Conquering chemoresistance in pancreatic cancer: Exploring novel drug therapies and delivery approaches amidst desmoplasia and hypoxia.

Pancreatic cancer poses a significant challenge within the field of oncology due to its aggressive behaviour, limited treatment choices, and unfavourable outlook. With a mere 10% survival rate at the 5-year mark, finding effective interventions becomes even more pressing. The intricate relationship between desmoplasia and hypoxia in the tumor microenvironment further complicates matters by promoting resistance to chemotherapy and impeding treatment efficacy. The dense extracellular matrix and cancer-associated fibroblasts characteristic of desmoplasia create a physical and biochemical barrier that impedes drug penetration and fosters an immunosuppressive milieu. Concurrently, hypoxia nurtures aggressive tumor behaviour and resistance to conventional therapies. a comprehensive exploration of emerging medications and innovative drug delivery approaches. Notably, advancements in nanoparticle-based delivery systems, local drug delivery implants, and oxygen-carrying strategies are highlighted for their potential to enhance drug accessibility and therapeutic outcomes. The integration of these strategies with traditional chemotherapies and targeted agents reveals the potential for synergistic effects that amplify treatment responses. These emerging interventions can mitigate desmoplasia and hypoxia-induced barriers, leading to improved drug delivery, treatment efficacy, and patient outcomes in pancreatic cancer. This review article delves into the dynamic landscape of emerging anticancer medications and innovative drug delivery strategies poised to overcome the challenges imposed by desmoplasia and hypoxia in the treatment of pancreatic cancer.

Building and behavior of a pH-stimuli responsive chitosan nanoparticles loaded with folic acid conjugated gemcitabine silver colloids in MDA-MB-453 metastatic breast cancer cell line and pharmacokinetics in rats.

The pH-stimuli release behavior of nanoformulations may enhance the success rate of chemotherapeutic drugs in cancers by site-specific delivery of drugs to cancer tissues. The aim of the present study was to prepare chitosan (CS) nanoparticles (NPs) with previously synthesized folic acid (FA) capped silver nanoparticles (AgNPs) loaded with the anti-cancer drug gemcitabine (GEM) (FA-GEM-AgNPs). The CS-FA-GEM-AgNPs (CS-NPs) were characterized with dynamic light scattering (DLS), transmission electron microscopy (TEM), energy dispersive x-ray analysis (EDAX), selected area electron diffraction (SAED), and differential scanning calorimetric (DSC) analyses. The in-vitro drug release of GEM was evaluated in media of different pH. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cytotoxic effects of the prepared nanoformulations in media with various pH. The time- and pH-dependent apoptotic cell death induced by CS-NPs with MDA-MB-453 human breast cancer cell line was observed using acridine orange (AO)/ethidium bromide (EtBr) staining. The pharmacokinetic parameters were studied with high-performance liquid chromatography (HPLC) and atomic absorption spectroscopy (AAS). Two batches of CS-NPs formulations were prepared, one with AgNPs of particle size 143 nm and the other with 244 nm. The particle size for CS-NPs-I (FA-GEM-AgNPs-143 nm) and CS-NPs-II (FA-GEM-AgNPs-244 nm) was found to be 425 and 545 nm, respectively. The zeta potential was found to be 36.1 and 37.5 mV for CS-NPs-I and CS-NPs-II, respectively. CS-NPs-I and CS-NPs-II showed a polydispersity index (PDI) of 0.240 and 0.261, respectively. A TEM study confirmed the spherical nature of the NPs. The nanoformulations exerted pH-dependant effect against MDA-MB-453 cells with relatively higher cytotoxicity at the lower pH than at higher pH levels. The pharmacokinetic profile and tissue distribution of CS-NPs in rats exerted drug release in a pH-dependent manner with enhanced excretion of Ag+. An optimized nanoformulation for pH-stimuli responsive release of GEM was successfully developed for future therapeutic exploration.

Validation Evidence from using Generalizability Theory in a Basic-Science Course: Reliability of Course-Grades from Multiple Examinations.

DESCRIPTION OF THE PROBLEM: Reliability is critical validation evidence on which to base high-stakes decision-making. Many times, one exam in a didactic course may not be acceptably reliable on its own. But how much might multiple exams add when combined together? THE INNOVATION: To improve validation evidence towards high-stakes decision-making, Generalizability Theory (G-Theory) can combine reliabilities from multiple exams into one composite-reliability (G_String IV software). Further, G-Theory decision-studies can illustrate changes in course-grade reliability, depending on the number of exams and exam-items. CRITICAL ANALYSIS: 101 first-year PharmD students took two midterm-exams and one final-exam in a pharmaceutics course. Individually, Exam1 had 50MCQ (KR-20=0.69), Exam2 had 43MCQ (KR-20=0.65), and Exam3 had 67MCQ (KR-20=0.67). After combining exam occasions using G-Theory, the composite-reliability was 0.71 for overall course-grades-better than any exam alone. Remarkably, increased numbers of exam occasions showed fewer items per exam were needed, and fewer items over all exams, to obtain an acceptable composite-reliability. Acceptable reliability could be achieved with different combinations of number of MCQs on each exam and number of exam occasions. IMPLICATIONS: G-Theory provided reliability critical validation evidence towards high-stakes decision-making. Final course-grades appeared quite reliable after combining multiple course exams-though this reliability could and should be improved. Notably, more exam occasions allowed fewer items per exam and fewer items over all the exams. Thus, one added benefit of more exam occasions for educators is developing fewer items per exam and fewer items over all exams.

