Hydrogel Microneedles with Programmed Mesophase Transitions for Controlled Drug Delivery.

Microneedle-based drug delivery offers an attractive and minimally invasive administration route to deliver therapeutic agents through the skin by bypassing the stratum corneum, the main skin barrier. Recently, hydrogel-based microneedles have gained prominence for their exceptional ability to precisely control the release of their drug cargo. In this study, we investigated the feasibility of fabricating microneedles from triblock amphiphiles with linear poly(ethylene glycol) (PEG) as the hydrophilic middle block and two dendritic side-blocks with enzyme-cleavable hydrophobic end-groups. Due to the poor formation and brittleness of microneedles made from the neat amphiphile, we added a sodium alginate base layer and tested different polymeric excipients to enhance the mechanical strength of the microneedles. Following optimization, microneedles based on triblock amphiphiles were successfully fabricated and exhibited favorable insertion efficiency and low height reduction percentage when tested in Parafilm as a skin-simulant model. When tested against static forces ranging from 50 to 1000 g (4.9-98 mN/needle), the microneedles showed adequate mechanical strength with no fractures or broken segments. In buffer solution, the solid microneedles swelled into a hydrogel within about 30 s, followed by their rapid disintegration into small hydrogel particles. These hydrogel particles could undergo slow enzymatic degradation to soluble polymers. In vitro release study of dexamethasone (DEX), as a steroid model drug, showed first-order drug release, with 90% released within 6 days. Eventually, DEX-loaded MNs were subjected to an insertion test using chicken skin and showed full penetration. This study demonstrates the feasibility of programming hydrogel-forming microneedles to undergo several mesophase transitions and their potential application as a delivery system for self-administration, increased patient compliance, improved efficacy, and sustained drug release.

Incorporating surfactants into PCL microneedles for sustained release of a hydrophilic model drug.

Polymeric microneedles (MNs) are widely used for sustained drug release due to their distinct advantages over other types of MNs. Poly-ε-caprolactone (PCL) stands out as a biodegradable and biocompatible hydrophobic polymer commonly employed in drug delivery applications. This study explores the impact of surfactants on the encapsulation and release rate of a model hydrophilic drug, minoxidil (MXD), from PCL MNs. Three nonionic surfactants, Tween 80, Span 60, and polyethylene glycol (PEG), were integrated into PCL MNs at varying concentrations. Compared to the other types of surfactants, PEG-containing PCL MNs exhibit enhanced insertion capabilities into a skin-simulant parafilm model and increased mechanical strength, suggesting facile penetration into the stratum corneum. Furthermore, MXD-PEG MNs show the highest encapsulation efficiency and are further characterized using FTIR, DSC and XRD. Their mechanical strength against different static forces was measured. The MNs exhibit a sustained release pattern over 20 days. Eventually, MXD-PEG MNs were subjected to penetration testing using chicken skin and required minimal insertion forces with no observed MN failure during experimentation even after compression with the maximum force applied (32 N per patch). Taken together, the present work demonstrates the feasibility of incorporating nonionic surfactants like PEG into the tips of hydrophobic PCL MNs for sustained delivery of a model hydrophilic drug. This formulation strategy can be used to improve patient compliance by allowing self-administration and achieving prolonged drug release.

Rapidly Dissolving Microneedles for the Delivery of Steroid-Loaded Nanoparticles Intended for the Treatment of Inflammatory Skin Diseases.

