Drug Delivery Kinetics Research Articles

Polymer homologue-mediated formation of hydrogel microneedles for controllable transdermal drug delivery

Poly(ethylene glycol) diacrylate (PEGDA) microneedles (MNs) are hydrogel-based devices that achieve controlled drug delivery kinetics by adjusting the crosslinking density. However, the biosafety of many crosslinking agents used to regulate crosslinking density is not ideal. To avoid crosslinking agents and simplify the preparation process, using two types of polymer homologues with different number-average molecular weights, we have successfully developed a series of PEGDA MNs with controllable crosslinking density (abbreviated as TP-X MNs). The research showed that the mechanical properties and drug release behavior of TP-X MNs could be tuned by simply controlling the weight proportion of two different PEGDA components in MNs. Ex vivo drug delivery experiments indicated that all TP-X MNs exhibited a sustained release profile, and their control range of 336-hour accumulative release rates was from 6.24% to 40.93%. Moreover, we prepared a novel dual-layer PEDGA MN, which can customize the drug loading and release rate in each layer of MN. This work demonstrates a new way to develop hydrogel MNs with adjustable crosslink density and broadens the applications of PEGDA MN in the biomedical field.

Tricalcium phosphate-loaded injectable hydrogel as a promising osteogenic and bactericidal teicoplanin-delivery system for osteomyelitis treatment: An in vitro and in vivo investigation

Osteomyelitis is an inflammation of bone tissue usually caused by pyogenic bacteria. The most recurrent clinical approach consists of bone debridement followed by parenteral administration of antibiotics. However, systemic antibiotic treatment has limitations regarding absorption rate and bioavailability over time. The main challenge of osteomyelitis treatment consists of coupling the persistent infection treatment with the regeneration of the bone debrided. In this work, we developed an injectable drug delivery system based on poloxamer 407 hydrogel containing undoped Mg, Zn-doped tricalcium phosphate (β-TCP), and teicoplanin, a broad-spectrum antibiotic. We evaluated how the addition of teicoplanin and β-TCP affected the micellization, gelation, particle size, and surface charge of the hydrogel. Later, we studied the hydrogel degradation and drug delivery kinetics. Finally, the bactericidal, biocompatibility, and osteogenic properties were evaluated through in vitro studies and confirmed by in vivo Wistar rat models. Teicoplanin was found to be encapsulated in the corona portions of the hydrogel micelles, yielding a bigger hydrodynamics radius. The encapsulated teicoplanin showed a sustained release over the evaluated period, enough to trigger antibacterial properties against Gram-positive bacteria. Besides, the formulations were biocompatible and showed bone healing ability and osteogenic properties. Finally, in vivo studies confirmed that the proposed locally injected formulations yielded osteomyelitis treatment with superior outcomes than parenteral administration while promoting bone regeneration. In conclusion, the presented formulations are promising drug delivery systems for osteomyelitis treatment and deserve further technological improvements.

Nanoscopic gel particle for intra-articular injection formulation

Hyaluronic acid (HA) based nanogels showed effective intracellular delivery efficacy for anti-cancer and anti-inflammatory drugs, characterized by their ability targeting relevant cell receptors. In the present study, we demonstrate the ability of hyaluronic acid-polyethyleneimine (HA-PEI) nanogels as a promising dual-functional interfacial active for intra-articular injection to intervene arthritis. Nanomechanical measurements on both model substrates and human cartilage samples confirm that the HA-PEI nanogels can significantly improve interfacial lubrication, in comparison to HA molecules, or silica-based nanoparticles. We show that the Coefficient of Friction significantly decreases with a decreasing nanogel size. The exceptional lubricating performance, coupled with the proven drug delivery capability, evidences the great potential of nanoscopic hydrogels for early-stage arthritis treatment. The flexibility in choosing the chemical nature, molecular architecture, and structural characteristics of nanogels makes it possible to modulate both drug delivery kinetics and interfacial lubrication, thus representing an innovative approach to treat degenerative joint diseases.

