Multifunctional Drug Delivery System Research Articles

RGD-modified ZIF-8 nanoparticles as a drug carrier for MR imaging and targeted drug delivery in myocardial infarction.

Aim: A multifunctional nanoplatform has been developed to enhance the targeting capability and biosafety of drug/siRNA for better diagnosis and treatment of myocardial infarction (MI). Materials & methods: The nanoplatform's chemical properties, biodistribution, cardiac magnetic resonance imaging (MRI) capabilities, therapeutic effects and biocompatibility were investigated. Results: The nanoplatform exhibited MI-targeting properties and pH-sensitivity, allowing for effective cardiac MRI and delivery of drugs to the infarcted myocardium. The GCD/Qt@ZIF-RGD demonstrated potential as a reliable MRI probe for MI diagnosis. Moreover, the GCD/si-SHP1/Qt@ZIF-RGD effectively suppressed SHP-1 expression, increased pro-angiogenesis gene expression and reduced cell apoptosis in HUVECs exposed to hypoxia/reoxygenation. Conclusion: Our newly developed multifunctional drug delivery system shows promise as a nanoplatform for both the diagnosis and treatment of MI.

Influence of bonding variance on electron affinity in graphene quantum dot-barium titanate nanocomposites for drug delivery system

Although chemotherapy remains a prevalent option in cancer treatment, its adverse effects on normal cells and suboptimal pharmacokinetics often limit its effectiveness. To address these challenges, this study successfully developed a new multifunctional drug delivery system comprising a covalent composite of graphene quantum dots and barium titanate nanoparticles. Notably, despite numerous reports on the surface modification of graphene quantum dots, studies focusing on cancer cell inhibition via different covalent bonds are scarce. To bridge this gap, this system was synthesized using eco-friendly esterification and amidation pathways. The anticancer drug doxorubicin was employed as a model drug, and hyaluronic acid was used to encapsulate the delivery system, enhancing its sustained release capabilities. Comprehensive material characterization confirmed the successful synthesis of the system. Its high drug loading capacity and acid-sensitive release can be attributed to the unique structure of the graphene quantum dots. Subsequent in vitro and in vivo biological evaluations not only demonstrated the system’s remarkable cancer inhibition efficacy but also accentuated the distinct impacts of the two bonding types. The underlying mechanism is believed to involve bonding affinity and electron transfer, findings that are corroborated by the experimental data. Additionally, results from animal models provide clear evidence for the potential application of this system (HA-DOX-GQD@BTNPs) in cancer therapeutics and imaging. In conclusion, this research elucidates the variances in drug carrier efficacy based on different covalent bond modifications for cancer treatment and introduces a novel drug delivery system that synergistically combines imaging and targeting capabilities.

Hybrid Nanogel Drug Delivery Systems: Transforming the Tumor Microenvironment through Tumor Tissue Editing.

The future of drug delivery offers immense potential for the creation of nanoplatforms based on nanogels. Nanogels present a significant possibility for pharmaceutical advancements because of their excellent stability and effective drug-loading capability for both hydrophobic and hydrophilic agents. As multifunctional systems, composite nanogels demonstrate the capacity to carry genes, drugs, and diagnostic agents while offering a perfect platform for theranostic multimodal applications. Nanogels can achieve diverse responsiveness and enable the stimuli-responsive release of chemo-/immunotherapy drugs and thus reprogramming cells within the TME in order to inhibit tumor proliferation, progression, and metastasis. In order to achieve active targeting and boost drug accumulation at target sites, particular ligands can be added to nanogels to improve the therapeutic outcomes and enhance the precision of cancer therapy. Modern "immune-specific" nanogels also have extra sophisticated tumor tissue-editing properties. Consequently, the introduction of a multifunctional nanogel-based drug delivery system improves the targeted distribution of immunotherapy drugs and combinational therapeutic treatments, thereby increasing the effectiveness of tumor therapy.

Rational Design of Coordination Polymers Composited Hollow Multishelled Structures for Drug Delivery.