Drug delivery through the skin has immense advantages compared to other routes of administration and offers an optimal way to treat inflammatory skin diseases, where corticosteroids are the cornerstone of topical therapy. Still, their therapeutic efficiency is limited due to inadequate skin permeability, potential side effects, and reduced patient compliance. To overcome these drawbacks, we propose a drug delivery system consisting of dexamethasone (DEX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) incorporated in sodium alginate (SA) microneedles (MNs) as a minimally invasive dosage form for controlled drug release. Drug-loaded PLGA NPs were prepared by a nanoprecipitation method with a high encapsulation yield. They exhibited a controlled release pattern over 120 h. A modified vacuum-deposition micromolding method was used to load the obtained DEX-NPs into the tips of dissolving MNs. The NP-MNs showed improved insertion capabilities into the skin-simulant parafilm model and enhanced mechanical strength when tested against different static forces compared to their counterparts (SA-MNs). The results of an MN dissolution study following application to ex vivo chicken skin and agarose gel indicate that the NP-loaded segments of MNs dissolve within 15 s, in which the NPs are released into the skin. Taken together, the incorporation of DEX-NPs into SA-MNs could be a promising approach to bypass the limitations of conventional topical treatment of skin diseases, allowing for self-administration, increased patient compliance, and controlled drug release.

Preparation and characterization of flexible furosemide-loaded biodegradable microneedles for intradermal drug delivery.

Transdermal drug delivery systems are a useful and minimally invasive alternative to other drug administration routes. Biodegradable polymeric microneedles (MNs) are widely used in controlled-release drug delivery due to their tunable properties and ease of patient self-administration. Polylactic-co-glycolic acid (PLGA) is often used for sustained drug release owing to special intrinsic properties including biocompatibility and biodegradability, which offer excellent applicability in preparing MNs. Congestive heart failure (CHF) is characterized by fluid overload during acute exacerbation, necessitating frequent patient hospitalization for continuous intravenous (i.v.) diuretic therapy. In the present study, we incorporated furosemide (FUR) as a model drug into flexible PLGA MN skin patches for potential intradermal delivery to overcome the limitations associated with i.v. diuresis. The MNs were fabricated by a casting-mold technique and consisted of two main parts, PLGA needle tips loaded with varying concentrations of FUR and a flexible backing layer comprising sodium alginate and glycerol. MN formulations were characterized by SEM and exhibited a uniform pyramidal shape. The measured surface pH of all samples suggested that no skin irritation is expected upon application. High encapsulation efficiency was obtained for FUR-MN formulations in which a decrease was noted as the FUR/PLGA ratio decreased. Drug loading content ranged from 19.1 ± 1% to 28.9 ± 1.4%. Successful insertion of MNs into a Parafilm® skin simulant model suggested that MNs will easily penetrate the skin's outermost layer, the stratum corneum, and will permit intradermal delivery of FUR. The MNs were further characterized by analytical methods. Finally, the MNs exhibited an initial burst release followed by a sustained release of FUR. Self-administered FUR-MNs can open new avenues to overcome i.v. drip limitations and increase patient compliance.

Biodistribution and efficacy of the anticancer drug, oxaliplatin palmitate acetate, in mice.

Oxaliplatin palmitate acetate (OPA), a platinum (IV) oxaliplatin derivative, was previously designed with the aim to improve the platinum-based anti-cancer therapy. In this work, we further explore the potential of OPA in extensive in vitro and in vivo studies. OPA in pancreatic (BxPC3-luc), lung (NCI-H1993) and liver (Hep3B) cancer cell lines showed a higher toxicity in comparison to oxaliplatin. The in vitro release kinetic experiments of OPA from the nanoparticles (NPs) under sink conditions exhibited a very rapid profile. Furthermore, OPA cannot be considered a prodrug of oxaliplatin, based on the OPA intact molecule pharmacokinetic profile study in rats. The formation of oxaliplatin from the biodegradation of OPA ranges only from 5% to 7% and both drugs were rapidly eliminated from the plasma. Pharmacokinetics of OPA PLGA nanoparticles in mice showed that nanoparticles failed to prolong the release of OPA in the plasma and did not add any therapeutic benefit over OPA solution, as suggested by the rapid in vitro release of OPA from nanoparticles. In pancreatic xenograft BxPC3-luc cancer model, both OPA in solution and OPA nanoparticles inhibited the tumor growth, equally and significantly, as compared to oxaliplatin. In liver xenograft Hep3B cancer model, OPA solution and cisplatin demonstrated good and similar antitumor efficacy. In lung xenograft NCI-H1993 cancer model, OPA solution, with a significant antitumor efficacy, was superior to cisplatin, which did not differ from the vehicle. In conclusion, OPA may offer a promising advance in platinum-based chemotherapy against various forms of cancers in an adequate dose and schedule.

