Development Of Drug Delivery Systems Research Articles

Facile preparation of copper-gallic acid nanoparticles as a high reproducible and drug loading platform for doxorubicin

PurposeDoxorubicin (DOX) is the first line drug for cancer chemotherapy but its application is limited by the poor bioavailability and high side effects. Current drug delivery systems (DDSs) of DOX can overcome the above mentioned shortages, but also brings new challenges including low reproducibility and DOX loading. Therefore, the one-step preparation of related DDSs with high DOX loading capacity is highly desirable. MethodsHerein, taking advantage of the high complexing ability of both gallic acid (GA) and DOX to metal ions, copper ion was selected as a model ion to serve as a medium, not only to form nanostructured platform with GA, but also as a linker to give high DOX loading capacity to the developed DDSs. ResultsWe herein introduced a facile method to conveniently prepare DOX loaded DDSs (Cu-GA-DOX NPs) with high reproducibility and drug loading of DOX (23.07%), which also showed uniform particle size, good biocompatibility as well as decent anticancer performance on model colorectal cancers (CT26). ConclusionThis study provides a new strategy and pave the way for the subsequent development of DDS with high reproducibility and DOX loading.

Sustainable Green Synthesis of Yttrium Oxide (Y2O3) Nanoparticles Using Lantana camara Leaf Extracts: Physicochemical Characterization, Photocatalytic Degradation, Antibacterial, and Anticancer Potency.

Due to their appropriate physicochemical properties, nanoparticles are used in nanomedicine to develop drug delivery systems for anticancer therapy. In biomedical applications, metal oxide nanoparticles are used as powerful and flexible multipurpose agents. This work described a green synthesis of Y2O3 nanoparticles (NPs) using the sol-gel technique with the use of aqueous leaf extracts of Lantana camara L (LC). These nanoparticles were characterized with the aid of different methods, including UV, X-ray diffraction (XRD), Fourier transformed infrared spectroscopy (FTIR), transmitted electron microscopy (TEM), and photocatalytic degradation. Y2O3 nanoparticles showed excellent antibacterial activity against Gram-positive Bacillus subtilis and Gram-negative Escherichia coli with a 10 to 15 mm inhibitory zone. Green Y2O3 NPs were released with a 4 h lag time and 80% sustained release rate, indicating that they could be used in drug delivery. In addition, the bioavailability of green Y2O3 NPs was investigated using cell viability in cervical cancer cell lines. These green-synthesized Y2O3 NPs demonstrated photocatalytic degradation, antibacterial, and anticancer properties.

Customized 3D-printed hollow capsular device filled with norfloxacin-loaded micropellets for controlled-release delivery.

Pharmacotherapy has become more focused on the personalized treatment of patients with various diseases. This field of pharmacology and pharmacogenomics focuses on developing drug delivery systems designed to address the unique characteristics of individual patients. Three-dimensional printing technology can be used to fabricate personalized drug delivery systems with desired release properties according to patient needs. Norfloxacin (NOR)-loaded micropellets (MPs) were fabricated and filled inside a stereolithography (SLA) 3D printing technology-mediated hollow capsular device in accordance with a standard size of 09 (8.4mm length × 2.70mm diameter). The prepared 3D-printed hollow capsular device filled with pristine NOR and NOR-loaded MPs were characterized in terms of both in vitro and in vivo means. MPs with the particle size distribution of 1540.0 ± 26µm showed 95.63 ± 2.0% NOR content with pellet-shaped surface morphology. The in vitro release profile showed an initial lag phase of approximately 30min, followed by the sustained release of NOR from MPs from the 3D-printed hollow capsular device. The pharmacokinetic profile showed prolonged Tmax, AUC, and evidence of good RBA of NOR compared to pure NOR after a single oral administration in the experimental animal model. The overall results confirm the feasibility of SLA-mediated 3D printing technology for preparing customized solid oral unit dosage carriers that can be filled with pure NOR- and NOR-loaded MPs with controlled-release delivery features.

Chemical Conjugation in Drug Delivery Systems.