Multifunctional drug delivery systems (DDS) are in high demand for effectively targeting specific cells, necessitating excellent biocompatibility, precise release mechanisms, and sustained release capabilities. The hollow multishelled structure (HoMS) presents a promising solution, integrating structural and compositional design for efficient DDS development amidst complex cellular environments. Herein, starting from a Fe-based metal-organic framework (MOF), amorphous coordination polymers (CP) composited HoMS with controlled shell numbers are fabricated by balancing the rate of MOF decomposition and shell formation. Fe-CP HoMS loaded with DOX is utilized for synergistic chemotherapy and chemodynamic therapy, offering excellent responsive drug release capability (excellent pH-triggered drug release 82% within 72h at pH 5.0 solution with doxorubicin (DOX) loading capacity of 284mg g-1). In addition to its potent chemotherapy attributes, Fe-CP-HoMS possesses chemodynamic therapy potential by continuously catalyzing H2O2 to generate ·OH species within cancer cells, thus effectively inhibiting cancer cell proliferation. DOX@3S-Fe-CP-HoMS, at a concentration of 12.5µg mL-1, demonstrates significant inhibitory effects on cancer cells while maintaining minimal cytotoxicity toward normal cells. It is envisioned that CP-HoMS could serve as an effective and biocompatible platform for the advancement of intelligent drug delivery systems in the realm of cancer therapy.

Strategically Designed Bifunctional Polydopamine Enwrapping Polycaprolactone-Hydroxyapatite-Doxorubicin Composite Nanofibers for Osteosarcoma Treatment and Bone Regeneration.

This study presents a new multifunctional nanofibrous drug delivery system to provide effective combination therapy with enormous potential for the treatment of osteosarcoma. We developed a composite nanofiber scaffold comprising poly(ε-caprolactone) (PCL) and hydroxyapatite (HAp)-loaded doxorubicin (DOX) coated with polydopamine (PDA) to combine cancer cell inhibition with bone tissue regeneration. DOX was conjugated with HAp and then mixed with a PCL solution to prepare a PCL/HAp-DOX (labeled PCLDH) nanofiber. Then, in situ polymerization of PDA on the PCLDH occurred to produce the PCLDH@PDA composite nanofiber. The morphology, XRD, FT-IR, wettability, photothermal characteristics, cumulative drug release, and in vitro bioactivities were evaluated. We found that the PDA coating not only enhanced the hydrophilic properties but also controlled drug release. The PCLDH@PDA composite scaffold significantly suppressed the proliferation of bone cancer cells initially and, consequently, improved the adhesion and proliferation of human mesenchymal stem cells (hMSCs). The PDA coating boosted the composite scaffold's bioactivity, as demonstrated through ALP activity, ARS assay, and biomineralization results. This strategy offers a promising dual-function scaffold to treat residual cancer and reconstruct defects after osteosarcoma surgery.

PLGA-based nanocarriers for combined delivery of colchicine and purpurin 18 in cancer therapy: Multimodal approach employing cancer cell spheroids

Improving the anticancer efficacy of chemotherapeutic drugs and photosensitizers requires innovative multifunctional nanoplatforms. This study introduces a chemo- and phototherapeutic drug delivery system (DDS) based on poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), both PEGylated and non-PEGylated, with a mean size of 200 ± 75 nm. Colchicine (Colch) and purpurin18 (P18) were co-encapsulated into these NPs, and their in vitro drug release profiles were investigated. The anticancer potential of these systems was evaluated across various cell lines (i.e., CaCo-2, PC-3, MCF-7, and MRC-5 cells), demonstrating enhanced NP uptake by cancer cells compared to free drugs. Co-administration of Colch and P18 in 2D and 3D cell line models exhibited a synergistic effect, harnessing both chemotherapeutic and photodynamic effects, leading to higher cancer cell elimination efficacy. This newly developed multifunctional DDS presents a promising platform for combined chemo- and photodynamic therapy in cancer treatment.

