side effects, poor efficacy, and patient compliance due to limited accessibility to the tumor site. To address these issues, the localized drug delivery system has emerged as a promising approach. In this study, we developed an iontophoresis-based transdermal drug delivery system (TDDS) controlled by a smartphone application for cancer treatment. Iontophoresis, a low-intensity electric current-based TDDS, enhances drug permeation across the skin to provide potential for localized drug delivery and minimize systemic side effects. The fundamental mechanism of our system was modeled using finite element analysis and its performance was corroborated through the flow-through skin permeation tests using a plastic-based microfluidic chip. The results of in vitro cell experiments and skin deposition tests successfully demonstrated that our smartphone-controlled iontophoresis system significantly enhanced the drug permeation for cancer treatment. Therefore, this hand-held smartphone-based iontophoresis TDDS could be a powerful tool for self-administrated anticancer drug delivery applications.

Development and evaluation of rosmarinic acid loaded novel fluorescent porous organosilica nanoparticles as potential drug delivery system for cancer treatment

Rosmarinic acid is a bioactive compound that possesses high anticancer activity, but its poor water-solubility and ineffective membrane permeability are the main causes of low bioavailability. This study aimed to improve these limitations by encapsulating rosmarinic acid in tetrasulfide-based porous organosilica nanoparticles to deliver it to cancer cells. To date, no reports on the use of these organosilica nanoparticles as a nanocarrier for rosmarinic acid. The synthesized nanoparticles were small, approximately 50 nm in size, with a high surface area of around 498.1 m2/g and an average pore diameter of 2.3 nm. Especially, fluorescent-labeled nanospheres were synthesized and further indicated the effective accumulation in the cytosol after 24 h incubation. In addition, the nanoparticles were non-toxic to human AGS gastric adenocarcinoma cells and mouse CT26 colon cancer cells within concentrations ranging from 0 to 240 μg/mL. Treatment with nanoparticles containing 140 μg/mL of rosmarinic acid resulted in the death of approximately 39.2 % of AGS cells and 36.9 % of CT26 cells after 72 h. Importantly, neither the silica nanospheres nor the rosmarinic acid-containing nanoparticles showed any significant toxic effects on HEK-293T and NIH-3T3 fibroblasts at the tested concentrations. These results suggested that the pharmacological effects of rosmarinic acid can be enhanced by encapsulating it into our novel synthesized biodegradable tetrasulfide-based porous organosilica nanoparticles.

Experimental and theoretical investigation of phytochemical euphol incorporated in ZIF-8 as a drug delivery system for cancer treatment

Cancer is one of the main causes of human death around the world. Nature can be a powerful source of bioactives with strong anticancer activity. Euphol, a triterpene alcohol extracted from the sap of E. tirucalli possesses antitumoral activity and could be a viable alternative for cancer treatment. However, drug delivery strategies could be required to minimize its toxicity and improve its stability. Metal–organic frameworks (MOFs) stand out among systems used as platforms for drug delivery. In this work, we report the extraction and isolation of euphol from nature, its adsorption in nanosized ZIF-8 (zeolitic imidazolate framework) with high-load, and we study the efficacy of this system against cancer cells. The ZIF-8 loaded with euphol is characterized by X-ray diffraction, infrared spectroscopy and scanning electron microscopy. To gain insights into the incorporation mechanism, host–guest interactions have been investigated through molecular docking simulations, suggesting that the interaction occurs at the surface, being driven mainly by euphol's hydroxyl binding to the Zn2+ cations on the framework as well as π - π staking interactions. Finally, in vitro investigations reveal that ZIF-8 considerably enhances the effectivity of euphol against cancer cell lines, while displaying selectivity for targeting cancer cells instead of healthy cells. This is the first report of the incorporation of euphol in a drug delivery system. The findings from this study can guide the development of novel biomaterials for cancer treatment.

Review of the efficacy of nanoparticle-based drug delivery systems for cancer treatment

This review evaluates the literature on nanoparticle-based drug delivery systems for cancer treatment and assesses their efficacy. Nanoparticles have shown potential for improving anticancer agent delivery, reducing systemic toxicity, and enhancing therapeutic outcomes. Extensive studies have shown promising results in preclinical and clinical trials. However, challenges such as limited drug loading capacity, stability issues, and potential side effects need to be addressed to enhance clinical translation. Researchers are exploring strategies to improve drug loading capacity, such as modifying nanoparticle surfaces or developing novel drug encapsulation techniques. By increasing drug loading, the therapeutic efficacy of these systems can be significantly enhanced. Stability issues also pose a hurdle in clinical translation. To overcome stability issues, researchers are investigating methods to enhance the stability of nanoparticles, such as using protective coatings or optimising the formulation. Additionally, efforts are being made to minimise potential side effects by carefully selecting biocompatible materials for nanoparticle synthesis and conducting rigorous toxicity studies before moving forward with clinical trials.