Biocompatability chitosan /Aloe barbadensis miller loaded moxifloxacin composite film: A multifunctional bio-platform for the treatment of breast cancer

Binary biodegradable polymers exhibit excellent functional behavior but the limited mechanical integrity for regulating drug release within the polymeric matrix, hence it needs modification in the polymer network to overcome the limitations. The compatibility of bipolymer blends with incorporation of drugs within their matrices to enhance physicochemical properties and drug delivery kinetics have garnered significant attention in recent research. Herein, we examine the influence of the film produced by the casting technique, which consists of chitosan (CS) and Aloe barbadensis miller (ABM) gel, embedded with moxifloxacin (MoF), on attenuating the breast cancer (MCF-7) cell line. Firstly, spectroscopy confirmed the intermolecular interactions between the matrixes and the grafting of components. Notably, the addition of ABM produces significant changes in the film properties, such as decreased elongation. The pivotal moment resulted in the generation of more stable films that displayed enhanced stability at temperatures below 200 °C, as confirmed by TGA analysis. Additionally, film surfaces exhibiting strong water affinity were found to be more favorable for cell adhesion, subsequently hindering the proliferation of compromised cells. Remarkably, the In vitro cytotoxicity study showed the antibiotic-grafted CS-ABM/MoF scaffolds exhibited high cell adhesion and improved the rate of cell death was higher compared to other films. The antibacterial activity against S. aureus and E. coli results strongly suggests the enhanced antibiotic ability of the polymeric CS- ABM/MoF film. These results findings indicated that the CS- ABM/MoF scaffolds' hydrophilic surface significantly contributes to the improved cell adhesion efficiently used for biomedical applications.

Advancements in Stimulus-Responsive Co-Delivery Nanocarriers for Enhanced Cancer Immunotherapy.

Cancer immunotherapy has emerged as a novel therapeutic approach against tumors, with immune checkpoint inhibitors (ICIs) making significant clinical practice. The traditional ICIs, PD-1 and PD-L1, augment the cytotoxic function of T cells through the inhibition of tumor immune evasion pathways, ultimately leading to the initiation of an antitumor immune response. However, the clinical implementation of ICIs encounters obstacles stemming from the existence of an immunosuppressive tumor microenvironment and inadequate infiltration of CD8+T cells. Considerable attention has been directed towards advancing immunogenic cell death (ICD) as a potential solution to counteract tumor cell infiltration and the immunosuppressive tumor microenvironment. This approach holds promise in transforming "cold" tumors into "hot" tumors that exhibit responsiveness to antitumor. By combining ICD with ICIs, a synergistic immune response against tumors can be achieved. However, the combination of ICD inducers and PD-1/PD-L1 inhibitors is hindered by issues such as poor targeting and uncontrolled drug release. An advantageous solution presented by stimulus-responsive nanocarrier is integrating the physicochemical properties of ICD inducers and PD-1/PD-L1 inhibitors, facilitating precise delivery to specific tissues for optimal combination therapy. Moreover, these nanocarriers leverage the distinct features of the tumor microenvironment to accomplish controlled drug release and regulate the kinetics of drug delivery. This article aims to investigate the advancement of stimulus-responsive co-delivery nanocarriers utilizing ICD and PD-1/PD-L1 inhibitors. Special focus is dedicated to exploring the advantages and recent advancements of this system in enabling the combination of ICIs and ICD inducers. The molecular mechanisms of ICD and ICIs are concisely summarized. In conclusion, we examine the potential research prospects and challenges that could greatly enhance immunotherapeutic approaches for cancer treatment.