Engineered Extracellular Vesicles in Chronic Kidney Diseases: A Comprehensive Review.

Chronic kidney diseases (CKD) present a formidable global health challenge, characterized by a deficiency of effective treatment options. Extracellular vesicles (EVs), recognized as multifunctional drug delivery systems in biomedicine, have gained accumulative interest. Specifically, engineered EVs have emerged as a promising therapeutic approach for targeted drug delivery, potentially addressing the complexities of CKD management. In this review, we systematically dissect EVs, elucidating their classification, biogenesis, composition, and cargo molecules. Furthermore, we explore techniques for EV engineering and strategies for their precise renal delivery, focusing on cargo loading and transportation, providing a comprehensive perspective. Moreover, this review also discusses and summarizes the diverse therapeutic applications of engineered EVs in CKD, emphasizing their anti-inflammatory, immunomodulatory, renoprotective, and tissue-regenerating effects. It critically evaluates the challenges and limitations in translating EV therapies from laboratory settings to clinical applications, while outlining future prospects and emerging trends.

Investigation on the structural and dynamical properties of cationic, anionic, and catanionic niosomes as multifunctional controlled drug delivery system for cabozantinib

BackgroundNiosomes are versatile nanocarriers for therapeutic compounds, and optimizing their structures via ionic surfactants can enhance their functionality considerably. Catanionic niosomes, which have the capability of both cationic and anionic niosomes, are attractive vehicles for drug delivery objectives. Here, we aim to design and evaluate catanionic niosome as a vehicle for anticancer agents. MethodsA molecular modeling pipeline was performed to model the physicochemical properties of cationic, anionic, and catanionic niosomes as a multifunctional drug delivery system for Cabozantinib. SPAN60 was used as the nonionic surfactant, cholesterol was the stabilizer, DOTAP and DCP were used as the cationic and anionic surfactants, respectively, and cabozantinib, an FDA-approved c-Met inhibitor was chosen as the drug compound. Some meaningful parameters relevant to the cabozantinib molecule and its characteristics in the bilayer, such as hydrogen bonding, total energy, the radius of gyration (Rgyr), mean square displacements (MSD), diffusion coefficient, and the radial distribution function (RDF) were evaluated and compared between the formulations. ResultsThe outcomes revealed that hydrogen bonding of cabozantinib is more probable with DOTAP, and the total energy of the drug is lower in anionic formulation (-180 kcal/mol). The MSD showed that cationic niosome restricts the movement of cabozantinib, while the drug could be efficiently released from the anionic niosome, and catanionic niosome can equilibrate the movement of the drug with a diffusion coefficient of 5.73 × 10−12 (m2/s). ConclusionsThis technique could effectively describe the behavior of drugs in various bilayer compositions, and the catanionic niosomes are potential multifunctional carriers for anticancer agents.

Synthesis and characterization of the redox-responsive amphiphilic fluorescent alginate derivatives as the multi-functional hydrophobic anticancer drug delivery system with visualization and sustained release