Biodegradable Controlled-Release Device for Localized Chemotherapeutic Treatment of Bladder Cancer.

Intravesical therapy for the treatment of superficial urinary bladder tumors is promising. However, it is also challenging, due to bladder contraction and relaxation and drug elimination via urination or dilution by urine production. We developed a biodegradable drug-eluting device positioned in the renal pelvis as an alternative strategy for bladder instillation. The urine drains from the renal pelvis into the ureter, collects the eluted drug, and transports it into the bladder. The combination of the renal pelvis and the bladder creates a two-compartment system. The drug is administered into the depot compartment, the renal pelvis, and is instantly and homogeneously distributed into the central compartment, the bladder. This results in an increase in its residence time and in gradual adsorption into the urothelium. The device is inserted through the ureter, followed by upset bulging after reaching the renal pelvis in order to guarantee fixation, while preventing urinary obstruction. The device is made of electrospun poly(lactic-co-glycolic acid) (PLGA) fibers that encapsulate a chemotherapeutic drug, cisplatin (1.17-2.34% w/w). Experimental studies of the stresses developed during the bulging and simulations of the urine flow interaction with the device demonstrated structural longevity and operational safety of the device. Sustained release of 94% of the device content was demonstrated after 1 week in vitro with a flow rate of 30 mL/h. We believe that the drug-eluted device may offer a significant advantage over existing therapies for treatment of nonmuscle invasive bladder cancer.

Biomimetic clotrimazole-loaded PLGA films with enhanced adhesiveness for controlled drug release.

Biomimetic adhesive surfaces have a number of potential applications in the pharmaceutical and biomedical fields. Fabrication techniques must be adapted to biocompatible and biodegradable materials required for controlled drug release applications. In this study biomimetic adhesive poly(lactic-co-glycolic acid) (PLGA) films loaded with different concentrations of clotrimazole (CTZ) were prepared without combining other adhesive excipients as a controlled release system for potential local oral drug delivery. The films were fully characterized from morphological point of view, and CTZ-loaded biomimetic films exhibited adequate surface pH values, high drug encapsulation efficiency, and loading content. The adhesion strength of the obtained films was significantly higher compared to a flat film reference under different contact conditions. Thermal analysis indicated a decrease of drug crystallinity upon incorporation into PLGA films. The in vitro release of CTZ from PLGA biomimetic films was tested in simulated saliva, and it exhibited an initial burst release, accompanied by a sustained release phase over 10 days. Finally, the mucoadhesive properties of the obtained films was studied using agar/mucin plate as a representative mucosal substrate, and the results demonstrated superior mucoadhesion potential of CTZ-loaded biomimetic film in comparison to its flat counterpart. Having demonstrated the ability to load CTZ into PLGA biomimetic films with enhanced adhesion capacity, the potential use in local oral drug delivery applications warrants further in vitro and in vivo investigations.

Local Delivery of Mometasone Furoate from an Eluting Endotracheal Tube Reduces Airway Morbidity Following Long-Term Animal Intubation.