Cancer is one of the diseases with the highest mortality rate. Treatments to mitigate cancer are usually so intense and invasive that they weaken the patient to cure as dangerous as the own disease. From some time ago until today, to reduce resistance generated by the constant administration of the drug and improve its pharmacokinetics, scientists have been developing drug delivery system (DDS) technology. DDS platforms aim to maximize the drugs’ effectiveness by directing them to reach the affected area by the disease and, therefore, reduce the potential side effects. Erythrocytes, antibodies, and nanoparticles have been used as carriers. Eleven antibody–drug conjugates (ADCs) involving covalent linkage has been commercialized as a promising cancer treatment in the last years. This review describes the general features and applications of DDS focused on the covalent conjugation system that binds the antibody carrier to the cytotoxic drug.

Polyaphron Formulations Stabilised with Different Water-Soluble Polymers for Ocular Drug Delivery.

As drug delivery to the eye has evolved over the last decades, researchers have explored more effective treatments for ocular diseases. Despite this, delivering drugs to the cornea remains one of the most problematic issues in ophthalmology due to the poor permeability of the cornea and tear clearance mechanisms. In this study, four different types of polyaphron formulations are prepared with 10% poloxamer 188 (P188), 10% poly(2-ethyl-2-oxazoline), 1% polyquaternium 10, and 3% sodium carboxymethylcellulose solutions mixed with 1% Brij® L4 in a caprylic/capric triglycerides solution. Their physicochemical characteristics, rheological properties, and stability are assessed. Additionally, a polyaphron with 3% polyquaternium 10 was prepared for the assessment of ex vivo corneal retention along with four other polyaphrons. The best retention on the ex vivo cornea was displayed by the 3% polyquaternium 10-based formulation. The 10% poloxamer 188 along with 1% polyquaternium 10-based polyaphrons appeared to be the most stable among the four prepared formulations. A toxicological evaluation of these formulations was performed using a slug mucosal irritation test and bovine corneal opacity and permeability assay, with all four polyaphrons proving good biocompatibility with ocular tissues. The developed drug delivery systems demonstrated an excellent potential for ocular drug delivery.

The emerging potential of crystalline drug‐polymer combination for medical applications

AbstractThere is a great potential in combining carrier‐free crystalline‐based drug delivery systems (DDSs) within polymeric implants/scaffolds in a manner that preserves each components' independent functionality, stability, and advantages. We believe that this will open new avenues in drug delivery research as well as accelerate polymers and crystalline‐based DDSs developments.

Fabrication and Modelling of a Reservoir-Based Drug Delivery System for Customizable Release.

Localized therapy approaches have emerged as an alternative drug administration route to overcome the limitations of systemic therapies, such as the crossing of the blood–brain barrier in the case of brain tumor treatment. For this, implantable drug delivery systems (DDS) have been developed and extensively researched. However, to achieve an effective localized treatment, the release kinetics of DDS needs to be controlled in a defined manner, so that the concentration at the tumor site is within the therapeutic window. Thus, a DDS, with patient-specific release kinetics, is crucial for the improvement of therapy. Here, we present a computationally supported reservoir-based DDS (rDDS) development towards patient-specific release kinetics. The rDDS consists of a reservoir surrounded by a polydimethylsiloxane (PDMS) microchannel membrane. By tailoring the rDDS, in terms of membrane porosity, geometry, and drug concentration, the release profiles can be precisely adapted, with respect to the maximum concentration, release rate, and release time. The release is investigated using a model dye for varying parameters, leading to different distinct release profiles, with a maximum release of up to 60 days. Finally, a computational simulation, considering exemplary in vivo conditions (e.g., exchange of cerebrospinal fluid), is used to study the resulting drug release profiles, demonstrating the customizability of the system. The establishment of a computationally supported workflow, for development towards a patient-specific rDDS, in combination with the transfer to suitable drugs, could significantly improve the efficacy of localized therapy approaches.

