Potential Drug Delivery System Research Articles

Effect of ionic strength on porosity and surface charge of chitosan nanoparticles

Chitosan, a natural cationic polymer, is gaining popularity due to its biodegradable and biocompatible properties. The parameters such as ionic strength (I) and porosity play an important role in case of chitosan nanoparticles (CSNPs) contributing to their formation, stability, and suitable biomedical applications. To explore these findings, we varied the concentration of acetic acid (I) and studied physicochemical properties of CSNPs, which revealed the effect of ionic strength on the surface properties and porosity of CSNPs. Further, ionic strength of CSNPs simulated using COMSOL Multiphysics. Thus, our conclusions give important understanding on the applicability of CSNPs as a potential drug delivery system for future applications.

Hybrid Lipid Nanoparticles Loaded with Doxorubicin for the Therapy of Breast Cancer

Breast cancer is the leading cause of death in women and its incidence is growing fast worldwide. Due to the poor benefits of doxorubicin (Dox), the first line chemotherapeutic drug for breast cancer treatment, the development of new drug delivery systems (DDSs) for Dox is critical to improve the breast cancer treatment efficacy. Here in this study, we used a film dispersion method to construct hybrid lipid nanoparticles (HLN) containing different lipids, including biotin conjugated lipid, during which Dox was loaded into the carrier to finally construct Dox loaded HLN (HLN/Dox) as a potential DDS for targeted breast cancer therapy. Our results showed that HLN/Dox were nanosized formulation with increased accumulation to MCF-7 cells due to biotin modification both in vitro and in vivo . In addition, the cellular cytotoxicity as well we in vivo antitumor assay also showed the promising cancer cell killing and tumor inhibition effects of HLN/Dox, which suggested its potential to be applied in future clinical practice.

Drug Delivery Systems and Flavonoids: Current Knowledge in Melanoma Treatment and Future Perspectives.

Melanoma is an aggressive form of skin cancer with a high prevalence in the population. An early diagnosis is crucial to cure this disease. Still, when this is not possible, combining potent pharmacological agents and effective drug delivery systems is essential to achieve optimal treatment and improve patients' quality of life. Nanotechnology application in biomedical sciences to encapsulate anticancer drugs, including flavonoids, in order to enhance therapeutic efficacy has attracted particular interest. Flavonoids have shown effectiveness against various types of cancers including in melanoma, but they show low aqueous solubility, low stability and very poor oral bioavailability. The utilization of novel drug delivery systems could increase flavonoid bioavailability, thereby potentiating its antitumor effects in melanoma. This review summarizes the potential of different flavonoids in melanoma treatment and the several nanosystems used to improve their biological activity, considering published information that reported improved biological and pharmacological properties of encapsulated flavonoids.

Redox-responsive polyurethane-polyurea nanoparticles targeting to aortic endothelium and atherosclerosis

Aortic endothelial cell dysfunction is an early trigger of atherosclerosis, the major cause of the cardiovascular disease (CVD). Nanomedicines targeting vascular endothelium and lesions hold great promise as therapeutic solutions to vascular disorders. This study investigates the vascular delivery efficacy of polyurethane-polyurea nanocapsules (Puua-NCs) with pH-synchronized shell cationization and redox-triggered release. Fluorescent lipophilic dye DiI was encapsulated into Puua-NCs of variable sizes and concentrations. Invitro cellular uptake studies with human aortic endothelial cells showed that these Puua-NCs were taken up by cells in a dose-dependent manner. In apolipoprotein E-deficient mice fed a Western diet, a model of atherosclerosis, circulating Puua-NCs were stable and accumulated in aortic endothelium and lesions within 24 hours after intravenous administration. Treatment with thiol-reducing and oxidizing reagents disrupted the disulfide bonds on the surface of internalized NCs, triggering disassembly and intracellular cargo release. Ultimately, Puua-NCs are a potential redox-controllable cardiovascular drug delivery system.