BACKGROUND: upper airway complications are common sequelae of endotracheal tube (ETT) intubation, and systemic corticosteroids are considered a mainstay treatment for this problem. Drug-eluting ETT may present an attractive option for topical steroid delivery while avoiding systemic side effects and improving the therapeutic outcome. The objective of the present study is to evaluate the reduction of tube-related tracheal morbidity via a self-designed steroid-eluting ETT with controlled sustained release properties in an animal model. METHODS: steroid-eluting ETTs were coated by poly(lactic-co-glycolic acid) -electrospun nanofibers loaded with mometasone furoate (MF) as a model drug. Animals were randomly assigned into three equal groups: non-intubated, blank-ETT, and loaded-ETT. The intubation interval was 1 week. Specimens were analyzed by histology, specific fibrosis staining, and scanning electron microscopy (SEM). RESULTS: the blank-ETT group exhibited a significant increase in tracheal mucosal thickness compared to the loaded-ETT and control groups. Average tracheal mucosal thickness was 112 ± 34, 242 ± 49, and 113 ± 43 µm in the control, blank-ETT, and loaded-ETT groups, respectively. The blank-ETT group exhibited a significant increase in tracheal fibrosis compared to the loaded-ETT and control groups. Relative fibrosis values were 0.07 ± 0.05, 0.154 ± 0.1, and 0.0984 ± 0.084% for the control, blank-ETT, and loaded-ETT groups, respectively. While SEM imaging showed normal surface structures in the control group, intubated blank-ETT rats showed severe surface structural damage, whereas only mild damage was observed in the loaded-ETT group. CONCLUSIONS: local sustained release of MF via a self-designed drug-eluting ETT is a potential therapeutic approach which may significantly reduce tube-related upper airway morbidity.

Developing Biodegradable Nanoparticles Loaded with Mometasone Furoate for Potential Nasal Drug Delivery.

Intranasal drug administration is considered a routine in the treatment of many nasal conditions including chronic rhinosinusitis (CRS), which is a common disease involving long-term inflammation of the nasal mucosa. Topical nasal steroid treatment is safe and easy to use and plays a basic role in both nonsurgical and surgical treatments for CRS. Intranasal steroid therapy for various time intervals is commonly used before and after endoscopic CRS nasal surgeries to reduce inflammation and edema and to improve mucosal healing. The medication is currently administered via conventional nasal sprays; therefore, there is an incentive to develop more efficient drug delivery systems for the controlled release of topical steroids into the sinonasal cavities over a prolonged period of time. In this study, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with mometasone furoate (MF) were generated using the nanoprecipitation method and characterized physicochemically and morphologically. MF NPs exhibited adequate physicochemical properties and high drug encapsulation efficiency and loading content. MF exhibited sustained release from NPs over 7 days in vitro with an initial burst release; various mathematical models were applied to determine the kinetics of drug release. Having demonstrated the ability to load MF in PLGA-NPs using the nanoprecipitation method for the first time, these NPs urge the need for additional investigations to demonstrate their therapeutic potential in nasal delivery applications.

Amphotericin B-loaded nanoparticles for local treatment of cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is an infectious, parasitic disease caused by the protozoan Leishmania. Amphotericin B (AMB) is a macrolide polyene antibiotic presenting potent antifungal and antileishmanial activity, but due to poor water solubility at physiological pH, side effects, and toxicity, its therapeutic efficiency is limited. In the present study, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with AMB were generated to reduce drug toxicity and facilitate localized delivery over a prolonged time. AMB NPs were characterized for particle size, zeta potential, polydispersity index, and degree of aggregation. In vitro assessments demonstrated its sustained activity against Leishmania major promastigotes and parasite-infected macrophages. A single intralesional administration to infected BALB/c mice revealed that AMB NPs were more effective than AMB deoxycholate in terms of reducing lesion area. Taken together, these findings suggest that AMB NPs improve AMB delivery and can be used for local treatment of CL.

Local delivery of mometasone furoate from an eluting endotracheal tube.

