Drug-loaded Nano Research Articles

A drug-loaded nano chitosan/hyaluronic acid hydrogel system as a cartilage tissue engineering scaffold for drug delivery

Cartilage lesions, especially osteoarthritis (OA), usually arise from aging, trauma, or obesity and require medical intervention due to the damaged site's inflammation and the cartilage tissue's poor self-healing capacity. This study aimed to prepare a drug-loaded nanoparticle hydrogel system with anti-inflammatory and chondroprotective effects to treat OA. First, hyaluronic acid (HA) was oxidized to create aldehyde functional groups and then cross-linked with adipic acid dihydrazide (ADH) to form a hydrogel. Next, chitosan nanoparticles (CS NPs) loaded with an anti-inflammatory molecule (fisetin) and or a chondrogenic and chondroprotective agent (kartogenin) were incorporated into the hyaluronan hydrogel to improve the release profile of the drug and increase its retention time in the joint cavity. Incorporating drug-loaded NPs into the hyaluronan hydrogel provided the hydrogel with controlled release features and improved properties. In addition, the real-time PCR (Polymerase chain reaction) results showed that the hyaluronan hydrogel containing both drug-loaded NPs performed better than either constituent alone on an in vitro model of OA. Finally, based on the results of in vitro evaluation, this drug-loaded nanoparticle hydrogel system can be a promising technique for treating OA by rapidly suppressing inflammation and supporting cartilage regeneration and requires further investigation in an animal model of OA. Meanwhile, this study investigated, for the first time, the effect of the simultaneous use of fisetin and kartogenin together with a nano CS/HA hydrogel system to treat OA.

Assessment of In Vitro Release Testing Methods for Colloidal Drug Carriers: The Lack of Standardized Protocols.

Although colloidal carriers have been in the pipeline for nearly four decades, standardized methods for testing their drug-release properties remain to be established in pharmacopeias. The in vitro assessment of drug release from these colloidal carriers is one of the most important parameters in the development and quality control of drug-loaded nano- and microcarriers. This lack of standardized protocols occurs due to the difficulties encountered in separating the released drug from the encapsulated one. This review aims to compare the most frequent types of release testing methods (i.e., membrane diffusion techniques, sample and separate methods and in situ detection techniques) in terms of the advantages and disadvantages of each one and of the key parameters that influence drug release in each case.

Synthesis and properties of novel drug-loaded nano micelles based on Jerusalem Artichoke polysaccharides.

To develop a novel polymeric nano micelle drug delivery system, JAP-based drug-loaded nano micelles (FFC/JAP-HA) were prepared by chemical modification/ultrasound/molecular self-assembly method. The results showed that JAP was connected with hyaluronic acid (HA) by an ester bond, the particle sizes of FFC/JAP-HA were 329.8 ± 2.3 nm, and the critical micelle concentration (CMC) of FFC/JAP-HA was 3.3 × 10−2 mg/mL. The hemolysis results, cytotoxicity test results, and histological results also showed that the FFC/JAP-HA had good biocompatibility. Furthermore, pharmacokinetic results suggested that the retention time (MRTINF_obs) of FFC/JAP-HA could be extended to 918.23 ± 37.25 min, which laid a foundation for the development of a new polymeric nano micelle drug loading system.

A novel convex acoustic lens-attached ultrasound drug delivery system and its testing in a murine melanoma subcutaneous model