Gold nanoparticles loaded TNF-α and CALNN peptide as a drug delivery system and promising therapeutic agent for breast cancer cells

ABSTRACT We investigated the anti-cancer properties of gold nanoparticles loaded TNF- and CALNN peptides, which we proposed as a potential drug delivery system using in vitro and in vivo models. The binding of GNPs-TNF- and GNPs-TNF-CALNN was characterized using a UV, ELISA and SEM analysis. The outcomes demonstrated that a novel drug delivery system had an anti-proliferative activity against breast cancer cell lines through a mechanism of apoptosis induction. In vivo model involved studying the cytotoxic influence of a drug delivery system GNPs, GNPs-TNF-α and GNPs-TNF-α-CALNN when applied to the transplanted AN-3 cell line. tumor sections were examined using microarray. In-vivo studies demonstrated that GNPs alone had less of a growth inhibitory effect on tumors implanted in mice when compared to GNPs-TNF – CALNN combined therapy. The cytotoxic assay showed that GNPs, GNPs-TNF-α and GNPs-TNF-α-CALNN exhibit selective toxicity towards cancer cells, inducing cell apoptosis through activation of caspase-3 and 7, p53 protein.

Nanostructured lipid carriers of alkannins and shikonins: Experimental design, characterization and bioactivity studies

The chiral pair alkannin and shikonin and their ester derivatives (A/S), are lipophilic secondary metabolites possessing a wide spectrum of pharmacological activities. Their incorporation in lipid-based drug delivery systems can enhance their therapeutic efficacy, especially for dermal or transdermal applications. In this work, A/S in the form of oily extracts and isolated mixture of pigments from Alkanna tinctoria roots were entrapped in lipid based nanocarriers for dermal applications. In both cases, Experimental Design was carried out to evaluate the effect of process parameters on mean particle size, ζ-potential and entrapment efficiency, aiming to identify the optimum process conditions. The optimum oily extract loaded liposomes showed a mean particle size of 106 nm, ζ-potential value of −45.1 mV and entrapment efficiency (EE%) up to 72%. On the other hand, the optimum nanocarriers for the incorporation of A/S mixture showed a mean particle size of 138 nm, ζ-potential value of −15.6 mV and EE% up to 56%. The in vitro release profiles for both drug delivery systems were satisfactory and revealed that, in both cases, the release of the active pharmaceutical ingredients from the nanocarriers is controlled by diffusion. Moreover, we evaluated the effect of the optimum formulations on the viability of human dermal fibroblasts and we found that, A/S mixture loaded nanocarriers enhance cell viability. In order to assess the effect of A/S derivatives loaded nanocarriers on human fibroblasts we targeted genes related to the antioxidant cellular response, cell aging and extracellular matrix organization. The findings showed that nanocarriers induced the antioxidant response, presented a positive impact on cells’ longevity and promoted extracellular matrix organization. Based on these findings, formulated nanocarriers can be used as a potential drug delivery system for dermal applications in cosmetic products.

A nano-preparation approach to enable the delivery of daphnoretin to potentiate the therapeutical efficacy in hepatocellular cancer.

Daphnoretin (DAP), isolated from a traditional Chinese medicine Wikstroemia indica (Linn. C. A. Meyer), could induce apoptosis of hepatocellular cancer (HCC) and inhibit tumor growth. However, the application of DAP in cancer therapies was hampered because to its poor solubility. Herein, this study aimed to design an approach of double-targeted nano-preparation to enable the delivery of DAP to potentiate the therapeutical efficacy in liver cancer via glycyrrhetinic acid-polyethylene glycol-block-poly (D,L-lactic acid)/polyethylene glycol-block-poly (D,L-lactic acid)-DAP (GPP/PP-DAP). In particular, the purity of separated DAP was up to 98.12% for preparation research. GPP/PP-DAP was successfully prepared by the thin-film hydration method. Subsequently, the GPP/PP-DAP was optimized by univariate analysis and the response surface methodology, producing a stable and systemically injectable nano-preparation. Impressively, on the one hand, cytotoxicity studies showed that the IC50 of the GPP/PP-DAP was lower than that of free DAP. On the other hand, the GPP/PP-DAP was more likely to be endocytosed by HepG2 cells and targeted to the liver with orthotopic tumors, potentiating the therapeutical efficacy in HCC. Collectively, both in vitro and in vivo results indicated the excellent tumor inhibition and liver targeting of GPP/PP-DAP, suggesting the nano-preparation could serve as a potential drug delivery system for natural ingredients with anti-hepatoma activity to lay the theoretical foundation for clinical application.