Laryngeal and tracheal morbidity is a common complication of endotracheal tube (ETT)-based airway management, and manifests as local irritation, inflammation, and edema. Systemic corticosteroids are commonly administered to manage these conditions; however, their efficacy is inadequate and limited by potential severe side effects. In the present study, a steroid delivery system for local therapy was developed to generate relatively high local drug concentrations and to improve drug efficacy. ETTs were coated with electrospun poly (lactic-co-glycolic acid) (PLGA) nanofibers loaded with mometasone furoate (MF), creating a microscale thick layer. MF exhibited sustained release from coated ETTs over 14days in vitro. An in vivo efficacy study in rats demonstrated the therapeutic benefit of MF-coated ETTs over bare ETTs, as measured by reduced laryngeal mucosal thickness and submucosal laryngeal edema. The fiber coating remained intact during tube intubation and extubation, demonstrating good adhesion to the tubes even after 24h in aqueous solution at 37°C. These findings demonstrate the potential of drug-loaded ETTs to revolutionize the standard of care for endotracheal intubation.

Differentiation of Pancreatic Cyst Types by Analysis of Rheological Behavior of Pancreatic Cyst Fluid.

Differentiation between mucinous and non-mucinous pancreatic cysts is exceedingly important and challenging, particularly as the former bears malignant transformation potential. Pancreatic cyst fluid (PCF)-based diagnostics, including analyses of biochemical markers, as well as cytology, has shown inadequate accuracy. Herein, a preliminary single-center study of 22 PCF samples, collected by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), assessed the rheological behavior of PCF and its correlation with lesion type. The dependence of PCF shear viscosity on shear rate was found to follow a power law and could be fitted using Ostwald-de Waele model. Three types of flow curves were identified, where two types correlated with non-mucinous cysts, differing by their power law exponent, and the third type corresponding to mucinous cysts. Viscosity measured at a high shear rate was shown to serve as an accurate and independent marker distinguishing between mucinous and non-mucinous cysts, with an optimal cutoff value of ηc = 1.3 cP The accuracy of this novel technique proved superior to string-sign, cytology, carcinoembryonic antigen, and amylase assessments. Moreover, the combined predictive value of ηc and patient age provided for sensitivity and specificity of 100% and 95.5%, respectively. This simple and rapid diagnostic tool can be immediately implemented after EUS-FNA sampling.

Design of starch-formate compound fibers as encapsulation platform for biotherapeutics.

Effective encapsulation and protection of biotherapeutics using a bio-based carrier, preferably issued from renewable resources, remains a challenge. Herein, we demonstrate application of coaxial electrospinning to fabric starch-based core-sheath compound fibers as a bacterial cells' carrier. Starch-formate is employed as an encapsulation agent, while the fiber core is made of glycerol, serving as a cell suspension medium. SEM microscopy reveals a distinct core-sheath morphology of the starch-formate/glycerol (SFG) compound fibers with mean diameters of 4.13±1.05µm. Calorimetric and thermomechanical analyses and FTIR spectroscopy show a progressive interaction between the starch-formate and the glycerol with time, pronounced with temperature increase. SFG fibers with encapsulated Lactobacillus paracasei are proved stable with retained bacterial viability when stored at 4°C and room temperature for up to 21days. SFG fibers present a potential biotherapeutic products' encapsulation platform, guaranteeing the stability at refrigerated and ambient storage conditions, as determined in this study.

A Lipophilic Pt(IV) Oxaliplatin Derivative Enhances Antitumor Activity.

Side effects and acquired resistance by cancer cells limit the use of platinum anticancer drugs. Modification of oxaliplatin (OXA) into a lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)] (1), containing both lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles. Complex 1 exhibited unique potency against a panel of cancer cells, including cisplatin-resistant tumor cells. [Pt(DACH)(OAc)(OPal)(ox)] incorporated nanoparticles (2) presented a mean diameter of 146 nm with encapsulation yields above 95% as determined by HPLC. Complexes 1 and 2 showed enhanced in vitro cellular Pt accumulation, DNA platination, and antiproliferative effect compared to OXA. Results of an orthotopic intraperitoneal model of metastatic ovarian cancer (SKOV-3) and a xenograft subcutaneous model of colon (HCT-116) tumor in SCID-bg mice showed that the activity of 1 and 2 significantly decreased tumor growth rates compared to control and OXA treatment groups. Consequently, these findings warrant further development toward clinical translation.