Recent advances in PLGA-based nanofibers as anticancer drug delivery systems

Polymeric nanofibers (NFs) as biocompatible and biodegradable scaffolds have been investigated in numerous biomedical fields such as cancer treatment and drug delivery systems. Electrospun nanofibers illustrate unique characteristics such as ease of fabrication, low cost, simple surface functionalization, high surface-to-volume ratio, and a high potential for drug encapsulation, hence attracting great interest in their development as efficient drug delivery systems (DDS). Nanofibers mats can be used to incorporate antitumor drugs for spatiotemporal controlled release of chemotherapeutic agents at a localized site over a period of time to reduce the toxicity and side effects to the healthy cells. This makes polymeric NFs as promising implantable patches in localized drug delivery systems for cancer treatment with empowered on-site delivery of chemotherapeutic drugs in a sustainable release manner after surgical resection. In this regard, Poly (lactic-co-glycolic acid) (PLGA) as one of the most widely used biocompatible and biodegradable polymers has attracted more attention in the fabrication of polymeric NFs. In the present review, we focus on the fabrication of PLGA-based nanofibers and the incorporation of chemotherapeutic agents into polymeric NFs for several biomedical applications covering controlled/implantable drug delivery systems, cancer detection, and local cancer treatment. We also discuss the current approaches, future perspectives, advantages, and limitations related to nanofibers in DDS and cancer treatment.

Ultrasound-mediated nano-sized drug delivery systems for cancer treatment: Multi-scale and multi-physics computational modeling.

Computational modeling enables researchers to study and understand various complex biological phenomena in anticancer drug delivery systems (DDSs), especially nano-sized DDSs (NSDDSs). The combination of NSDDSs and therapeutic ultrasound (TUS), that is, focused ultrasound and low-intensity pulsed ultrasound, has made significant progress in recent years, opening many opportunities for cancer treatment. Multiple parameters require tuning and optimization to develop effective DDSs, such as NSDDSs, in which mathematical modeling can prove advantageous. In silico computational modeling of ultrasound-responsive DDS typically involves a complex framework of acoustic interactions, heat transfer, drug release from nanoparticles, fluid flow, mass transport, and pharmacodynamic governing equations. Owing to the rapid development of computational tools, modeling the different phenomena in multi-scale complex problems involved in drug delivery to tumors has become possible. In the present study, we present an in-depth review of recent advances in the mathematical modeling of TUS-mediated DDSs for cancer treatment. A detailed discussion is also provided on applying these computational models to improve the clinical translation for applications in cancer treatment. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Exploring Capsaicin-Based Drug Delivery Systems for Cancer Treatment: A Review

Exploring Capsaicin-Based Drug Delivery Systems for Cancer Treatment: A Review

Enhanced anticancer effect of Artemisia turcomanica extract in niosomal formulation on breast cancer cells: In-vitro study

Artemisia turcomanica is a medicinal plant that has been used to treat hepatitis, fever, malaria, cancer, tumors and asthma, and is considered inexpensive. In this work, we report the synthesis of niosomes loaded with Artemisia turcomanica extract and its anti-cancer properties against MCF-7 cells, as model breast cancer cells. The formulation with the highest surfactant concentration had a maximum entrapment efficiency of approximately 71.21%. Moreover, at physiological pH (7.4), the niosomal formulations exhibited a slow-release profile within three days, while at lower pH (5.4), the release rate was more significant. While the designed drug delivery system showed high biocompatibility against non-tumorigenic breast cells (MCF-10A), it showed high cytotoxicity against breast cancer cells (MCF-7 cell line). The anti-cancer effect of the Artemisia turcomanica-loaded niosomal formulation was significantly higher than free Artemisia turcomanica and pristine niosomes. The enhanced anti-cancer effect was further confirmed by regulation of different gene expression levels in MCF-7 cells and cell cycle analysis. The results of this study show the great potential of plant extract-loaded niosomes, in particular Artemisia turcomanica-loaded niosomes, as effective drug delivery systems for cancer treatment, which could impact on the future of traditional medicine cum modern medicine.

Emerging Trends in Nano-Theranostics: Platinum-based Drug Delivery Systems for Cancer Treatment

Nanotechnology is the most common and frequently used technology that aims to improve the efficacy of medical procedures, sometimes known as Nanomedicine. With their impressive pharmacological efficacy as nanomedicines and delivery systems, nano materials have been recognized as attractive diagnostic and chemotherapeutic tools to treat diseases. To treat a wide range of solid malignant tumors, Drugs built on platinum complexes are now the foundation for many other therapies. They are often used to treat a varietym of solid tumors in the clinic, including head and neck, colorectal, lung and other malignancies. Cell-specific targeting with nano-carriers is possible using both active and passive techniques. This paper provides a thorough overview of platinum-based drug delivery system with the help of nanotechnology. Their mechanisms of action used in the treatment of cancer and potential for further development are all anticipated.