Drug Release Test Research Articles

Solid Lipid Microparticles by Spray Congealing of Water/Oil Emulsion: An Effective/Versatile Loading Strategy for a Highly Soluble Drug.

Spray congealing technique was exploited to produce solid lipid microparticles (SLMp) loaded with a highly water-soluble drug (metoclopramide hydrochloride) dissolved in the aqueous phase of a water in oil (W/O) emulsion. The use of an emulsion as starting material for a spray congealing treatment is not so frequent. Moreover, for this application, a W/O emulsion with a drug dissolved in water is a totally novel path. A ternary diagram was built to optimize the emulsion composition, a factorial design was used to identify the factors affecting the properties of the microparticles and a Design of Experiment strategy was applied to define the impact of process conditions and formulation variables on the SLMp properties. SLMp were characterized by particle size distribution, morphology, residual moisture, drug content, release behavior, FT-IR analysis and XRPD. The obtained microparticles presented a spherical shape, particle size distribution between 54-98 µm depending on atomizing pressure used during the production step and 2-5% residual moisture 4 days after the preparation. XRPD analysis revealed that lipid polymorphic transition alfa-beta occurs depending on the presence of water. In vitro drug release tests highlighted that all the formulations had a reduced release rate compared to the drug alone. These results suggest that spray congealing of a W/O emulsion could be proposed as a good strategy to obtain SLMp with a high loading of a hydrophilic drug and able to control its release rate.

Surfactant Mediated Accelerated and Discriminatory In Vitro Drug Release Method for PLGA Nanoparticles of Poorly Water-Soluble Drug.

In vitro drug release testing is an important quality control tool for formulation development. However, the literature has evidence that poly-lactide-co-glycolide (PLGA)-based formulations show a slower in vitro drug release than a real in vivo drug release. Much longer in vitro drug release profiles may not be reflective of real in vivo performances and may significantly affect the timeline for a formulation development. The objective of this study was to develop a surfactant mediated accelerated in vitro drug release method for the PLGA nanoparticles (NPs) of a novel chemotherapeutic agent AC1LPSZG, a model drug with a poor solubility. The Sotax USP apparatus 4 was used to test in vitro drug release in a phosphate buffer with a pH value of 6.8. The sink conditions were improved using surfactants in the order of sodium lauryl sulfate (SLS) < Tween 80 < cetyltrimethylammonium bromide (CTAB). The dissolution efficiency (DE) and area under the dissolution curve (AUC) were increased three-fold when increasing the CTAB concentration in the phosphate buffer (pH 6.8). Similar Weibull release kinetics and good linear correlations (R2~0.99) indicated a good correlation between the real-time in vitro release profile in the phosphate buffer (pH 6.8) and accelerated release profiles in the optimized medium. This newly developed accelerated and discriminatory in vitro test can be used as a quality control tool to identify critical formulation and process parameters to ensure a batch-to-batch uniformity. It may also serve as a surrogate for bioequivalence studies if a predictive in vitro in vivo correlation (IVIVC) is obtained. The results of this study are limited to AC1LPSZG NPs, but a similar consideration can be extended to other PLGA-based NPs of drugs with similar properties and solubility profiles.

On the influence of polyethyleneimine modification in nanogel-driven drug delivery

Nanogels are nanometric three-dimensional structures formed by chemically or physically cross-linked polymers with hydrophilic or amphiphilic macromolecular chains. Biocompatibility, biodegradability, water solubility and nontoxicity are the properties of these colloids that make them very interesting to be used in biomedical fields and especially in drug delivery applications. Several strategies have been proposed for the preparation of nanogels capable to uptake and release a great variety of drug compounds; however, the encapsulation of hydrophobic compounds inside the structure of nanogels has been proven difficult. The goal of this work is to study how drug delivery performances can be influenced by the chemical modification of linear polyethyleneimine (PEI) structure and if the ability to load and release hydrophobic drugs from nanogels can be improved in this way. In vitro drug release tests were performed by using rhodamine B and pyrene as model hydrophilic and hydrophobic drug mimetics, respectively. The maintenance of an efficient drug release ability was confirmed for hydrophilic compounds (cumulative release up to 80 % in 120 h) like in our previous formulations, but an optimal loading and encapsulation efficiency, with a time-controlled release, emerged also for hydrophobic molecules, due to the introduction of the modifications in the nanogel framework.

Topical Semisolid Products-Understanding the Impact of Metamorphosis on Skin Penetration and Physicochemical Properties.