Taguchi Design for Development of Lipid-Polymer Effervescent Floating Tablets for Metformin Prolonged Release

TFloating drug delivery systems (FDDS) formulated with hydrophilic polymers and effervescent agents are a promising gastro retentive tool for prolonged drug release, especially with drug with low bioavailability and low solubility. Lately, it has been reported that the combination of lipids with hydrophilic polymers in the development of blends or composite hybrid materials may bring together the properties of individual components. This study proposed four formulations of effervescent lipid-polymer FDDS through a Taguchi experimental design for metformin’s prolonged release. Tablets were obtained by wet granulation, and the effect of HPMC, Compritol®, and sodium bicarbonate was studied. All formulations were evaluated with pharmacotechnical and biopharmaceutical properties such as in-vitro drug delivery, flotation, swelling, erosion and release kinetics. Effervescent lipid-polymer FDDS were obtained with prologued release until 24 hours. Formulation F1 meets the acceptance criteria of USP extended delivery. Compritol®, combined with HPMC and sodium bicarbonate, impacted release behavior and buoyancy properties. Formulations with high amounts of HPMC and Compritol® were found to have the lowest release rates and followed the Peppas-Sahlin kinetic model. Successful preparation of effervescent lipid-polymer was achieved and evaluated through a Taguchi experimental design, expected to result in prologued release and better therapeutic behavior

Silk Protein-Based Nanoporous Microsphere for Controllable Drug Delivery through Self-Assembly in Ionic Liquid System.

Ionic liquids (ILs) showed a promising application prospect in the field of biomedicine due to their unique recyclability, modifiability, and structure adjustability. In this study, nanoporous microsphere of silk protein and blending with poly(d,l-lactic acid) as model drug delivery was fabricated, respectively, through an IL-induced self-assembly method. Their morphology, structure, and thermal properties were comparably investigated through scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, differential scanning calorimetry, X-ray diffraction, and thermogravimetric analyses, and the interaction mechanisms were also discussed to elucidate the effect of structure on drug delivery kinetics. The pure protein exhibited a bigger nanopore size in the microsphere compared to the composite one, facilitating more effective drug loading up to 88.7%. However, drug release was over 53.5% for the composite during initial 4 h, while pure protein was only about half of the composite. Both of them exhibited sustained slow release after 24 h and anticancer efficacy. Furthermore, the favorable compatibility between drug and microsphere vehicle was found and experienced improved thermal stability upon encapsulation, which could protect the drug molecules in high temperature at 200 °C. When the protein and its composite self-assembled to microspheres in ILs due to electrostatic and hydrophobic interaction, the drug could be infiltrated into the nanoporous matrix through biophysical action, and the protein structure displayed reversible transition during delivery. The sustained slow release from pure SF was attributed to the high β-sheet block action and strong drug-protein interactions, whose strength could be tuned through blending poly(d,l-lactic acid) with protein. These findings indicated that the SF-based nanoporous microspheres formed from IL self-assembled system are an ideal and potential drug delivery vehicle which can be incorporated into various biomaterials in the future.

Revealing microscopic dynamics: in situ liquid-phase TEM for live observations of soft materials and quantitative analysis via deep learning.

In various domains spanning materials synthesis, chemical catalysis, life sciences, and energy materials, in situ transmission electron microscopy (TEM) methods exert a profound influence. These methodologies enable the real-time observation and manipulation of gas-phase and liquid-phase reactions at the nanoscale, facilitating the exploration of pivotal reaction mechanisms. Fundamental research areas like crystal nucleation, growth, etching, and self-assembly have greatly benefited from these techniques. Additionally, their applications extend across diverse fields such as catalysis, batteries, bioimaging, and drug delivery kinetics. However, the intricate nature of 'soft matter' presents a challenge due to the unique molecular properties and dynamic behavior of these substances that remain insufficiently understood. Investigating soft matter within in situ liquid-phase TEM settings demands further exploration and advancement compared to other research domains. This research harnesses the potential of in situ liquid-phase TEM technology while integrating deep learning methodologies to comprehensively analyze the quantitative aspects of soft matter dynamics. This study centers on diverse phenomena, encompassing surfactant molecule nucleation, block copolymer behavior, confinement-driven self-assembly, and drying processes. Furthermore, deep learning techniques are employed to precisely analyze Ostwald ripening and digestive ripening dynamics. The outcomes of this study not only deepen the understanding of soft matter at its fundamental level but also serve as a pivotal foundation for developing innovative functional materials and cutting-edge devices.