Lipid-Coated Hybrid Nanoparticles for Enhanced Bacterial Biofilm Penetration and Antibiofilm Efficacy.

Up to 80% of all infections are biofilm-mediated and they are often challenging to treat as the underlying bacterial cells can become 100- to 1000-fold more tolerant toward antibiotics. Antibiotic-loaded nanoparticles have gained traction as a potential drug delivery system to treat biofilm infections. In particular, lipid-coated hybrid nanoparticles (LCHNPs) were investigated on their capability to deliver antibiotics into biofilms. In this study, LCHNPs composed of a poly(lactic-co-glycolic acid) (PLGA) core and dioleoyl-3-trimethylammonium propane (DOTAP) lipid shell were developed and loaded with vancomycin (Van). In vitro antibacterial and antibiofilm tests were performed to evaluate the antimicrobial efficacy of the LCHNPs. LCHNPs were successfully fabricated with high vancomycin encapsulation and loading efficiencies, and exhibited enhanced antibacterial effects against planktonic Staphylococcus aureus USA300 when compared against Free-Van and Van-PLGANPs. When used to treat USA300 biofilms, Van-LCHNPs eradicated up to 99.99% of the underlying biofilm cells, an effect which was not observed for Free-Van and Van-PLGANPs. Finally, we showed that by possessing a robust DOTAP shell, LCHNPs were able to penetrate deeply into the biofilms.

Preparation and Evaluation of Poly(lactic acid)/Poly(vinyl alcohol) Nanoparticles Using the Quality by Design Approach.

The aim of the study was to prepare and evaluate the potential use of poly(lactic acid)/poly(vinyl alcohol) (PLA/PVA) nanoparticle formulations as a drug delivery system. The nanoparticle formulations were successfully developed by the double emulsification/solvent evaporation method. The developed formulations were optimized using the quality by design approach of the ICH Q8 (Pharmaceutical Development) guideline. In the studies, the effects of emulsifying devices, evaporation technique, centrifugation effect, and polymer concentrations on the physicochemical parameters of the formulations were investigated to obtain the best results. Furthermore, the prepared formulations were evaluated for clarity, particle size, distribution, zeta potential, surface and morphological features, preparation efficiency, and long-term stability. Based on the obtained results, the nanoparticle formulation containing 12.5% PLA, 1% primer, and seconder PVA has a suitable particle size (181.7 ± 2.194 nm) and distribution (0.104 ± 0.049), zeta potential (−0.88 ± 0.45 mV), and high preparation efficiency (65.38%), and nanoparticles were spherical, had a smooth surface, and were stable up to 12 months. In conclusion, this novel formulation can be used as a potential drug delivery system.

Targeted chitosan nanoparticles embedded into graphene oxide functionalized with caffeic acid as a potential drug delivery system: New insight into cancer therapy

As a novel drug delivery technology, chitosan (CHI) nanoparticles are encapsulated in graphene oxide (GO) with caffeic acid (CA). The nanocarrier technique combines targeted drug delivery with molecular imaging to provide new cancer insights. Attachment of CA, an anticancer agent for controlled drug release, to functionalized graphene oxide (GON) utilizing 3-aminopropyltriethoxysilane (APTES) was followed by encapsulation of GO with folic acid (FA) attached CHI to produce this novel system. FT-IR was used to characterize and confirm the chemical production process. Brunau–Emmet–Teller (BET) analysis was used to validate multi-holes and nanometric dimensions (1–100 nm) and assess their drug administration use. Release and loading tests showed a pH dependence and implied CA hydrogen-bonding in GON. CA encapsulation and loading percentages are 86 % and 67 %, respectively. The acidic environment (pH 5.3) of tumor cells may produce a larger release of CA, and the release rate of CA maintains a constant trend, indicating the drug is released for more than a week (because the release rate has not reached zero). The proposed method provides a potential candidate for a novel drug delivery system in cancer therapy. The resulting nanohybrid system is a new way to combine biodegradable materials, that can be used in biomedical applications.