Recently, the United States Food and Drug Administration published a series of product-specific guidance for the development of topical drugs, with in vitro options consisting of qualitative sameness (Q1) and quantitative sameness (Q2) assessment of formulations, physiochemical and structural characterization of formulations (Q3), and, potentially, in vitro drug release and permeation tests. In these tests, the topical semisolid product's critical quality attributes (CQAs), such as rheological properties, thermodynamic activity, particle size, globule size, and rate/extent of drug release/permeation, are evaluated to ensure the desired product quality. However, alterations in these CQAs of the drug products may occur under 'in use' conditions because of various metamorphosis events, such as evaporation that leads to supersaturation and crystallization, which may eventually result in specific failure modes of semisolid products. Under 'in use' conditions, a limited amount of formulation is applied to the skin, where physicochemical characteristics of the formulation are substantially altered from primary state to secondary and, eventually, tertiary state on the skin. There is an urgent need to understand the behavior of topical semisolid products under 'in use' conditions. In this review, we attempt to cover a series of metamorphosis events and their impact on CQAs (Q3 attributes), such as viscosity, drug activity, particle size, globule size, and drug release/permeation of topical semisolid products.

3D-Printed EVA Devices for Antiviral Delivery and Herpes Virus Control in Genital Infection.

Herpes viruses are widespread in the human population and can cause many different diseases. Genital herpes is common and can increase the risk of HIV infection and neonatal herpes. Acyclovir is the most used drug for herpes treatment; however, it presents some disadvantages due to its poor oral bioavailability. In this study, some ethylene vinyl acetate devices with different acyclovir amounts (0, 10, and 20 wt.%) were manufactured by fused filament fabrication in two different geometries, an intrauterine device, and an intravaginal ring. Thermal analyses suggested that the crystallinity of EVA decreased up to 8% for the sample loaded with 20 wt.% of acyclovir. DSC, SEM, and FTIR analyses confirmed that the drug was successfully incorporated into the EVA matrix. Moreover, the drug release tests suggested a burst release during the first 24 h followed by a slower release rate sustained up to 80 days. Biological assays showed the biocompatibility of the EVA/ACV device, as well as a 99% reduction in vitro replication of HSV-1. Finally, the EVA presented a suitable performance for 3D printing manufacturing that can contribute to developing personalized solutions for long-term herpes treatment.

An injectable hyperthermic nanofiber mesh with switchable drug release to stimulate chemotherapy potency.

We developed a smart nanofiber mesh (SNM) with anticancer abilities as well as injectability and fast recovery from irregular to non-compressible shapes. The mesh can be injected at the tumor site to modulate and control anticancer effects by loading the chemotherapeutic drug, paclitaxel (PTX), as well as magnetic nanoparticles (MNPs). The storage modulus of the mesh decreases when applied with a certain shear strain, and the mesh can pass through a 14-gauge needle. Moreover, the fibrous morphology is maintained even after injection. In heat-generation measurements, the mesh achieved an effective temperature of mild hyperthermia (41-43°C) within 5min of exposure to alternating magnetic field (AMF) irradiation. An electrospinning method was employed to fabricate the mesh using a copolymer of N-isopropylacrylamide (NIPAAm) and N-hydroxyethyl acrylamide (HMAAm), whose phase transition temperature was adjusted to a mildly hyperthermic temperature range. Pplyvinyl alcohol (PVA) was also incorporated to add shear-thinning property to the interactions between polymer chains derived from hydrogen bonding, The "on-off" switchable release of PTX from the mesh was detected by the drug release test. Approximately 73% of loaded PTX was released from the mesh after eight cycles, whereas only a tiny amount of PTX was released during the cooling phase. Furthermore, hyperthermia combined with chemotherapy after exposure to an AMF showed significantly reduced cancer cell survival compared to the control group. Subsequent investigations have proven that a new injectable local hyperthermia chemotherapy platform could be developed for cancer treatment using this SNM.

Multipurpose vaginal rings for HIV prevention and non-hormonal contraception

Vaginal rings releasing antiretrovirals - either alone or in combination with contraceptive progestins - are being developed for contraception and prevention of human immunodeficiency virus (HIV) transmission via vagina. However, hormonal contraceptives are associated with numerous side effects and contraindications, and many women are interested in using hormone-free contraceptives. The aim of this project is to develop multipurpose vaginal rings to release copper and/or zinc ions and dapivirine over a month for contraception and HIV prevention. Ring manufacture, swell testing, and in vitro drug release testing have been conducted. The experimental results obtained currently are encouraging and support the continued development of these ring formulations as a novel and interesting multipurpose prevention technology strategy.