Unraveling In vivo Potential of Curcumin-loaded Graphene Quantum Dots on Drug Delivery and Release Kinetics Aspects of Cancer Treatment.

This study introduces an innovative magnetic-based multifunctional anti-cancer drug carrier aiming to enhance the efficacy of curcumin in cancer therapy. The research investigates the potential of Graphene Quantum Dots (GQDs) as a curcumin drug delivery system for inhibiting in vivo cancer growth. GQDs with a particle diameter below 10 nm were synthesized via hydrothermal and Hummers methods, exhibiting homogeneity and crystalline structure according to AFM and XRD analyses. FTIR analysis confirmed functionalization success, revealing the formation of bonds between GQDs and curcumin. The optical properties of GQDs were assessed using a UV-Vis spectrophotometer and spectrofluorometer, resulting in vigorous fluorescence with a quantum yield of 1.32%. Subsequently, loading curcumin onto GQDs (CQDs/cur) resulted in an efficient system for delivering the anti-cancer drug, demonstrating significant in vivo efficacy. It was indicated by reduced tumor diameter and increased body weight in mice. Furthermore, the release kinetics of curcumin from GQDs were analyzed using the Peppas-Sahlin equation under varying pH conditions (4, 7, and 9), revealing the highest release rate in acidic conditions. In conclusion, this study highlights the potential of GQDs as highly efficient carriers for targeted curcumin delivery, showcasing promising prospects in cancer treatment.

Synthesis of oxidized carboxymethyl cellulose/chitosan hydrogels doped with graphene oxide for pH- and NIR-responsive drug delivery

Biological macromolecules hydrogels are synthesized via the Schiff base reaction between oxidized carboxymethyl cellulose (oxCMC) and chitosan (CS), and graphene oxide (GO) and 5-fluorouracil (5-FU) are co-doped in the oxCMC/CS hydrogels during the cross-linking process. The acylhydrazone bonds (–HC = N–) between oxCMC and CS can be easily hydrolyzed in acidic solutions, leading to the swelling of the hydrogels and facilitated delivery of 5-FU. On the other hand, the doped GO is a promising photothermal agent, and the delivery of 5-FU can also be facilitated by the generated hyperthermia upon near infrared (NIR) irradiation. Therefore, pH- and NIR-responsive delivery of 5-FU from the hydrogels can be achieved. The kinetics of drug delivery indicate that the delivery of 5-FU from the hydrogels is controlled by first-order model. The drug-free carrier (oxCMC/CS/GO) has excellent biocompatibility while the developed drug delivery system (oxCMC/CS/GO/5-FU) exhibits high cytotoxicity against human hepatoma SMMC-7721 cells.

Investigations of hybrid infill pattern in additive manufactured tablets: A novel approach towards tunable drug release.

The significance of 3D printing has risen exponentially in biomedical and pharmaceutical applications. Its potential in the field of fabricating drug delivery systems, by virtue of processing biocompatible polymers, has been very lucrative. This work aims to tap the interstitial drug delivery kinetics that are often inaccessible through machine-specific infill patterns in additive manufactured tablets fabricated using PVA biopolymer as an excipient. In this regard, a myo-inositol containing tablet has been printed using Fused Deposition Modeling preceded by Hot Melt Extrusion drug loading route. Two machine-specific infill patterns were taken, namely straight and grid. Later, these two distinct patterns were juxtaposed to obtain novel hybrid infill patterns in the tablets. Then, these tablets and their filament were subjected to various thermal, mechanical, imaging and pharmaceutical characterization tests to assess the feasibility of the research attempt. Finally, dissolution tests were conducted to evaluate their dissolution behavior over a time period. The characterization tests proved the scientific viability of this attempt along with amorphous existence of drug in the polymeric filament. The dissolution results showed favorable drug release by achieving interstitial dissolution timings with surface area/volume (SA/V) ratio being found to be the principal factor.