Embelin and Its Derivatives: Design, Synthesis, and Potential Delivery Systems for Cancer Therapy.

Embelin is a naturally occurring benzoquinone that inhibits the growth of cancer cells, making it a potent anticancer drug. However, the low water solubility of embelin restricts its clinical applicability. This review provides a concise summary and in-depth analysis of the published literature on the design and synthesis of embelin derivatives possessing increased aqueous solubility and superior therapeutic efficacy. In addition, the potential of drug delivery systems to improve the anticancer capabilities of embelin and its derivatives is discussed.

Development of Polymeric-Based Formulation as Potential Smart Colonic Drug Delivery System.

Conventional oral formulations are mainly absorbed in the small intestine. This limits their use in the treatment of some diseases associated with the colon, where the drug has to act topically at the inflammation site. This paved the way for the development of a smart colonic drug delivery system, thereby improving the therapeutic efficacy, reducing the dosing frequency and potential side effects, as well as improving patient acceptance, especially in cases where enemas or other topical preparations may not be effective alone in treating the inflammation. In healthy individuals, it takes an oral medication delivery system about 5 to 6 h to reach the colon. A colonic drug delivery system should delay or prohibit the medication release during these five to six hours while permitting its release afterward. The main aim of this study was to develop a smart drug delivery system based on pH-sensitive polymeric formulations, synthesized by a free-radical bulk polymerization method, using different monomer and crosslinker concentrations. The formulations were loaded with 5-amino salicylic acid as a model drug and Capmul MCM C8 as a bioavailability enhancer. The glass transition temperature (Tg), tensile strength, Young’s modulus, and tensile elongation at break were all measured as a part of the dried films’ characterization. In vitro swelling and release studies were performed to assess the behavior of the produced formulations. The in vitro swelling and release evaluation demonstrated the potential ability of the developed system to retard the drug release at conditions mimicking the stomach and small intestine while triggering its release at conditions mimicking the colon, which indicates its promising applicability as a potential smart colonic drug delivery system.

Gelation Properties and Drug Release Kinetics of a Thermoreversible Hydrogel as a Drug Carrier

Pluronic F-127 (PF-127) is a thermoreversible hydrogel that is a promising candidate for drug delivery. This hydrogel has a unique property that transforms its phase between liquid and gel as the temperature changes. PF-127 can be explored as a potential drug delivery system to treat diseases due to its low toxicity and controllable, sustained drug release. This study aims to determine the optimized relationship between concentration and temperature for successful PF-127 gelation and to characterize its drug release kinetics. PF-127 powder was dissolved in a saline solution to make concentrations ranging from 10% to 30%. The temperature was increased gradually to determine the precise temperature at which each PF-127 solution at a different concentration turned to gel. Concentrations under 16% did not turn to gel at any range of temperature. From 20% to 24% concentrations, PF-127 was a liquid at room temperature, while 26% to 30% concentrations were in a gel state. To characterize the drug release kinetics of PF-127, calf thymus DNA was loaded into PF-127. It showed sustained DNA release over a prolonged period of time as opposed to an immediate burst release. Sustained release kinetics shown in our study is preferable because it may steadily release a drug at an optimal concentration, preventing toxicity from a high drug concentration while maintaining therapeutic potential. The outcomes of this study elucidate a broad application of PF-127 as a potential drug carrier.

Erythrocyte nanovesicles as chemotherapeutic drug delivery platform for cancer therapy

The use of biodegradable nanoparticles (NPs) as a carrier for therapeutic and diagnostic agents has gained immense attention in recent years worldwide. Due to their nano-size and high drug loading capacity they have several other characteristics over other nanoparticles including their role in biocompatibility and convenient release of the drug or any cargo agent at the target tumour site, these biological nanoparticles are used in a variety of applications. Due to the prolonged circulation time; erythrocytes or red blood cells (RBC's) can be used as potential drug delivery systems with the enhanced cargo-loading ability with less toxicity. In the present work, erythrocyte-derived nanovesicles were extracted from mice whole blood with consistent reproducibility. These nanovesicles, known for being efficient drug nanocarriers were encapsulated with and doxorubicin anticancer drug (1 mg/mL) for targeted cancer chemotherapy. To further understand the surface markers, present on these biologically derived nanovesicles we have used a mass spectrometry-based approach for identifying significant proteins and surface membrane lipids and their potential role as targeting ligands for cancer cells. Uniform particle size distribution is confirmed through dynamic light scattering measurements. Further cell viability and confocal microscopy studies showed the effective killing of cancer cells with these drug-loaded biocompatible nanocarriers.