To develop the multi-functional hydrophobic anticancer drug carriers with visualization and sustained release, a novel amphiphilic alginate derivative (LSA-SS-DEAC) containing chromophobe groups was designed and synthesized by grafting hydrophobic fluorescent molecule, 7-(diethylamino-coumarin-3-carboxylic acid (DEAC-COOH) onto hydrophilic low molecular alginate backbone through cystamine by water-soluble carbodiimide chemical method. The molecular structure and self-assembly properties of the synthesized LSA-SS-DEAC were characterized. Furthermore, the encapsulation of anti-cancer drugs, doxorubicin hydrochloride (DOX) in LSA-SS-DEAC self-assembled micelles was realized by ultrasonic dialysis method. Subsequently, the in vitro drug release behavior and in vitro cytotoxicity of LSA-SS-DEAC micelles in simulated tumor microenvironment were also studied. The resultant LSA-SS-DEAC with the critical micelle concentration (CMC) of 0.26 mg/mL exhibited the ability to spontaneously form spherical micelles with the particle size of 250.2 ± 4.3 nm (PDI = 0.23) and zeta potential of −49.1 ± 0.4 mV, which presented good stability in pH 7.4 PBS and excellent fluorescence properties and redox responsiveness. The drug-loaded LSA-SS-DEAC micelles had the optimal EE value of about 42.2% when the DOX/LSA-SS-DEAC mass ratio was 3:10. Meanwhile, The drug-loaded LSA-SS-DEAC micelles exhibited sustained release in GSH-free environment, and the cumulative drug release rates were 40.3% and 46.6% in pH 7.4 and 5.0 PBS for 48 h, respectively. However, in the simulated tumor cell microenvironment (pH 5.0 PBS + 10 mM GSH), the disulfide bond between the core-shell was broken under the GSH trigger, and the LSA-SS-DEAC micelles collapsed, resulting in a cumulative drug release rate of about 64% at 12 h. In vitro cytotoxicity results showed that LSA-SS-DEAC had low cytotoxicity, and revealed obvious inhibitory effect on HeLa cells after DOX loading. Fluorescence imaging results indicated that LSA-SS-DEAC micelles could emit green light after ingested by cells, and their fluorescence properties were not affected after encapsulation of DOX. Accordingly, LSA-SS-DEAC micelles had the potential for drug localization tracking and rapid drug release at focal sites, which could be expected to be an ideal drug carriers for hydrophobic anticancer drug delivery.

АНАЛИТИКА ПАРАМЕТРОВ САЛИВАРНОГО СТАТУСА СТУДЕНТОВ-КУРИЛЬЩИКОВ ПРИ ИСПОЛЬЗОВАНИИ СПРЕЯ С МУКОПРОТЕКТОРОМ

Subject. The subject of this study is the salivary status in the patients.
 Objectives. The objective is to identify specifics of data analytics of the salivary status in student smokers effected by using a mucoptorotective dental spray. 
 Methodology. The study is made by the Ural State Medical University Department of Preventive Dentistry and Propedeutics of Dental Disease, the Ural State Medical University Department of General Chemistry, the Ural Federal University Department of Control Systems Modeling. The objects of the study are unstimulated mixed saliva and a mucoptorotective spray that helps to protect the oral mucosa against inflammations, facilitates penetration across epithelial membranes, acts as a controlled multifunctional drug delivery system for parodontium tissues. The two study groups were formed from 20 volunteers in the age of 20 to 24 years old (4 women and 36 men, the average age was 22,35 years old): the first (main) group consisted of smoking patients, the second (reference) group consisted of non-smokers. The clinical assessment of the oral cavity of patients included: analysis of complaints, analysis of anamnesis, examination, evaluation of the hygiene index (OHI, Greene, Vermillion, 1964), dental caries severity index (using DMFT and DMFS indices), the state of gingival inflammation, PMA index (Parma). Unstimulated mixed saliva was studied, the quantitative analysis of the secretion was made by analyzing color, transparency, presence of inclusions, pH value, the functional activity of minor salivary glands. The statistical analysis of results was made using a PC with Microsoft Excel 2007 software program; the statistical significance was assessed using Student’s t-distribution by Statistica 6.0 software package.
 Conclusions. Given the reduction of objective values of index assessment of oral health status used as indicators of changes in oral health, the study of the data analytics of salivary status in student smokers in the course of using a mucoptorotective spray revealed the harmful effects of tobacco on salivary composition and parameters. The findings prove smoking-related oral homeostatic disruption promoting development and progression of dental diseases of the hard tissues, parodontium, oral mucosa. Application of the dental spray with titanium glycerosolvate aquacomplex is proved to be an effective way to prevent development and progression of such diseases.

Therapeutic Potential of Hydrogel Based Sodium Alginate and Chitosan as A Multifunctional Drug Delivery System for Atopic Dermatitis

Therapeutic Potential of Hydrogel Based Sodium Alginate and Chitosan as A Multifunctional Drug Delivery System for Atopic Dermatitis

Responsive ZIF-90 nanocomposite material: targeted delivery of 10-HCPT to enhance the therapeutic effect of HCT116 cells

There is significant value in developing multifunctional drug delivery systems with high therapeutic efficiency for diagnosing and treating tumors. In this study, we synthesized the ATP-triggered and pH-sensitive material ZIF-90...