Target-specific drug release is indispensable to improve chemotherapeutic efficacy as it enhances drug uptake and penetration into tumors. Sono-responsive drug-loaded nano-/micro-particles are a promising solution for achieving target specificity by exposing them to ultrasound near tumors. However, the complicated synthetic processes and limited ultrasound (US) exposure conditions, such as limited control of ultrasound focal depth and acoustic power, prevent the practical application of this approach in clinical practice. Here, we propose a convex acoustic lens-attached US (CALUS) as a simple, economic, and efficient alternative of focused US for drug delivery system (DDS) application. The CALUS was characterized both numerically and experimentally using a hydrophone. In vitro, microbubbles (MBs) inside microfluidic channels were destroyed using the CALUS with various acoustic parameters (acoustic pressure [P], pulse repetition frequency [PRF], and duty cycle) and flow velocity. In vivo, tumor inhibition was evaluated using melanoma-bearing mice by characterizing tumor growth rate, animal weight, and intratumoral drug concentration with/without CALUS DDS. US beams were measured to be efficiently converged by CALUS, which was consistent with our simulation results. The acoustic parameters were optimized through the CALUS-induced MB destruction test (P = 2.34 MPa, PRF = 100 kHz, and duty cycle = 9%); this optimal parameter combination successfully induced MB destruction inside the microfluidic channel with an average flow velocity of up to 9.6 cm/s. The CALUS also enhanced the therapeutic effects of an antitumor drug (doxorubicin) in vivo in a murine melanoma model. The combination of the doxorubicin and the CALUS inhibited tumor growth by ∼ 55% more than doxorubicin alone, clearly indicating synergistic antitumor efficacy. Our tumor growth inhibition performance was better than other methods based on drug carriers, even without a time-consuming and complicated chemical synthesis process. This result suggests that our novel, simple, economic, and efficient target-specific DDS may offer a transition from preclinical research to clinical trials and a potential treatment approach for patient-centered healthcare.

Nanomedicine - a boon for respiratory disease management

Respiratory diseases affect the lungs and other parts of the respiratory system. The respiratory disease affects hundreds of millions of humans, and premature death is observed in nearly four million people yearly. The major cause of the increase in this disease is the increased level of air pollution and higher tobacco usage in public places.We have used the search engines PubMed and Google Scholar for the keywords Respiratory diseases, Nanomaterials, diagnosis, Nanomedicine, and Target drug delivery; recent and relevant articles are selected for reviewing this paper.Nanomedicine is a recent field of research that deals with monitoring, repairing, theragnosis, and development of human biological systems at the sub-atomic level, where we utilize engineered nanodevices and nanostructures. The conventional therapeutic strategies designed for respiratory diseases have limited solubility and bioavailability. Moreover, the robust effect of the drugs led to adverse side effects due to their high dose requirement. The local delivery of therapeutic Nanoparticles (NPs) or drug-loaded nano vehicles to the lung is a safe technique for managing various respiratory tract-related diseases like chronic obstructive pulmonary diseases, cystic fibrosis, lung cancer, tuberculosis, asthma, and infection. To overcome the difficulties of conventional treatment with antibiotics and anti-inflammatory drugs, nano-enabled drug delivery, nanoformulations of drugs as well as drug nanoencapsulation have been used recently. In this mini-review, we will discuss the importance and application of nanomedicine for diagnosis, treatment and clinical research involved in the different types of respiratory diseases.Nanomedicine provides an alternative delivery of drugs with the help of various nanocarriers, which enhances controlled drug delivery at the pulmonary region and can be used for treating and diagnosing respiratory diseases in vivo and in vitro studies. Further experiments followed by clinical examination are warranted to prove the potential application of nanomedicine in treating respiratory disease.This mini-review will help the readers and budding scientists apply new methods for developing highly efficient drugs with low side effects and improved targeted sites of action.

Controlled Delivery of Corticosteroids Using Tunable Tough Adhesives.

Hydrogel-based drug delivery systems typically aim to release drugs locally to tissue in an extended manner. Tissue adhesive alginate-polyacrylamide tough hydrogels are recently demonstrated to serve as an extended-release system for the corticosteroid triamcinolone acetonide. Here, the stimuli-responsive controlled release of triamcinolone acetonide from the alginate-polyacrylamide tough hydrogel drug delivery systems (TADDS) and evolving new approaches to combine alginate-polyacrylamide tough hydrogel with drug-loaded nano and microparticles, generating composite TADDS is described. Stimulation with ultrasound pulses or temperature changes is demonstrated to control the release of triamcinolone acetonide from the TADDS. The incorporation of laponite nanoparticles or PLGA microparticles into the tough hydrogel is shown to further enhance the versatility to control and modulate the release of triamcinolone acetonide. A first technical exploration of a TADDS shelf-life concept is performed using lyophilization, where lyophilized TADDS are physically stable and the bioactive integrity of released triamcinolone acetonide is demonstrated. Given the tunability of properties, the TADDS are a suggested technology platform for controlled drug delivery.