Statistically designed vitamin D3 Encapsulated PLGA microspheres dispersed in thermoresponsive in-situ gel for nasal delivery

Vitamin D deficiency is a cause of concern across the world. It is a fat-soluble vitamin and exhibits two molecular forms (D2 and D3). The aim of the present study is the development and optimization of vitamin D3 loaded PLGA microspheres by using Box Behnken Design. Additionally, to enhance nasal permeation these microspheres were dispersed in the thermoreversible in-situ gel. Microspheres revealed particle size in the range of 9182 ± 1 nm with 75.5 ± 0.5%EE of vitamin D3. Polydispersity index and zeta potential of microspheres were found 0.509 and −7.56 mV, respectively confirming uniformity and colloidal stability. FTIR and DSC studies revealed no interaction between excipients and vitamin D3. Scanning electron microscopy demonstrated spherical morphology of microspheres. The thermoreversible in-situ dispersed with vitamin D3 loaded microspheres exhibit the gelation temperature between 35 °C to 37 °C. The viscosity of the gel was 35698–5032 cps. The gel strength was found 1.1 ± 0.2 mJ with hardness (27 g), adhesiveness (22 g), and stringiness (3.2 mm) measured by a texture analyzer. In vitro dissolution study revealed that microspheres showed 79% VD3 release. Whereas microspheres dispersed gel showed 69% of VD3 release up to one week as compared to an oily solution. The mucoadhesion of gel was found 19600 dyne/cm2 suggesting the extraordinary high mucoadhesive property. Ex vivo permeation study through goat's nasal mucosa suggests that gel formulation showed 2.5 folds high permeation than microspheres and solution. Thus, it could be a potential drug delivery system for the delivery of vitamin D3 via nasal route.

Investigation of self-assembled poly(ethylene glycol)-poly(L-lactic acid) micelle as potential drug delivery system for poorly water soluble anticancer drug abemaciclib

Polymer-based drug delivery systems have the ability to organize stable self-assembled nanocarriers containing hydrophobic cores allow to delivery of poorly water-soluble anticancer drugs by drug encapsulation process. Computational investigations can assist in designing of efficient drug-delivery systems. However, the high computational cost of simulation of nanocarrier self-assembly processes due to long-timescale required for equilibration are challenging. In this study we investigated the assembly mechanism of the abemaciclib anticancer drug encapsulated by the PEG-PLA copolymer micelle; molecular dynamics simulations were carried out for analyzing the aggregation of the PEG-PLA copolymer chains. The process of drug encapsulation is mostly operated by the hydrophobic and hydrophilic interactions. The hydrogen bonding and electrostatic interactions also play an important role in aggregation of the PEG-PLA copolymer chains. Analyses of radial distribution function and solvent accessible surface area show that the PEG-PLA copolymer micelles can increase the hydrophobic drugs solubility. The study presents insights into the mechanism of the structure of drug-loaded PEG-PLA copolymer micelles to design the drug delivery systems with helpful properties.

Lipid-Based Nanomaterials for Drug Delivery Systems in Breast Cancer Therapy.

Globally, breast cancer is one of the most prevalent diseases, inducing critical intimidation to human health. Lipid-based nanomaterials have been successfully demonstrated as drug carriers for breast cancer treatment. To date, the development of a better drug delivery system based on lipid nanomaterials is still urgent to make the treatment and diagnosis easily accessible to breast cancer patients. In a drug delivery system, lipid nanomaterials have revealed distinctive features, including high biocompatibility and efficient drug delivery. Specifically, a targeted drug delivery system based on lipid nanomaterials has inherited the advantage of optimum dosage and low side effects. In this review, insights on currently used potential lipid-based nanomaterials are collected and introduced. The review sheds light on conjugation, targeting, diagnosis, treatment, and clinical significance of lipid-based nanomaterials to treat breast cancer. Furthermore, a brighter side of lipid-based nanomaterials as future potential drug delivery systems for breast cancer therapy is discussed.