Temperature and Tumor Microenvironment Dual Responsive Mesoporous Magnetic Nanospheres for Magnetothermal Effect-Induced Cancer Theranostics

Temperature and Tumor Microenvironment Dual Responsive Mesoporous Magnetic Nanospheres for Magnetothermal Effect-Induced Cancer Theranostics

Drug Delivery Systems for Photodynamic Therapy: The Potentiality and Versatility of Electrospun Nanofibers

Recently, photodynamic therapy (PDT) has become a promising approach for the treatment of a broad range of diseases, including oncological and infectious diseases. This minimally invasive and localized therapy is based on the production of reactive oxygen species able to destroy cancer cells and inactivate pathogens by combining the use of photosensitizers (PSs), light, and molecular oxygen. To overcome the drawbacks of drug systemic administration, drug delivery systems (DDS) can be used to carrier the PSs, allowing higher therapeutic efficacy and minimal toxicological effects. Polymeric nanofibers produced by electrospinning emerged as powerful platforms for drug delivery applications. Electrospun nanofibers exhibit outstanding characteristics, such as large surface-area-to-volume ratio associated with high drug loading, high porosity, flexibility, ability to incorporate and release a wide variety of therapeutic agents, biocompatibility, and biodegradability. Due to the versatility of this technique, fibers with different morphologies and functionalities, including drug release profile can be produced. The possibility of scalability makes electrospinning even more attractive for the development of DDS. This review aims to explore and show an up to date of the huge potential of electrospun nanofibers as DDS for different PDT applications and discuss the opportunities and challenges in this field.

DNA‐Based Nanoarchitectures as Eminent Vehicles for Smart Drug Delivery Systems

AbstractIn order to cure diseases efficiently with minimal side effects in sophisticated medicine, eminent drugs must be selectively delivered to diseased parts and allow to work only there. However, most of drug delivery systems (DDSs) previously proposed are not yet sufficiently selective and effective. This review covers recent developments of DDS in which DNA nanoarchitectures are employed as drug carriers. From short DNA fragments, a variety of complicated nanomedicines are fabricated to show unprecedentedly smart DDS functions. Encapsulated drugs are released mostly through controlled disassembly of DNA nanoarchitectures. Recent attention has been focusing to the use of appropriate stimuli to regulate each process in the DDS (delivery of drug, its release, and others) for further improved therapy. As intracellular stimuli for the regulation, various endogenous compounds (e.g., mRNA and enzymes), which are specifically abundant in target cells, are employed. Alternatively, physical perturbation (e.g., light irradiation) is provided from outside of tissues to control DDS. By combining multiple strategies in terms of new concepts, enormously smart DDSs are being achieved. Further progresses of these approaches in the future are guaranteed by complete freedom of molecular design in DNA nanoarchitectonics.

A Review on Chitosan in Drug Delivery for Treatment of Neurological and Psychiatric Disorders.

Neurological diseases are known as global health problems with a growing number of patients annually. Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease as well as spinal cord injury, hypoxic ischemia injury, epilepsy, depression and etc., are some examples of neurological diseases. One of the main problems in the treatment of these diseases is the delivery of drugs across the blood-brain barrier (BBB). These days, researchers have tended to find non-invasive and non-toxic strategies for solving this problem. As a non-toxic, safe, and potential agent, chitosan has attracted attention for use in drug delivery systems. Recently, numerous studies have been designed to develop drug delivery systems by using chitosan to treat various neurological diseases. In this paper, the latest developments of chitosan and its derivatives utilization in the drug delivery systems for the treatment of different neurological and psychiatric diseases were reviewed.

A higher dose of PEGylated gold nanoparticles reduces the accelerated blood clearance phenomenon effect and induces spleen B lymphocytes in albino mice.