Engineering thio-/seleno-ether linkers into zwitterionic small molecule nano-prodrugs for traceable cancer theranostics

Given the over-production of glutathione (GSH) and hydrogen peroxide (H2O2) in tumor cells, redox-responsive linkers such as disulfide bonds have been widely used to develop site-specific prodrug system, but may suffer from their poor sensitivity that results in low efficacy. Herein, we report the development of a class of redox-triggered small molecule prodrugs (RhB-S(Se)-CPT), by conjugating zwitterionic rhodamine B (RhB) and camptothecin (CPT) with thio-/seleno-ether linkers. The amphiphilic prodrug can self-assemble into stable nanoparticles in water, and zwitterionic RhB is located on the surface of RhB-S(Se)-CPT nanoparticles, tracking the distribution and kinetics of drug delivery in real time, and reducing the non-specific binding to in vivo components, thus decreasing the side effects of nanomedicines. The thio-/seleno-ether linkers enable selective and rapid release of CPT in response to a redox heterogeneous intratumoral microenvironment. Interestingly, selenoether bonds exhibit significant advantages over thioether in terms of CPT release rate, intracellular toxicity and therapeutic efficacy against large tumors (∼ 200 mm3) in mice. These results provide insights to the rational design of subsequent redox-responsive nanoprodrug system, which may contribute to the material selection and structural design of next-generation nanomedicines for tumor theranostics.

Zwitterionic rhodamine-CPT prodrug nanoparticles with GSH/H2O2 responsiveness for cancer theranostics.

Rationale: Fluorescently traceable prodrugs, which can monitor their biodistribution in vivo and track the kinetics of drug delivery in living cells, are promising for constructing theranostic medicines. However, due to their charge and hydrophobicity, most of the fluorescently traceable prodrugs exhibit high protein binding and non-specific tissue retention affecting in vivo distribution and toxicity, with high background signals. Methods: Herein, the zwitterionic rhodamine (RhB) and camptothecin (CPT) were bridged with a disulfide bond to construct a tumorous heterogeneity-activatable prodrug (RhB-SS-CPT). The interaction of zwitterionic RhB-SS-CPT with proteins was detected by UV and fluorescence spectroscopy, and further demonstrated by molecular docking studies. Then, intracellular tracking and cytotoxicity of RhB-SS-CPT were determined in tumor and normal cells. Finally, the in vivo biodistribution, pharmacokinetics, and anticancer efficacy of RhB-SS-CPT were evaluated in a mouse animal model. Results: The tumorous heterogeneity-activatable RhB-SS-CPT prodrug can self-assemble into stable nanoparticles in water based on its amphiphilic structure. Particularly, the zwitterionic prodrug nanoparticles reduce the non-specific binding to generate a low background signal for better identification of cancerous lesions, achieve rapid internalization into cancer cells, selectively release bioactive CPT as a cytotoxic agent in response to high levels of GSH and H2O2, and exhibit high fluorescence that contributes to the visual chemotherapy modality. In addition, the RhB-SS-CPT prodrug nanoparticles show longer circulation time and better antitumor activity than free CPT in vivo. Interestingly, the zwitterionic nature allows RhB-SS-CPT to be excreted through the renal route, with fewer side effects. Conclusions: Zwitterionic features and responsive linkers are important considerations for constructing potent prodrugs, which provide some useful insights to design the next-generation of theranostic prodrugs for cancer.