The history of small extracellular vesicles and their implication in cancer drug resistance.

Small extracellular vesicles (EVs) in the last 20 years are demonstrated to possess promising properties as potential new drug delivery systems, biomarkers, and therapeutic targets. Moreover, EVs are described to be involved in the most important steps of tumor development and progression including drug resistance. The acquired or intrinsic capacity of cancer cells to resist chemotherapies is one of the greatest obstacles to overcome to improve the prognosis of many patients. EVs are involved in this mechanism by exporting the drugs outside the cells and transferring the drug efflux pumps and miRNAs in recipient cells, in turn inducing drug resistance. In this mini-review, the main mechanisms by which EVs are involved in drug resistance are described, giving a rapid and clear overview of the field to the readers.

Synthesis and Evaluation of Thermoresponsive Renewable Lipid-Based Block Copolymers for Drug Delivery.

Polymeric micelle forming from self-assembly of amphiphilic macromolecules is one of the most potent drug delivery systems. Fatty acids, naturally occurring hydrophobic lipid components, can be considered as potential candidates for the fabrication of block copolymer micelles. However, examples of synthesis of responsive block copolymers using renewable fatty acids are scarce. Herein, we report the synthesis, characterization and testing of block copolymer micelles composed of a renewable fatty-acid-based hydrophobic block and thermoresponsive hydrophilic block for controlled drug delivery. The block copolymers of functionalized fatty acid and poly(N-isopropylacrylamide) (PNIPAM) were prepared via consecutive microwave-assisted reversible addition fragmentation chain transfer (RAFT) polymerization. The block copolymers with variable hydrophobic block length self-assembled in aqueous media and formed spherical nanoparticles of ~30 nm with low critical micelle concentration (CMC). To demonstrate the proof-of-concept, carbamazepine (CBZ) was used as a hydrophobic model drug to evaluate the performance of these micelles as nanocarriers. The in vitro drug release tests were carried out below (25 °C) and above (37 °C) the lower critical solution temperature (LCST) of the block copolymer. The drug release showed obvious temperature-triggered response and an accelerated drug release at 37 °C.

Design of a nanofibrous guided tissue regeneration carrier as a potential drug delivery system for tetracycline hydrochloride in the management of periodontitis

To accelerate the recovery process in the treatment of periodontitis, a guided tissue regeneration (GTR) nanofibrous membrane containing the antibacterial agent, tetracycline hydrochloride (TCH), was prepared and evaluated for its in vivo performance as a drug carrier in a rabbit model. Polycaprolactone (PCL) solutions containing tetracycline were electrospun to obtain nanofibers and characterized. The surface morphology was investigated and Fourier-transform infrared spectroscopy (FTIR) was performed to detect any potential interactions that may have led to a major alteration of the pharmacologically active moiety. The release behavior was investigated both in vitro and in vivo. The in vitro cytotoxicity was performed to determine the non-toxic nature of the formulation. The antibacterial efficacy was examined against common periodontal pathogens. The formulations possessed suitable strength to preserve their integrity during administration with enough flexibility. A uniform morphology with a mean fiber diameter of 261–324 nm was achieved due to the high potential of the electrospinning process. The antibacterial efficacy and the FTIR confirmed the fact that no major interactions occurred between the drug and polymer. Appropriate cell viability of more than 80% was achieved with no sign of irritation after the implantation of the membranes in a rabbit model. Both in vitro and in vivo studies demonstrated an extended release of the drug for more than 6 days. Suitable biocompatibility in rat and rabbit models was observed. The obtained result suggests that TCH-loaded GTR membranes can be suitable for intrapacket delivery during periodontitis to reduce the frequency of administration and to accelerate the recovery process.