Polyethylene glycol (PEG) is a multifunctionalpolymer that has many uses in medical and biological applications. Recently, PEG has been mainly used in developing nanomaterial-based drug delivery systems (DDS). PEG is characterized by its high solubility, biological inertness, and ability to escape from immune cells (stealthiness) after systemic injection. The most challenging problem for PEGylated nanomaterials is their rapid elimination from the bloodstream after repeated doses of systemic injection, called accelerated blood clearance (ABC). Therefore, in this study, the effect of PEGylated nanomaterial dose concentration on ABC induction will be investigated using quantitative, histological, and immunohistochemical analyses. A higher dose concentration (2mg/kg) of PEGylated gold nanoparticles (PEG-coated AuNPs) reduced the ABC phenomenon when intravenously injected into mice preinjected with the same dose. In contrast, a lower dose concentration (< 1mg/kg) significantly induced the ABC phenomenon by the rapid elimination of the second dose of PEG-coated AuNPs from the bloodstream. To explain the relationship between the dose concentration (from PEG and AuNPs) and the induction of ABC, the biodistribution of PEG-coated AuNPs in liver and spleen [reticuloendothelial systems (RES)-rich organs] was investigated. The injected dose of PEG-coated AuNPs accumulated mainly in the hepatic Kupffer cells and hepatocytes. Similarly, spleen red pulp received a higher amount of the injected dose of PEG-coated AuNPs. However, the biodistriution profiles of PEG-coated AuNPs after the first and second dose for different dose concentrations varied in RES-rich organs. Additionally, the number of B lymphocytes, which have an important role in producing anti-PEG immunoglobulin (Ig)M, was affected by the repeated dose of PEG-coated AuNPs in the spleen. Therefore, for effective nanomaterial-based DDS development, dose optimization of PEG molecules that express PEGylated nanomaterials is important to reduce the ABC phenomenon effect. The ideal concentration of PEG molecules used to coat nanomaterials and the role of RES-rich organs must be determined to control the ABC phenomenon effect of PEGylated nanomaterials.

The Intracellular and Extracellular Microenvironment of Tumor Site: The Trigger of Stimuli-Responsive Drug Delivery Systems.

The tumor microenvironment (TME), including intracellular and extracellular microenvironment, contains many biochemical indicators (such as acidity/alkalinity, oxygen content, and enzymatic activity) that are different from the normal physiological environment. These abnormal biochemical indicators can accelerate the heterogeneity of tumors, but on the other hand, they also provide opportunities for the design of intelligent drug delivery systems (DDSs). The TME-responsive DDSs have shown great potential in reducing the side effects of chemotherapy and improving the curative effect of tumors. In this review, the abnormal biochemical indicators of TME are introduced in detail from both the extracellular and intracellular aspects. In view of the various physiological barriers encountered during drug delivery, the strategy of constructing TME-responsive DDSs is discussed. By summarizing the typical research progress, the authors prospect the development of TME-responsive DDS in the future.

Simultaneous quantification of oligo-nucleic acids and a ferritin nanocage by size-exclusion chromatography hyphenated to inductively coupled plasma mass spectrometry for developing drug delivery systems.

An analytical methodology, which can quantify nucleic acids, ferritin nanocages, and their complexes in a single injection, was established by means of size-exclusion chromatography hyphenated with inductively coupled plasma mass spectrometry (SEC-ICP-MS). In this study, several oligo-nucleic acids and ferritin (a human-derived cage-shaped protein) were used as model compounds of nucleic acid drugs (NAD) and drug delivery system (DDS) carriers, respectively. A fraction based on the nucleic acid-ferritin complex was completely distinguished from one based on free nucleic acids by SEC separation. The nucleic acids and ferritin were quantified based on the number of phosphorus and sulfur atoms, respectively. The quantification was carried out by an external calibration method using a series of elemental standard solutions without preparing designated standard materials for each drug candidate. The analytical performance, including sensitivity and accuracy, was evaluated to be appropriate for evaluating the medicines already launched in the market. As demonstrated in the latter part of this study, the encapsulation mechanism is possibly regulated by not only the averaged molecular size of nucleic acids but also the surface charge related to the number of (deoxy-) ribonucleotides. We believe that the methodology presented in this study has the potential to accelerate the development of new modalities based on NAD-DDS to realize therapies in the future.

Current situation and progress of drugs for reducing intraocular pressure.