3D printed biodegradable multifunctional implants for effective breast cancer treatment

By carefully controlling the dose administered and the drug release rate from drug-eluting implants, safety and efficacy of the therapeutic agent dispensed can be improved. The present work focuses on the promising advantages of 3D Bioprinting process in developing two layers’ implantable scaffolds. The two layers have different functions, in order to ensure a more effective and synergistic breast cancer therapy. First layer involves use of polymers such as Poly- ε-Caprolactone (PCL) and Chitosan (CS), and incorporation of 5-Fluorouracil (5-FU). The aim of the first layer is releasing the drug within 4 weeks, obtaining a prolonged and modified release. According to in vitro drug release tests performed, ∼32 % of 5-FU was released after one month, after an initial burst effect of 17.22 %. The sudden release of the drug into the body would quickly reach an effective therapeutic concentration, while the drug sustained release maintains an effective therapeutic concentration range during the administration time. The second layer is made exclusively from PCL as polymeric matrix, into which Gold Nanoparticles (AuNPs) were subsequently loaded, and its main purpose is to be radiation enhancement. The long biodegradation time of PCL would make the non-soluble scaffold an alternative to conventional chemotherapy, optimizing drug release to the specific needs of the patients.

A REVIEW: MICROEMULSION-BASED POLYMER MATRIX TRANSDERMAL PATCH FOR THE TREATMENT OF INFLAMMATION

The inflammation is the Immunogenic response when a foreign particle or material or any antigen is entered in the body. The topical delivery or a transdermal delivery is defined as it is a route of administration of a drug via skin or to protect the drug from the metabolism process. The topical formulations are of different types such as lotion, creams, patches, gels and ointments. The transdermal patches are the system where the medicine is diffused from the matrix of polymer and penetrates the skin and the drug shows the therapeutic benefit to the patient. Microemulsion patches are the novel delivery system in which the drug is in micron size ranges and then easily penetrates the skin and becomes a more successful drug delivery over the conventional patches. The microemulsions are the thermodynamically stable biphasic seen as a clear solution in which the drug is entrapped in a dispersed phase and the continuous phase is work as the vehicle for the administration of the dose. There are some tests like entrapment efficiency and Invitro drug release testing for determination of its efficacy. There are some characterization tests like electro conductivity study, rheological properties and centrifugation study has also performed the folding endurance surface pH and the water content and the stability testing has been performed. The microemulsion patch drug delivery system has been found to have more bioavailability and duration of action than the conventional patches or the topical formulation.

Unexpected Stability of a Prodrug to Enzymatic Hydrolysis within a Hydrated HPMC Matrix Tablet.

The uptake of alkaline phosphate present in dissolution medium into a hydrating hydroxypropyl methylcellulose matrix tablet and that its activity was retained therein was demonstrated. This presents a risk to the stability of prodrugs that are substrates of this enzyme such as phosphonooxymethyl derivative prodrugs. It was found that fostemsavir, a phosphonooxymethyl derivative prodrug being developed for the treatment of HIV-1 infection, was unexpectedly resistant to hydrolysis within a hydrated HPMC matrix when subjected to drug release testing in media containing alkaline phosphatase. Studies indicated that this was not due to microenvironmental pH effects, osmolality effects or effective phosphate concentration effects associated with the presence of the prodrug. That the prodrug and not its parent could affect enzyme activity in a concentration dependent manner, and that another phosphate ester prodrug fosphenytoin did not inhibit alkaline phosphatase activity within a hydrated HPMC matrix suggested that the unexpected stability of the HIV-1 therapy prodrug may be associated with the ability of the phosphate group-containing compound itself to inhibit the enzyme at the concentrations it exists at in the hydrated dosage form and so enables the development of the compound in this type of dosage form.