Effect of Air-Containing Liposome Ultrasound Nano-Bubbles in the Pathological Diagnosis of Ovarian Cancer

Compared with micron-sized ultrasound contrast agents, the use of nano-carriers and blood vessels to penetrate into the tissue for imaging and the installation of therapeutic agents in the contrast agent carrier has become one of the current development trends of contrast agents. In this study, based on the self-assembly characteristics of phospholipid molecules on the surface of free bubbles, lipid-encapsulated nano-bubbles were prepared and optimized. Firstly, sulfur hexafluoride (SF6) type nano-dissolved gas water was prepared based on the dissolved air pump method, and then it was combined with the dried phospholipids to form the air-containing liposomes (ACL). After the nano ACL was generated, it was undertaken as drug carrier, and Baze was used as a model drug to analyze its inhibitory effect on triple-negative breast cancer cells. Finally, in the clinical field, ultrasound combined with cancer antigen 125 (CA125) loaded with nano ACL was used for early pathological diagnosis of ovarian epithelial cancer. The test results showed that the distribution peak of the nano-dissolved gas water particles appeared at 140 nm, and the peak shifted after addition of sodium chloride (NaCl) or bazedoxifene (Baze), proving the existence of free nano-bubbles in the dissolved gas water. The number of layers of nano ACL was 4˜14, and the particle size was 193.8±6.2 nm. Under the conditions of in vitro ultrasound, both perfusion imaging and aggregation imaging showed strong ultrasound imaging effects. With the addition of drug-loaded ACL and 42.8 kPa ultrasound, the survival rate of MDA-MB-231 breast cancer cells was only 61.28±2.38%, which meant that the drug-loaded nano ACL + ultrasound can significantly inhibit the cells survival rate (P <0.05). Ultrasound combined with CA125 loaded with nano ACL can greatly improve the early pathological diagnosis rate of epithelial ovarian cancer, and the corresponding positive rate exceeded 90% (P <0.05).

Pharmaceutical Considerations of Nasal In-Situ Gel As A Drug Delivery System

In situ gelling drug delivery systems have gained enormous attention over the last decade. They are in a sol-state before administration, and they are capable of forming gels in response to different endogenous stimuli, such as temperature increase, pH change and the presence of ions. Such systems can be administered through different routes, to achieve local or systemic drug delivery and can also be successfully used as vehicles for drug-loaded nano- and microparticles. Natural, synthetic and/or semi-synthetic polymers with in situ gelling behaviour can be used alone, or in combination, for the preparation of such systems; the association with mucoadhesive polymers is highly desirable in order to further prolong the residence time at the site of action/absorption. Nasal drug delivery is a better alternative of oral and parental route due to high permeability of Nasal epithelium, rapid drug absorption, avoid Hepatic first pass metabolism, increased bioavailability of drug, minimized local and systemic side effects, Low dose required, Direct transport into systemic circulation and CNS is also possible (passing blood brain barrier), Improved patient compliance, Self-Medication is Possible, prevent Gastro intestinal tract Ulceration. Recently, it has been shown that many drugs have better bioavailability by nasal route than the oral route. Thus, this review focuses on nasal drug delivery, various aspects of nasal anatomy and physiology, nasal absorption mechanism, advantages & disadvantage composition of in situ gel, application and In-situ gels evaluations.

Design and optimization of nano invasomal gel of Glibenclamide and Atenolol combination: in vitro and in vivo evaluation