Gefitinib-loaded polydopamine-coated hollow mesoporous silica nanoparticle for gastric cancer application

Gastric cancer is a common malignancy that is the second cancer-associated mortality worldwide. This study aimed to develop a pH-sensitive drug delivery system including hollow mesoporous silica nanoparticles (HMSNs) loaded with gefitinib (GB) and encapsulated with mussel-inspired polydopamine (PDA) (HMSNs-GB-PDA) for the treatment of gastric cancer; where the HMSNs mainly function as drug storage platforms, and GB interrupts signaling through the epidermal growth factor receptor (EGFR) in cancer cells. In addition, PDA was used as an anticancer factor, mucoadhesive enhancing agent, stimuli, and gatekeeper to mediate the GB release. The drug delivery kinetics (in vitro), mucoadhesive properties (ex vivo), and cytocompatibility in both healthy (HGF) and gastric cancer (AGS) cell lines of this formulation were also investigated. The results showed that HMSNs-GB-PDA not only selectively killed AGS cells but also had no toxic effect on HGF cells, in such a way that more than 70% of AGS cells were eliminated at a GB concentration of 150 ug/ml, whereas only about 15% of HGF cells were killed at the same concentration. In addition, the PDA coating served as a gatekeeper, inhibited burst release, and resulted in a sustained release that lasted for a long time. The ex vivo mucoadhesiveness evaluation revealed the high mucoadhesive property (93.88%) of PDA-coated nanocarriers. According to the results, the suggested HMSNs-GB-PDA could potentially be used to treat gastric cancer.

8. Controlling the rate of presentation of BMP-2 from a highly structured composite for interbody fusion

<h3>BACKGROUND CONTEXT</h3> Clinical outcomes for patients with intervertebral disc injury or disease could be enhanced by a new generation of regenerative matrices that create tissue environments to control angiogenesis, chondrogenesis and bone formation. Regenerative matrices are a new class of controlled release biomaterials that use surface chemistry, materials architecture, and drug delivery kinetics to create optimised conditions for cell interactions that result in high quality tissue formation. A novel biodegradable polymer matrix that releases bone morphogenetic protein 2 (BMP-2) over a period of one month with a low Cmax and sustained presentation of active protein is investigated in this study. <h3>PURPOSE</h3> BMP-2 release kinetics and protein activity from a new regenerative matrix was quantified to develop an implant with 1-month release of the drug within a macroporous matrix. A rabbit posterolateral (PLF) vertebral fusion model was performed to assess bone formation and fusion outcomes as a function of dose and source of BMP-2 (E coli and CHO cells). <h3>STUDY DESIGN/SETTING</h3> The study was designed to investigate the effect of various biomaterial design factors and manufacturing methods on the rate of release of BMP-2, the activity of BMP-2 and the extent of in vivo bone formation. <h3>PATIENT SAMPLE</h3> This study did not involve patients. <h3>OUTCOME MEASURES</h3> Outcome measures were the mechanical properties of the regenerative matrix, the architecture and porosity of the matrix, BMP-2 release kinetics, BMP-2 activity as a function of release time and bone formation. <h3>METHODS</h3> BMP-2 activity was tested using two in vitro cell-based assays. BMP-2 solutions and regenerative matrix extracts were tested for their ability to induce alkaline phosphatase (ALP) activity in W-20-17 stromal cells using a modified version of the ASTM standard protocol for in vitro biological activity of recombinant human BMP-2 (F2131-02). Cells were exposed to serial dilutions of BMP-2 for 24 h, assayed for ALP activity and EC50s calculated allowing the relative potency to NIBSC WHO BMP-2 standard to be calculated. BMP-2 release was assessed with an in vitro assay of ALP activity in the mouse muscle myoblast cell line C2C12. Formulations were suspended above a C2C12 monolayer in an insert with a porous (8 µm) PET membrane. Following 3-4 days of exposure, the inserts containing LDGraft were transferred to fresh cells for a further 3-4 days. Cells exposed to LDGraft in this manner were assayed for ALP activity (normalised to protein content) once the inserts had been transferred to fresh cells. Fusion rate and new bone formation were compared to INFUSE in a single-level lumbar (L4-L5) posterolateral (PLF) vertebral fusion model in the New Zealand White rabbit based on standard protocols (Boden et al, 1995, ASTM F3207). Pre-formed implants (3 cc) of INFUSE (rhBMP-2 and absorbable collagen sponge) were implanted on decorticated dorsal surfaces of the transverse processes of L4 and L5 adjacent to the laminae. Fusion was assessed by radiograph at 6 weeks and by manual palpation, radiography and microCT at 12 weeks. <h3>RESULTS</h3> BMP-2 activity was retained over one month of release with the addition of protectants in the formulation and precise control of manufacturing processes. The matrix had a porosity of >70% with a high proportion of macropores (>200 micron diameter). Low doses of E. coli-produced BMP-2 induced fusion in the PLF model. <h3>CONCLUSIONS</h3> A one-month releasing BMP-2 formulation is described. This new regenerative matrix had internal architecture designed to host angiogenesis. Manufacturing and design challenges can be overcome to retain high biologic activity throughout the release period. <h3>FDA DEVICE/DRUG STATUS</h3> BMP-2, not approved for this indication.