Bioinspired surface functionalization of biodegradable mesoporous silica nanoparticles for enhanced lubrication and drug release

Osteoarthritis is associated with the significantly increased friction of the joint, which results in progressive and irreversible damage to the articular cartilage. A synergistic therapy integrating lubrication enhancement and drug delivery is recently proposed for the treatment of early-stage osteoarthritis. In the present study, bioinspired by the self-adhesion performance of mussels and super-lubrication property of articular cartilages, a biomimetic self-adhesive dopamine methacrylamide—poly(2-methacryloyloxyethyl phosphorylcholine) (DMA—MPC) copolymer was designed and synthesized via free radical polymerization. The copolymer was successfully modified onto the surface of biodegradable mesoporous silica nanoparticles (bMSNs) by the dip-coating method to prepare the dual-functional nanoparticles (bMSNs@DMA—MPC), which were evaluated using a series of surface characterizations including the transmission electron microscope (TEM), Fourier transform infrared (FTIR) spectrum, thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), etc. The tribological test and in vitro drug release test demonstrated that the developed nanoparticles were endowed with improved lubrication performance and achieved the sustained release of an anti-inflammatory drug, i.e., diclofenac sodium (DS). In addition, the in vitro biodegradation test showed that the nanoparticles were almost completely biodegraded within 10 d. Furthermore, the dual-functional nanoparticles were biocompatible and effectively reduced the expression levels of two inflammation factors such as interleukin-1β (IL-1β) and interleukin-6 (IL-6). In summary, the surface functionalized nanoparticles with improved lubrication and local drug release can be applied as a potential intra-articularly injected biolubricant for synergistic treatment of early-stage osteoarthritis.

Antifungal Nail Lacquer for Enhanced Transungual Delivery of Econazole Nitrate.

The fungal disease of the nail, onychomycosis, which is also the most prevalent nail disturbance, demands effective topical treatment options considering the possible adverse effects of systemic antifungal therapy. The current work is focused on development of an adhesive and resistant, drug-delivering and permeation-enhancing polymeric film containing econazole nitrate (ECN) for topical antifungal treatment. The development of the lacquer formulation was guided by the Quality by Design approach to achieve the critical quality attributes needed to obtain the product of desired quality. Eudragit RSPO at 10% w/w was found to be the ideal adhesive polymer for the application and an optimal permeation-enhancing lacquer formulation was achieved by the optimization of other formulation excipients, such as plasticizer and the solvent system. Additionally, novel experimental enhancements introduced to the research included refined D50 drying time and drying rate tests for lacquer characterization as well as a multi-mechanism permeation-enhancing pre-treatment. Moreover, a practical implication was provided by a handwashing simulation designed to test the performance of the lacquer during actual use. In vitro drug release testing and ex vivo nail permeation testing demonstrated that the optimized nail lacquer performed better than control lacquer lacking the permeation enhancer by achieving a faster and sustained delivery of ECN. It can be concluded that this is a promising drug delivery system for topical antifungal treatment of onychomycotic nails, and the novel characterization techniques may be adapted for similar formulations in the future.

Quality by Design Guided Development of Polymeric Nanospheres of Terbinafine Hydrochloride for Topical Treatment of Onychomycosis Using a Nano-Gel Formulation.

Superficial fungal diseases of the skin and nails are an increasingly common occurrence globally, requiring effective topical treatment to avoid systemic adverse effects. Polymeric nanoparticles have demonstrated sustained and effective drug delivery in a variety of topical formulations. The aim of this project was to develop polymeric antifungal nanospheres containing terbinafine hydrochloride (TBH) to be loaded into a hydrogel formulation for topical nail drug delivery. A quality by design (QbD) approach was used to achieve optimized particles with the desired quality target product profile (QTPP). Polyvinyl alcohol (PVA) at 2% w/v and a drug to polymer ratio of 1:4, together with a robust set of processes and material attributes, resulted in nanoparticles of 108.7 nm with a polydispersity index (PDI) of 0.63, 57.43% recovery, and other desirable characteristics such as zeta potential (ZP), particle shape, aggregation, etc. The nanospheres were incorporated into a carbomer-based gel, and the delivery of TBH through this formulation was evaluated by means of in vitro drug release testing (IVRT) and ex vivo nail permeation study. The gel containing the TBH nanospheres demonstrated a slower and controlled drug release profile compared with the control gel, in addition to a more efficient delivery into the nail. These antifungal nanospheres can be utilized for topical therapy of a multitude of superficial fungal infections.