Tetramethylpyrazine-loaded liposomes surrounded by hydrogel based on sodium alginate and chitosan as a multifunctional drug delivery System for treatment of atopic dermatitis

Tetramethylpyrazine (TMP) has low bioavailability due to its fast metabolism and short half-life, which is not conducive to transdermal treatment of atopic dermatitis (AD). Therefore, in this study, TMP was encapsulated into liposomes (Lip) by film dispersion method, and then the surface of Lip was modified by sodium alginate (ALG) and chitosan (CS). The tetramethylpyrazine-loaded liposomes in sodium alginate chitosan hydrogel called T-Lip-AC hydrogel. In vitro experiments, we found that T-Lip-AC hydrogel not only had the antibacterial effect of CS, but also enhanced the anti-inflammatory and antioxidant effects of TMP. In addition, T-Lip-AC hydrogel could also provide a moist healing environment for AD dry skin and produce better skin permeability, and can also achieve sustained drug release, which is conducive to the treatment of AD. The lesions induced by 1-chloro-2,4-dinitrobenzene were used as the AD lesions model to test the therapeutic effect of the T-Lip-AC hydrogel on AD in vivo. The studies have showed that T-Lip-AC hydrogel could effectively promote wound healing. Therefore, we have developed a T-Lip-AC hydrogel as multifunctional hydrogel drug delivery system, which could become an effective, safe and novel alternative treatment method for treating AD.

The Effect of Copolymer-Based Nanoparticle Composition (MEO2MA-OEGMA) on the Release Profile of Doxorubicin In Vitro

The release of drugs from core/shell nanoparticles (NPs) is a crucial factor in ensuring high reproducibility, stability, and quality control. It serves as the scientific basis for the development of nanocarriers. Several factors, such as composition, composition ratio, ingredient interactions, and preparation methods, influence the drug release from these carrier systems. The objective of our study was to investigate and discuss the relationship between modifications of core/shell NPs as multifunctional drug delivery systems and the properties and kinetics of drug release using an in vitro drug release model. In this paper, we prepared four core/shell NPs consisting of a superparamagnetic iron oxide NPs (Fe3−δO4) core encapsulated by a biocompatible thermo-responsive copolymer, poly(2-(2-methoxy) ethyl methacrylate-oligo (ethylene glycol) methacrylate) or P(MEO2MAx-OEGMA100−x) (where x and 100 − x represented the molar fractions of MEO2MA and OEGMA, respectively), and loaded with doxorubicin (DOX). Colloidal behavior measurements in water and PBS as a function of temperature showed an optimization of the lower critical solution temperature (LCST) depending on the molar fractions of MEO2MA and OEGMA used to form each NPs. In vitro studies of doxorubicin release as a function of temperature demonstrated a high control of release based on the LCST. A temperature of approximately 45 °C for 60 h was sufficient to release 100% of the DOX loaded in the NPs for each sample. In conclusion, external stimuli can be used to modulate the drug release behavior. Core/shell NPs hold great promise as a technique for multifunctional drug delivery systems.

Hierarchical Microcarriers Loaded with Peptide Dendrimer‐Grafted Methotrexate for Rheumatoid Arthritis Treatment