Glaucoma, the most common cause of irreversible blindness worldwide, usually causes characteristic optic nerve damage. Pathological intraocular pressure (IOP) elevation is a major risk factor. Drug reduction of IOP is the preferred treatment for clinicians because it can delay the progression of disease. However, the traditional IOP-lowering drugs currently used by patients may be poorly tolerated. Therefore, in recent years, some new drugs have been put into clinical application or in clinical phase I-III studies. They have a better IOP-lowering effect and fewer adverse reactions. Because glaucoma is a chronic disease, drugs need to be administered continuously for a long time. For patients, good compliance and high drug bioavailability have a positive effect on the prognosis of the disease. Therefore, clinicians and scientists have developed drug delivery systems to solve this complex problem. In addition, natural compounds and dietary supplements have a good effect of reducing IOP, and they can also protect the optic nerve through antioxidant action. We summarize the current traditional drugs, new drugs, sustained-release drug delivery systems, and complementary drugs and outline the mechanism of action and clinical effects of these drugs on glaucoma and their recent advances.

A preliminary study of the innate immune memory of Kupffer cells induced by PEGylated nanoemulsions

The accelerated blood clearance (ABC) phenomenon describes a dilemma of polyethylene glycol (PEG) applied in drug delivery system (DDS) caused by its immunogenicity, that results in the enhanced blood clearance rate and increased hepatic and splenic accumulation after secondary injection of PEGylated nanocarriers. However, the ABC index, as the judgement of ABC phenomenon, only describes the accelerated blood clearance rate, but ignores the enhanced hepatic and splenic accumulation. Therefore, we proposed the hepatic accumulation (HA) index and the splenic accumulation (SA) index as supplements for assessing the ABC phenomenon, to emphasize the contribution of liver and spleen, especially the liver, possessing the most population of tissue resident macrophages. By altering the first injection site from the tail vein to the liver portal vein, there was no impact on anti-PEG IgM production, and the secondary hepatic accumulation of PEGylated nanoemulsions (PE) was observed to be proportionate to the first PE stimulation strength on the liver. We also determined that Kupffer cells (KCs) were the main contributor to this enhancement. On this basis, we revealed a definite phenomenon that PE could induce innate immune memory in KCs, by enhancing the phagocytosis of KCs toward PE during the secondary stimulation. The PE-stimulated KCs could carry this memory to the naïve rats through adoptive transfer, resulting in increased hepatic accumulation in the recipient rats without antibody production. Studies examining the phagocytosis of KCs in vivo, ex vivo and in vitro revealed that the memory of KCs against PE triggered by first-stimulated PE could be maintained independently of other cells or components until 21 days after the first stimulation, and possessing specificity to PEG, which was invalid to long-circulating GE (GM1 modified nanoemulsions). The discovery of immune memory in KCs induced by PE highlights the importance of focusing on the relationship between the innate immune system and PEGylated nanocarriers during the development of DDS to improve medication safety in the clinic.

Advances in Injectable In Situ-Forming Hydrogels for Intratumoral Treatment.

Chemotherapy has been linked to a variety of severe side effects, and the bioavailability of current chemotherapeutic agents is generally low, which decreases their effectiveness. Therefore, there is an ongoing effort to develop drug delivery systems to increase the bioavailability of these agents and minimize their side effects. Among these, intratumoral injections using in situ-forming hydrogels can improve drugs’ bioavailability and minimize drugs’ accumulation in non-target organs or tissues. This review describes different types of injectable in situ-forming hydrogels and their intratumoral injection for cancer treatment, after which we discuss the antitumor effects of intratumoral injection of drug-loaded hydrogels. This review concludes with perspectives on the future applicability of, and challenges for, the adoption of this drug delivery technology.

Thioether-Based Polymeric Micelles with Fine-Tuned Oxidation Sensitivities for Chemotherapeutic Drug Delivery.