Dual drug delivery system based on layered double hydroxides/carboxymethyl cellulose-poly ethylene oxide bionanocomposite electrospun fibrous mats: Fabrication, characterization, in-vitro and in-vivo studies

The main goal of the present project was to design and develop ibuprofen (IBU) and layered double hydroxides-vancomycin (LDH-VAN) nanohybrid loaded bionanocomposite fibrous mats to increase the wound healing rate. Thus, first, LDH-VAN nanohybrid particles was synthesized by in-situ incorporation of VAN into the Mg-Al-LDH interlayers during the co-precipitation of hydroxides. Then, LDH-VAN/IBU/CMC-PEO bionanocomposite fibrous mats were fabricated by electrospinning technique. Test samples were examined XRD, SEM, TEM, TGA, and FTIR. In vitro drug release test was performed in the phosphate buffer solution (pH = 7.4) to prove the efficiency of the fabricated bionanocomposite fibrous mats as a sustained-release carrier for both VAN and IBU. All the fabricated bionanocomposite fibrous mats did not displayed any significant cytotoxicity on NIH/3 T3 fibroblast cells. The wound area in the rats treated with LDH-VAN/IBU/CMC-PEO bionanocomposite fibrous mats was less than other treatment groups. Based on histological analysis, the LDH-VAN/IBU/CMC-PEO bionanocomposite fibrous mats possess a faster wound healing than other nanofibrous mats. Data obtained from the present project indicated that LDH-VAN/IBU/CMC-PEO bionanocomposite fibrous mats could accelerate the wound healing process.

Mechanistic Study of Release Characteristics of Two Active Ingredients in Transdermal Patch Containing Lidocaine-Flurbiprofen Ionic Liquid.

Ionic liquids (ILs) have been proven to be an efficient technology for enhancing drug skin permeability. However, the question of whether the two components of ILs are released synchronously in transdermal preparations has remained unclear. Thus, this study aimed to investigate the release characteristics of two components of ILs and their underlying molecular mechanism. The ILs containing flurbiprofen (FLU) and lidocaine (LID) were synthesized and characterized. The four typical acrylates pressure sensitive adhesives (PSAs) with different functional groups were synthesized and characterized. The effects of PSAs on the release characteristics of two components of ILs were investigated by drug release tests and verified by skin permeation experiments. The action mechanisms were revealed by FTIR, Raman, dielectric spectrum, and molecular docking. The results showed that the average release amount of FLU (0.29 μmol/cm2) and LID (0.11 μmol/cm2) of ILs in the four PSAs was significantly different (p < 0.05), which illustrated that the two components did not release synchronously. The PSA−none and PSA−OH with low permittivity (7.37, 9.82) interacted with drugs mainly by dipole-dipole interactions and hydrogen bonds. The PSA−COOH and PSA−CONH2 with high permittivity (11.19, 15.32) interacted with drugs mainly by ionic bonds and ionic hydrogen bonds. Thus, this study provides scientific guidance for the application of ILs in transdermal preparations.

Polyvinyl Alcohol-Cellulose Nanocrystal Hydrogel Containing Anti-inflammatory Agent

Hydrogel wound dressings were developed through cross-linking reactions of polyvinyl alcohol (PVA) with glutaraldehyde and by the addition of diclofenac sodium and rutin as anti-inflammatory agents. Cellulose nanocrystals (CNC) were added to improve mechanically and release properties. CNC was isolated from pineapple leaf fibers through the ammonium persulfate method resulting in a mixture of rod-like whisker and spherical morphology. The mechanical properties of hydrogels are increasing with the addition of CNC. Hydrogels containing 8% CNC exhibited 7.266 N/mm2 tensile strength, 156.3% maximum strain, and 700.3 N/mm2 elastic modulus. Drug release tests containing sodium diclofenac were done by taking incubated phosphate buffer saline samples in a pH 7.4 environment and showed that all CNC variations tested are controllable for the first 30 min compared to the sample without CNC. Sodium diclofenac is easily eluted from hydrogel due to its polar properties, and all samples almost demonstrated the same release profile. PVA hydrogels showed fluctuating concentrations of diclofenac compared to others. While hydrogels containing rutin showed a controlled release mode, the addition of CNC in PVA resulted in a slower release of rutin, possibly due to the better binding between CNC and rutin. To conclude, CNC has successfully improved the performance of PVA hydrogels, including the drug release properties.