BackgroundThere are many circumstances where chronic disease is associated with other disorders, especially in diseases such as diabetes with noncommunicable disease risk factors, such as hypertension. The current therapies for treating such chronic comorbid diseases are limited and challenging due to the difficulties in overcoming the side effects from complex therapeutic treatment regimen. The present study is aimed to develop and optimize the combinational nano invasomal gel of Glibenclamide (GLB) and Atenolol (ATN) as a novel combination therapy for comorbid treatment of diabetic hypertensive patients. The developed formulations were characterized for various parameters, including in-vitro skin permeation, skin irritation, in-vivo antidiabetic, and antihypertensive activities.ResultsOCNIG showed that the % entrapment efficiency of GLB is 96.67 ± 0.65% and % entrapment efficiency of ATN is 93.76 ± 0.89%, flux of GLB (240.43 ± 1.76 μg/cm2/h), and flux of ATN (475.2 ± 1.54 μg/cm2/h) which was found to conform to the expected value. The results indicated desired release and permeation profiles. Optimized formulation showed significant pharmacokinetic properties, which shows improvement in bioavailability by 134.30% and 180.32% respectively for two drugs, when compared to marketed oral preparation. Pharmacodynamic studies showed improved and prolonged management of diabetes and hypertension in Wistar rats, compared to oral and drug-loaded nano invasomes formulations.ConclusionOverall, the results showed that nano invasomal gel was found to be a useful and promising transdermal delivery system for the treatment of concurrent diseases.

Recent Advances in the Development of In Situ Gelling Drug Delivery Systems for Non-Parenteral Administration Routes

In situ gelling drug delivery systems have gained enormous attention over the last decade. They are in a sol-state before administration, and they are capable of forming gels in response to different endogenous stimuli, such as temperature increase, pH change and the presence of ions. Such systems can be administered through different routes, to achieve local or systemic drug delivery and can also be successfully used as vehicles for drug-loaded nano- and microparticles. Natural, synthetic and/or semi-synthetic polymers with in situ gelling behavior can be used alone, or in combination, for the preparation of such systems; the association with mucoadhesive polymers is highly desirable in order to further prolong the residence time at the site of action/absorption. In situ gelling systems include also solid polymeric formulations, generally obtained by freeze-drying, which, after contact with biological fluids, undergo a fast hydration with the formation of a gel able to release the drug loaded in a controlled manner. This review provides an overview of the in situ gelling drug delivery systems developed in the last 10 years for non-parenteral administration routes, such as ocular, nasal, buccal, gastrointestinal, vaginal and intravesical ones, with a special focus on formulation composition, polymer gelation mechanism and in vitro release studies.

Targeted Theranostic Nano Vehicle Endorsed with Self‐Destruction and Immunostimulatory Features to Circumvent Drug Resistance and Wipe‐Out Tumor Reinitiating Cancer Stem Cells

The downsides of conventional cancer monotherapies are profound and enormously consequential, as drug-resistant cancer cells and cancer stem cells (CSC) are typically not eliminated. Here, a targeted theranostic nano vehicle (TTNV) is designed using manganese-doped mesoporous silica nanoparticle with an ideal surface area and pore volume for co-loading an optimized ratio of antineoplastic doxorubicin and a drug efflux inhibitor tariquidar. This strategically framed TTNV is chemically conjugated with folic acid and hyaluronic acid as a dual-targeting entity to promote folate receptor (FR) mediated cancer cells and CD44 mediated CSC uptake, respectively. Interestingly, surface-enhanced Raman spectroscopy is exploited to evaluate the molecular changes associated with therapeutic progression. Tumor microenvironment selective biodegradation and immunostimulatory potential of the MSN-Mn core are safeguarded with a chitosan coating which modulates the premature cargo release and accords biocompatibility. The superior antitumor response in FR-positive syngeneic and CSC-rich human xenograft murine models is associated with a tumor-targeted biodistribution, favorable pharmacokinetics, and an appealing bioelimination pattern of the TTNV with no palpable signs of toxicity. This dual drug-loaded nano vehicle offers a feasible approach for efficient cancer therapy by on demand cargo release in order to execute complete wipe-out of tumor reinitiating cancer stem cells.

Synthesis of core-crosslinked zwitterionic polymer nano aggregates and pH/Redox responsiveness in drug controlled release.