Oxidation-sensitive drug delivery systems (DDSs) have attracted attention due to the potential to improve efficacy and safety of chemotherapeutics. These systems are designed to release the payload in response to oxidative stress conditions, which are associated with many types of cancer. Despite extensive research on the development of oxidation-sensitive DDS, the lack of selectivity toward cancer cells over healthy cells remains a challenge. Here, we report the design and characterization of polymeric micelles containing thioether groups with varying oxidation sensitivities within the micellar core, which become hydrophilic upon thioether oxidation, leading to destabilization of the micellar structure. We first used the thioether model compounds, 3-methylthiopropylamide (TPAM), thiomorpholine amide (TMAM), and 4-(methylthio)benzylamide (TPhAM) to investigate the effect of the chemical structures of the thioethers on the oxidation by hydrogen peroxide (H2O2). TPAM shows the fastest oxidation, followed by TMAM and TPhAM, showing that the oxidation reaction of thioethers can be modulated by changing the substituent groups bound to the sulfur atom. We next prepared micelles containing these different thioether groups within the core (TP, TM, and TPh micelles). The micelles containing the thioether groups with a higher oxidation sensitivity were destabilized by H2O2 at a lower concentration. Micelle destabilization was also tested in human liver cancer (HepG2) cells and human umbilical vein endothelial cells (HUVECs). The TP micelles having the highest oxidation sensitivity were destabilized in both HepG2 cells and HUVECs, while the TPh micelles, which showed the lowest reactivity toward H2O2, were stable in these cell lines. The TM micelles possessing a moderate oxidation sensitivity were destabilized in HepG2 cells but were stable in HUVECs. Furthermore, the micelles were loaded with doxorubicin (Dox) to evaluate their potential in drug delivery applications. Among the micelles, the TM micelles loaded with Dox showed the enhanced relative toxicity in HepG2 cells over HUVECs. Therefore, our approach to fine-tune the oxidation sensitivity of the micelles has potential for improving therapeutic efficacy and safety of drugs in cancer treatment.

Nose to brain delivery of Efavirenz nanosuspension for effective neuro AIDS therapy: in-vitro, in-vivo and pharmacokinetic assessment

Efavirenz is inhibitor of non-nucleoside reverse transcriptase enzyme; BCS class II drug. The objective of the present research was to prepare and evaluate nanosuspension of Efavirenz for the treatment of neuro-AIDS. Efavirenz is the substrate for drug resistant proteins at BBB prone to efflux and could not reach brain with effective levels. Current need of the therapy is to develop drug delivery systems targeting viral reservoirs at effective concentration in the brain. With this need we developed Efavirenz nanosuspension for nose to brain drug transport to bypass blood brain barrier. Nanosuspension prepared with high-pressure homogenization had a mean particle size of 223 nm, PDI of 0.2 and -21.2 mV zeta potential. Histopathology study on goat nasal mucosa showed no adverse effects of formulation on nasal tissues. Gamma scintigraphy study and in-vivo study on Wistar rat model reveals drug transport to the CNS after nasal administration. Pharmacokinetic parameters and drug targeting potential of 99.46 % suggest direct nose to brain transport of Efavirenz nanoparticle. Results reveal that nose to brain delivery of Efavirenz is the best possible alternative for neuro –AIDS treatment.

Carboxylated chitosan-mediated improved efficacy of mesoporous silica nanoparticle-based targeted drug delivery system for breast cancer therapy

Nanoparticle-based targeting of overexpressed cell-surface receptors is a promising strategy that provides precise delivery of drugs to cancer cells. In the present study, we developed highly reproducible and monodispersed, chitosan-coated (pH-responsive), doxorubicin-loaded, aptamer-mesoporous silica nanoparticle (MSN) bioconjugates for actively targeting breast cancer cells harboring overexpression of EGF receptors (EGFR/HER2). The developed targeted MSNs demonstrated higher uptake and cytotoxicity of triple negative and HER2 positive breast cancer cells when compared to non-targeted MSNs. The chitosan coating imparted pH-responsiveness and endo/lysosomal escape ability to MSNs, which augmented cytosolic delivery of an anticancer drug. Partial carboxylation of chitosan coated on MSNs allowed for a greater release of drug in a shorter duration of time while retaining pH-responsiveness and endo/lysosomal escape ability. Overall, the coating of carboxylated-chitosan over MSNs enabled tunable drug release kinetics, conjugation of aptamers (targeting agents), and endo/lysosomal escape which together significantly enhanced the efficacy of the developed drug delivery system.