Effect of Morphology on the Drug Sustained‐Release Performance of HA/β‐TCP Composite

AbstractHydroxyapatite/tricalcium phosphate (HA/β‐TCP) has been widely studied as a drug carrier, but the drug loading and release rate of the composites with different morphology significantly vary. In this paper, needle‐shaped, rod‐shaped, and ordered porous HA/β‐TCP composite was prepared by chemical co‐precipitation method, and ibuprofen (IBU) was used as a drug model to study the sustained‐release properties of IBU in vitro. The results showed that morphology of the HA/β‐TCP composite had a significant effect on the drug loading of IBU. The IBU loading of the ordered porous composite was as high as 101.3 mg/g, which was 2.2 times and 3.46 times higher than that of the rod‐shaped and needle‐shaped composite to IBU, respectively. The drug release test of IBU showed that the release rate of the ordered porous HA/β‐TCP to IBU was slower than that of the rod‐shaped and needle‐shaped composite in the initial 10 h, and reached the drug release equilibrium after the subsequent 30 h. The cumulative release of the ordered porous HA/β‐TCP composite to IBU reached 83.79 %, which was significantly smaller than that of the needle‐shaped and the rod‐shaped, showing better slow‐release performance for IBU. The ordered porous HA/β‐TCP composite have great application potential in quantitative drug delivery systems.

Investigation of the properties of encapsulated hydrophilic and hydrophobic drugs in whey protein microparticles

In this study, the amoxicillin (AMX) and rifampicin (RIF) were loaded into the whey protein (WP) to form the hydrophilic and hydrophobic drugs loaded whey protein microparticles. Scanning electron microscopy (SEM) images demonstrated that AMX addition increased the particle size, but RIF addition decreased the dimensions of the particles. The Fourier-transformed infrared spectroscopy (FTIR) results showed that both drugs were successfully loaded into the protein. AMX and RIF were ultimately released from the WP microparticles after 1440 min, according to the drug release test. Two drugs exhibited the same behaviour, but in the first hour, AMX had more release than the RIF.

Patient-specific in vitro drug release testing coupled with in silico PBPK modeling to forecast the in vivo performance of oral extended-release levodopa formulations in Parkinson’s disease patients

Biorelevant in vitro release models are valuable analytical tools for oral drug development but often tailored to gastrointestinal conditions in ‘average’ healthy adults. However, predicting in vivo performance in individual patients whose gastrointestinal conditions do not match those of healthy adults would be of great value for optimizing oral drug therapy for such patients. This study focused on establishing patient-specific in vitro and in silico models to predict the in vivo performance of levodopa extended-release products in Parkinson’s disease patients. Current knowledge on gastrointestinal conditions in these patients was incorporated into model development. Relevant in vivo pharmacokinetic data and patient-specific in vitro release data from a novel in vitro test setup were integrated into patient-specific physiologically-based pharmacokinetic models. AUC, cmax and tmax of the computed plasma profiles were calculated using PK-Sim®. For the products studied, levodopa plasma concentration–time profiles modeled using this novel approach compared far better with published average plasma profiles in Parkinson’s disease patients than those derived from in vitro release data obtained from the ‘average’ healthy adult setup. Although further work is needed, results of this study highlight the importance of addressing patient-specific gastrointestinal conditions when aiming to predict drug release in such specific patient groups.

Enzyme and Thermo Dual-stimuli Responsive DOX Carrier Based on PNIPAM Conjugated Mesoporous Silica.

Stimuli-responsive drug delivery systems have been proven to be a promising strategy to enhance tumor localization, overcome multidrug resistance (MDR), and reduce the side effects of chemotherapy agents. In this study, a temperature and redox dual stimuli-responsive system using mesoporous silica nanoparticles (MSNs) for targeted delivery of doxorubicin (DOX) was developed. Mesoporous silica nanoparticles were capped with poly(N-isopropylacrylamide) (PNIPAM), a thermo-sensitive polymer, with atom transfer radical polymerization (ATRP) method, via disulfide bonds (DOX-MSN-S-S-PNIPAM) to attain a controlled system that releases DOX under glutathione-rich (GSH-rich) environments and temperatures above PNIPAM's lower critical solution temperature (LCST). Morphological and physicochemical properties of the nanoparticles were indicated using transmission electron microscopy (TEM), dynamic light scattering (DLS), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and Brunauer-Emmett-Teller (BET). The drug release tests were performed at 25°C and 41°C in the absence and presence of the DTT, and the obtained results confirmed the synergic effect of temperature and reductive agent on a dual responsive release profile with a 73% cumulative release at 41°C and reductive environment during 240 min. The average loaded drug content and encapsulation efficacy were reported as 42% and 29.5% at the drug: nanoparticle ratio of 1.5: 1. In vitro cytotoxicity assays on MCF-7 cell lines indicated significant viability decreased in cells exposed to DOX-MSN-S-S-PNIPAM compared to the free drug (DOX). Based on the results, DOX-MSN-S-S-PNIPAM has shown much more efficiency with stimuli-responsive properties in comparison to DOX on MCF-7 cancer cell lines.