A new kind of core-crosslinked zwitterionic polymer nano aggregates was prepared by two steps: (1) terpolymers of lipoic acid, polyethylene glycol diglycidyl ether and l-lysine were prepared, forming nano aggregates with hydrodynamic radius of 80 nm-183 nm by self-assembly; (2) the crosslinking of the nano aggregates took place through a reaction of side chain group in lipoic acid structural unit with 1,4-dimercaptothreotol, producing zwitterionic polymer core-crosslinked nano aggregates. The aggregates were stable against dilution and protein adsorption, and they demonstrated good pH/redox dual-responsiveness due to the introduction of disulfide bonds and zwitterionic groups to the nano aggregates. Doxorubicin (DOX) was loaded into the nano aggregates for controlled release. The drug-loaded nano aggregates exhibited obvious pH and reduction sensitivities in response to the environmental conditions in tumor cells. The nano aggregates were biocompatible and could be potentially applied as anticancer drug vehicles for enhancement of cellular uptake of anticancer drugs.

Electrohydrodynamic methods for the development of pulmonary drug delivery systems

Electrospinning and electrospraying are two highly versatile and scalable electrohydrodynamic methods, which have attracted considerable attention during the last years towards the fabrication of polymer-based drug delivery systems. The latter may be obtained in the form of nano- or microfibers (via electrospinning) or as drug-loaded nano- and microparticles (via electrospraying). This review article begins with an introduction on the basic principles and the important influencing parameters governing the electrospinning/electrospraying processes, followed by an overview on their use for the development of nano/microfibers and nano/microparticles destined for use in pharmaceutical applications. Focus is given on research efforts targeting in the formulation of drug delivery systems and devices designed for pulmonary drug delivery applications thus emphasizing on the potential use of electrospinning and electrospraying in the area of inhaled medicines.

Topical and Transdermal Delivery of Drug-Loaded Nano/ Microsystems with Application of Physical Enhancement Techniques.

Topical and transdermal delivery has been studied over last decades and it presents advantages for the treatment of several disorders, macromolecules delivery and vaccination. The greatest challenge is to overcome the stratum corneum (SC) barrier. Compared to traditional topical formulation strategies, nano /microsystems offer advantages such as increased stability, increased loading dose, coverage of undesired colors, reduced toxicity and prolonged release of active agents. However, there are no conclusive studies demonstrating the ability of such systems to penetrate the skin in relevant therapeutic amounts. The use of physical methods holds great promise for enhancing skin permeation through the SC and for targeting hair follicles. This review discusses the characteristics and feasibility of using a dual approach employing the application of physical methods of permeation enhancement to enable the topical or transdermal delivery of drug-loaded nano/microsystems.

Safety and Proof-of-Concept Efficacy of Inhaled Drug Loaded Nano- and Immunonanoparticles in a c-Raf Transgenic Lung Cancer Model

Pulmonary delivery of drug-loaded nanoparticles is a novel approach for lung cancer treatment and the conjugation of nanoparticles to a targeting ligand further promotes specificity of the carrier cargo to cancer cells. Notably, the epithelial cell adhesion molecule (EpCAM, CD326) is over expressed in lung cancer. Here, we report the safety and proof-of-concept efficacy of drug-loaded nanoparticles and EpCAM immunonanoparticles in a c-Raf transgenic lung cancer model. PEG-PLA nanoparticles and immunonanoparticles were prepared whereby paclitaxel palmitate (Pcpl) was incorporated as a medication for its common use in lung cancer treatment. Four doses of aerosolized nanoparticle formulations or vehicle were endotracheally administered to mice by consecutive or alternate regimes. Pulmonary delivery of drug loaded nano- and/or immunonanoparticle formulations elicited mild inflammation as evidenced by the slightly increased neutrophil and activated macrophage counts in bronchoalveolar lavage. No evidence for pulmonary toxicity following treatment with either blank or drug-loaded nano- and/or immunonanoparticles was observed. Proof-ofconcept efficacy was determined by serial CT scanning and histopathology. Animals treated with either EpCAM antibody or Pcpl solution or drug loaded nano- or immunonanoparticles inhibited disease progression. Conversely, disease progression was noted with vehicle treated animals with nearly 30% loss of their aerated lung volume. Importantly, treatment of mice with either Pcpl or EpCAM antibody solution caused 80% mortality and/or haemorrhage, respectively, thus causing unacceptable toxicity. In contrast, the survival of animals treated with either nano- or immunonanoparticles was 60 and 70%, respectively. Taken collectively, pulmonary delivered drug-loaded nano- and EpCAM immunonanoparticles were well tolerated and can be considered a promising strategy for improving lung cancer treatment.