Mechanical properties of nanoparticles in the drug delivery kinetics

Nanoparticle formulation is a recently developed drug delivery technology with enhanced targeting potential. Nanoparticles encapsulate the drug of choice and delivers it to the target via a targeting molecules (ex. antigen) located on the nanoparticle surface. Nanoparticles can even be targeted to deeply penetrating tissue and can be modeled to deliver drugs through the blood brain barrier. These advancements are providing better disease targeting such as to cancer and Alzheimer’s. Various polymers can be manufactured into nanoparticles. The polymers examined in this paper are polycaprolactone (PCL), poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), and poly(glycolic acid) (PGA). The purpose of this study is to analyze the mechanical properties of these polymers to establish drug delivery trends and model pharmacokinetics and biotransport. We found that, in general, as the melting point, elastic modulus and tensile strength increases, the degradation rate also increases. PLA composite material may be an ideal polymer for drug delivery due to its good control of degradation.

Fabrication, drug delivery kinetics and cell viability assay of PLGA-coated vancomycin-loaded silicate porous microspheres

Porous ceramic microspheres are a desirable substance for bone tissue reconstruction and delivery applications. This study focuses on Mg–Ca silicate microspheres encapsulated in biodegradable poly (lactic-co-glycolic acid) (PLGA) to serve as a biocompatible carrier for the controlled release of vancomycin hydrochloride. In this regard, diopside (MgCaSi 2 O 6 ), bredigite (MgCa 7 Si 4 O 16 ), and akermanite (MgCa 2 Si 2 O 7 ) powders were synthesized by sol-gel and subsequent calcination methods. Then, porous akermanite, diopside and bredigite microspheres of 700–1000 μm in diameter were fabricated by using carbon porogen, droplet extrusion and sintering, then loaded with the drug and eventually coated with PLGA. The bare microspheres showed a considerable burst release mode of the drug into a physiological medium, whereas PLGA coating of the microspheres reduced the burst release level. To investigate effective mechanisms governing in the drug release from the carriers, the contribution of burst, degradation, and diffusion was analyzed by the sequential quadratic programming algorithm method. It was found that the relative contribution of diffusion to bioresorption is ranked as diopside > akermanite > bredigite, whereas PLGA coating dominates the diffusion mechanism. The dental pulp stem cells cytocompatibility MTT assay of the microspheres also showed that the drug loading deteriorates but PLGA coating improves the cell biocompatibility significantly. Comparatively, the biocompatibility of the PLGA-coated microspheres was ranked as akermanite > diopside > bredigite, as a result of a compromise between the release of the constituting ions of the ceramic carriers and vancomycin molecules. It was eventually concluded that PLGA-coated Mg–Ca silicate microspheres are promising candidates for drug-delivery bone tissue engineering and dental bone grafting applications.

Generation of a 3D melanoma model and visualization of doxorubicin uptake by fluorescence imaging.