Rheumatoid arthritis (RA) is one of the leading causes of disability due to the autoimmune destruction of synovial joints. Great efforts have been put into developing multifunctional drug delivery systems for delaying the progression of RA. Herein, a novel locally injectable, hierarchically structured delivery system with a hyaluronic acid (HA) microparticle and an MTX‐conjugated nanoparticle for promoted RA treatment is proposed. In this system, MTX is chemically grafted onto a peptide dendrimer‐based nanoparticle (G‐MTX). These nanoparticles are encapsulated inside HA microparticles (H‐G‐MTX) using microfluidics to realize the system. The G‐MTX can be released from the degradable HA microparticles in the acidic environment of inflamed RA joints. As the G‐MTX shows an enhanced intracellular delivery of the conjugated MTX, the H‐G‐MTX can reverse the dominant macrophage phenotype from M1 to M2. Through a collagen‐induced arthritis (CIA) rat model, the great therapeutic outcomes of this hierarchically structured delivery system are demonstrated, including inflammation reduction, cartilage protection, and bone mineral density promotion. These results indicate that the proposed hierarchical delivery system has potential clinical value in the treatment of RA and other diseases.

In situ autophagy regulation in synergy with phototherapy for breast cancer treatment

Autophagy is an important factor in reducing the efficacy of tumor phototherapy (including PTT and PDT). Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT. This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy. To achieve this goal, we first synthesized TRANSFERRIN (Tf) biomimetic mineralized nano-tellurium (Tf-Te) as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly. The autophagy inhibitor hydroxychloroquine (HCQ) and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ. After entering breast cancer cells through the “self-guidance system”, Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation, to efficiently induce PTT/PDT effect. Meanwhile, the disulfide bond broke down in response to GSH, and the nanoparticles disintegrated to release Fe2+ and HCQ at fixed points. They simultaneously induce lysosomal alkalinization and increased osmotic pressure, effectively inhibit autophagy, and synergistically enhance the therapeutic effect of phototherapy. In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6% on 4T1 tumor-bearing mice. This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

Near‐Infrared Emission‐Cyanine 5.5 and Doxorubicin Loaded Magnetite Nanoparticles for Dual In Vivo Magnetic Resonance and Biodistribution Imaging

AbstractThe in vivo imaging of the drug distribution during cancer treatment plays an important role in helping physicians and pharmacists to monitor the progress of treatment and improve the effectiveness of therapy. Our goal in this work was to prepare a multifunctional nano drug delivery system that not only co‐loaded iron oxide nanoparticles (Fe3O4 NPs) and Doxorubicin (Dox) but also attached the near‐infrared fluorescent agent Cyanine 5.5 based on poly(lactide)‐tocopheryl polyethylene glycol 1000 succinate (PLA‐TPGS) copolymer. Cyanine 5.5 was attached to the surface Fe3O4 NPs via the NH−CO chemical bond, followed by co‐loading of Dox onto the PLA‐TPGS copolymer by the emulsion solvent evaporation method. The structural, morphological, dimensional, stability, and optical‐magnetic properties of the as‐synthesized nanosystem were fully characterized. From the drug‐released study, the prolonged release of Dox accelerated with increasing acidic conditions (at pH 5.0 and 6.5), while a slow release was observed at pH 7.4. Through the MTT assay, the nanosystem had cellular toxicity against Hep−G2 and HeLa cell lines with low IC50 values of 0.42 and 0.78 μg.mL−1 in terms of Dox concentration, respectively. At a magnetic field of 7 T, this nanosystem also exhibited a high r2/r1 ratio of 164.5 and a strong contrast magnetic resonance (MR) image in the liver. In vivo biodistribution studies revealed that the highest fluorescence intensity achived in the liver after 6 h, and the nanosystem was eliminated from the body after at least 24 h. Collectively, these results demonstrated that the PLA‐TPGS‐Fe3O4‐Cyanine 5.5‐Dox nanosystem is a good candidate for simultaneously increasing contrast for MR and near‐infrared fluorescence imaging.