Safety and Proof-of-Concept Efficacy of Inhaled Drug Loaded Nano- and Immunonanoparticles in a c-Raf Transgenic Lung Cancer Model

Pulmonary delivery of drug-loaded nanoparticles is a novel approach for lung cancer treatment and the conjugation of nanoparticles to a targeting ligand further promotes specificity of the carrier cargo to cancer cells. Notably, the epithelial cell adhesion molecule (EpCAM, CD326) is over expressed in lung cancer. Here, we report the safety and proof-of-concept efficacy of drug-loaded nanoparticles and EpCAM immunonanoparticles in a c-Raf transgenic lung cancer model. PEG-PLA nanoparticles and immunonanoparticles were prepared whereby paclitaxel palmitate (Pcpl) was incorporated as a medication for its common use in lung cancer treatment. Four doses of aerosolized nanoparticle formulations or vehicle were endotracheally administered to mice by consecutive or alternate regimes. Pulmonary delivery of drug loaded nano- and/or immunonanoparticle formulations elicited mild inflammation as evidenced by the slightly increased neutrophil and activated macrophage counts in bronchoalveolar lavage. No evidence for pulmonary toxicity following treatment with either blank or drug-loaded nano- and/or immunonanoparticles was observed. Proof-of-concept efficacy was determined by serial CT scanning and histopathology. Animals treated with either EpCAM antibody or Pcpl solution or drug loaded nano- or immunonanoparticles inhibited disease progression. Conversely, disease progression was noted with vehicle treated animals with nearly 30% loss of their aerated lung volume. Importantly, treatment of mice with either Pcpl or EpCAM antibody solution caused 80% mortality and/or haemorrhage, respectively, thus causing unacceptable toxicity. In contrast, the survival of animals treated with either nano- or immunonanoparticles was 60 and 70%, respectively. Taken collectively, pulmonary delivered drug-loaded nano- and EpCAM immunonanoparticles were well tolerated and can be considered a promising strategy for improving lung cancer treatment.

Drug-loaded nano materials by electrospinning

Drug-loaded nano materials by electrospinning

Novel Solvent-Free Methods for Fabrication of Nano- and Microsphere Drug Delivery Systems from Functional Biodegradable Polymers

Cholic acid functionalized branched poly-ε-caprolactones with different molecular weights were synthesized through the ring-opening polymerization of ε-caprolactone initiated by cholic acid with hydroxyl groups. On the basis of the specific physicochemical properties of the functional branched poly-ε-caprolactones, nano- and microsphere drug delivery systems were fabricated through a “melting ultrasonic dispersion method” and a “melting emulsion method”, respectively. Both methods did not involve toxic organic solvents. Using these very rapid and convenient methods, the drug-loaded nano- and microspheres with regular spherical shapes with narrow size distributions were obtained. The in vitro drug release behaviors of these drug release systems were investigated. The higher molecular weight of the polymer matrix resulted in a slower drug release rate. The drug release study showed the release of the drug could be effectively sustained by entrapment in the nano- and microspheres.

Study on Drug Release Behaviors of Poly-α,β-[N-(2-hydroxyethyl)-l-aspartamide]-g-poly(ε-caprolactone) Nano- and Microparticles

Biodegradable amphiphilic graft copolymers poly-alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide]-g-poly(epsilon-caprolactone) (PHEA-g-PCL) with different branch lengths were synthesized through the ring-opening polymerization of epsilon-caprolactone initiated by the macroinitiator PHEA bearing hydroxyl groups. With use of the graft copolymers with different compositions, nanoparticle drug delivery systems with sizes smaller than 100 nm were prepared by a dialysis method, and microparticle drug delivery systems with sizes smaller than 5 microm were fabricated by a melting-emulsion method. The regularly spherical shapes of the drug-loaded nano- and microparticles were verified by transmission electron microscopy and scanning electron microscopy. In vitro drug release properties of nano- and microparticle drug delivery systems were investigated, with the emphasis on the effects of polymer composition, particle size, and drug-loading content on the release behaviors.