Melanoma is the most dangerous type of skin cancer and is responsible for 75% of deaths from skin cancers. For an accurate evaluation of potential treatment efficacy, it is important to use study models as close as possible to the in vivo conditions. A 3D model consisting of B16F10 spheroids was developed using liquid overlay technique on plates coated with 1% agarose, in the presence of 1% methylcellulose and L929-conditioned medium. The model is suitable and can be further used for more complex in vitro drug testing than the classical 2D approach. For exemplification, the behavior of a well-known cytostatic, doxorubicin (DOX), was evaluated in spheroids as compared to classical 2D culture conditions. Fluorescence imaging was used to visualize DOX uptake by B16F10 spheroids at different periods of time. The results showed that a much higher DOX concentration is necessary to produce similar effects compared with the monolayer. The fluorescence images revealed that at least 4 h of stimulation is needed for a sufficient DOX uptake. The 3D model developed in this study was suitable to investigate drug penetration in time. Our findings may explain the decrease of the doxorubicin therapeutical effect, suggesting the need of maintaining the drug concentration at the tumoral place for at least 2 h upon administration. Similar or more advanced studies can lead to a better understanding of drug delivery kinetics and distribution upon administration, conducing toward a better performance in designing suitable delivery systems for obtaining the optimum dose-response effect.

Enzymatically Crosslinked In Situ Synthesized Silk/Gelatin/Calcium Phosphate Hydrogels for Drug Delivery.

Our research focuses on combining the valuable properties of silk fibroin (SF) and calcium phosphate (CaP). SF is a natural protein with an easily modifiable structure; CaP is a mineral found in the human body. Most of the new age biocomposites lack interaction between organic/inorganic phase, thus SF/CaP composite could not only mimic the natural bone, but could also be used to make drug delivery systems as well, which can ensure both healing and regeneration. CaP was synthesized in situ in SF at different pH values, and then crosslinked with gelatin (G), horseradish peroxide (HRP), and hydrogen peroxide (H2O2). In addition, dexamethasone phosphate (DEX) was incorporated in the hydrogel and drug delivery kinetics was studied. Hydrogel made at pH 10.0 was found to have the highest gel fraction 110.24%, swelling degree 956.32%, and sustained drug delivery for 72 h. The highest cell viability was observed for the hydrogel, which contained brushite (pH 6)—512.43%.

Crystallization of the Multi-Receptor Tyrosine Kinase Inhibitor Sorafenib for Controlled Long-Term Drug Delivery Following a Single Injection.

A major challenge in cancer medicine is the safe and effective delivery of drugs to the right tissue at the right time. Despite being designed for greater target specificity, many drugs still result in side effects and lack of safety in patients following global dissemination. Therefore, to develop new, more effective formulations capable of improving specificity and reducing off-target effects, here we describe formulation of drug crystals, from even a very hydrophobic and otherwise difficult to solubilize small molecule chemical compound, capable of providing constant drug release for weeks following a single injection. We chose to utilize the multi-tyrosine kinase inhibitor and multi-modal (anti-angiogenic and tumor cell cytotoxic) agent sorafenib, to combat aberrant angiogenesis and tumor growth which contribute to metastasis, ultimately responsible for poor patient outcomes. We tuned crystal size (surface area:volume ratios), imaged by SEM, to display controllability of drug delivery kinetics in in vitro drug release assays. Single and powder crystal X-ray diffraction (XRD) established that all crystals were the same polymorph and drug form. When utilized against an orthotopic triple negative breast cancer (TNBC) mouse model (4T1 in syngeneic BALB/c mice), we established anti-tumor activity from a single local, subcutaneous injection of crystalline sorafenib. From our findings, we support that engineering crystalline drug delivery systems has implications in the treatment of cancer or other diseases where high enough constitutive drug levels are needed to maintain target saturation and inhibition while also preventing emergence of drug resistance, which is a consequence often seen with suboptimal dosing. The online version contains supplementary material available at 10.1007/s12195-021-00708-6.