A multifunctional drug delivery cargo: Folate-driven gold nanoparticle-vitamin B complex for next-generation drug delivery

The gold nanoparticles have manifold applications as drug delivery agents. The larger surface-to-volume ratio of the gold nanoparticles is the primary reason for their high drug-loading efficiency. Currently, their application is transitioning into nuclear medicines and as a theranostic assay of biological tissues. Bioactive gold nanoparticles have the potential to bind with growth factors such as Vitamins to regulate the cellular functions of different organs of the human body. The present study focuses on the formation of folate-functionalized gold nanoparticles conjugated Vitamin B complex. AuNPs were fabricated using thiol-linkage to conjugate folic acid and Vitamin B complex using heterobifunctional PEG derivative and characterized by UV–visible spectroscopy, FTIR, XRD analysis and Dynamic light scattering DLS. Thiol-linked folate functionalized AuNP-Vitamin B complex can act as a selective targeting molecule and exert a synergistic therapeutic effect as a multifunctional drug delivery system in nanomedicines.

Degradation Kinetics of Disulfide Cross-Linked Microgels: Real-Time Monitoring by Confocal Microscopy.

Although biodegradable microgels represent a useful drug delivery system, questions remain regarding the kinetics of gel degradation and subsequent drug release. Spherical microgels (~Ø10-300 µm) were synthesized using an inverse suspension polymerization method. Specifically, acrylamide and acrylonitrile monomers were thermally co-polymerized with N,N'-bis(acryloyl)cystamine as a cross-linker with disulfide bridges. The kinetics and mechanism of degradation of these cross-linked, degradable, fluorescently labeled microgels (PAAm-AN-BAC-FA) were quantitatively studied under confocal microscopy at various concentrations of glutathione (reducing agent) ranging from 0.06 to 91.8 mM. It was found that polymer network degradation via the cleavage of disulfide bonds was accompanied by two overlapping processes: diffusion-driven swelling and dissolution-driven erosion. A slow increase in microgel size (swelling) resulted from partial de-cross-linking in the bulk of the microgel, whereas a faster decrease in fluorescence intensity (erosion) resulted from the complete cleavage of disulfide bonds and the release of uncleaved polymeric chains from the microgel immediate surface into the solution. Swelling and erosion exhibited distinct kinetics and characteristic times. Importantly, the dependence of kinetics on glutathione concentration for both swelling and erosion suggests that degradation would occur faster in cancer cells (higher concentration of reductants) than in normal cells (lower concentration of reductants), such that drug release profiles would be correspondingly different. A greater comprehension of microgel degradation kinetics would help in (i) predicting the drug release profiles for novel multifunctional drug delivery systems and (ii) using redox-sensitive degradable hydrogel particles to determine the concentrations of reducing agents either in vitro or in vivo.

Valine conjugated polymeric nanocarriers for targeted co-delivery of rivastigmine and quercetin in rat model of Alzheimer disease

Multifunctional nanocarriers are increasingly promising for disease treatment aimed at finding effective therapy and overcoming barriers in drug delivery. Herein, valine conjugated chitosan (VLCS) was used for surface modification of nanocarriers (NCs) based on Poly (ε-caprolactone)-Poly (ethylene glycol)-Poly (ε-caprolactone) (PCL-PEG-PCL) triblock copolymers (NCs@VLCS). The nanocarriers were co-loaded with rivastigmine (RV) and quercetin (QT) to yield the final RV/QT-NCs@VLCS as a multifunctional nanocarrier for Alzheimer’s disease (AD) treatment. The large amino acid transporter 1 (LAT-1) was selected for the direction of the NCs to the brain. The biocompatibility of the nanocarrier was studied in HEK-293 and SH-SY5Y cells and rats. The Morris water maze test demonstrated a faster regain of memory loss with RV/QT-NCs@VLCS compared to the other groups. Furthermore, RV/QT-NCs@VLCS and RV/QT-NCs improved GSH depletion induced by scopolamine (SCO), with RV/QT-NCs@VLCS having a superior effect. The real-time PCR analysis revealed that co-delivery of RV and QT by NCs@VLCS showed significantly higher efficacy than sole delivery of RV. RV/QT-NCs@VLCS treatment also modulated the expression of BDNF, ACHE, and TNF-α. The findings revealed that NCs@VLCS co-loaded with RV and QT, significantly increased efficacy relative to the single use of RV and could be considered a potent multifunctional drug delivery system for Alzheimer’s treatment.