Investigating the Potential to Deliver and Maintain Plasma and Brain Levels of a Novel Practically Insoluble Methuosis Inducing Anticancer Agent 5-Methoxy MOMIPP Through an Injectable In Situ Forming Thermoresponsive Hydrogel Formulation.

A new indole based chalcone molecule MOMIPP induced methuosis mediated cell death in gliobastoma and other cancer cell lines. But the drug was insoluble in water and had a very short plasma half-life. The purpose of this work was to develop a formulation that can provide sustained levels of MOMIPP in vivo. Initial studies established drug solubility in various solvents. N-methyl pyrrolidone (NMP) was determined as an excellent solvent for the drug. Subsequently a poloxamer-407 based thermoreversible gel containing NMP was used to develop the formulation. Rheological studies were performed via oscillatory temperature mode, continuous shear analysis, and oscillatory frequency mode experiments. The mechanical properties of the formulations were tested using a texture profile analyzer. The gelation temperature and time of formulations increased with increasing amounts of NMP. However, the viscosity at 20 °C and storage modulus decreased as the amount of NMP increased. Characterization studies helped to identify the gel formulation that was used to administer the drug orally, sub-cutaneously, and intra-peritoneally. When the gel was given intraperitoneally the target plasma and brain levels of over 5 µM was maintained for about 8 h. Thus, a thermoreversible gel formulation that can deliver MOMIPP in animal studies was successfully developed.

Development and evaluation of a calcium alginate based oral ceftriaxone sodium formulation.

The purpose of this work was to develop a multiparticulate system exploiting the pH-sensitive property and biodegradability of calcium alginate beads for intestinal delivery of ceftriaxone sodium (CS). CS was entrapped in beads made of sodium alginate and sodium carboxymethylcellulose (CMC), acacia, HPMC K4M and HPMC K15M as drug release modifiers. Beads were prepared using calcium chloride as a cross-linking agent, followed by enteric coating with cellulose acetate phthalate (CAP). The beads were then evaluated for entrapment efficiency using HPLC, in vitro drug release examined in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8), swellability, particle size and surface characterization using optical microscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM). Thermal gravimetric analysis (TGA) was utilized to check the polymer matrix strength and thermal stability. The drug entrapment efficiency of the optimized formulation was determined to be 75 ± 5 %. Swelling properties of drug-loaded beads were found to be in a range of 0.9-3.4. Alginate beads coated with CAP and containing CMC as a second polymer exhibited sustained release. The drug release followed first-order kinetics via non-Fickian diffusion and erosion mechanism. The particle size of the beads was between 1.04 ± 0.20 and 2.15 ± 0.36 mm. TGA, AFM, and SEM data showed composition and polymer-dependent variations in cross-linking, thermal stability, surface structure, morphology, and roughness. The physico-chemical properties of the developed formulation indicate suitability of the formulation to deliver CS orally.

Development and evaluation of dexamethasone nanomicelles with potential for treating posterior uveitis after topical application.

PURPOSE: This study aims at the development and preliminary evaluation of dexamethasone nanomicelles for treating posterior uveitis. Nanomicelles were formulated using polyoxyl 40 stearate (P40S) and polysorbate 80 (P80), which are approved by the FDA for ocular use. METHODS: Dexamethasone nanomicelles were prepared and characterized for critical micellar concentration, solubility of dexamethasone, particle size, surface charge, morphology, in vitro drug release, clarity, stability, filtration efficiency, and sterility. Ocular tolerance and the tissue drug distribution of dexamethasone were assessed in rabbits after single and multiple topical administration. RESULTS: Dexamethasone nanomicelles (0.1% w/v) were successfully developed and characterized with an optimized composition of P40S/P80=7/3 by weight. The mean diameter of blank and drug-loaded nanomicelles was 13.3±0.4 and 14.5±0.4 nm, respectively. Transmission electron microscopy images revealed the spherical structure of nanomicelles. Nanomicelles were found to be stable with respect to clarity, size and drug content at 4°C and 25°C for up to 6 months. No irritation or redness was observed in the treated eyes as compared with the untreated control rabbit eyes. Therapeutic concentrations of dexamethasone were observed in the retina and choroid after single and multiple topical application in rabbits. CONCLUSION: In conclusion, the nanomicelles of P40S and P80 could efficiently solubilize 0.1% dexamethasone in their cores. The results also indicate that mixed nanomicelles could be utilized as a potential delivery system for delivering dexamethasone to treat the back of the eye diseases such as posterior uveitis after topical application.

Thermoresponsive fluconazole gels for topical delivery: rheological and mechanical properties, in vitro drug release and anti-fungal efficacy.

The aim of this study was to develop thermosensitive gels using poloxamers for topical delivery of fluconazole (FLZ). Eight different formulations containing 1% FLZ in poloxamer and a particular co-solvent (propylene glycol (PG) or Transcutol-P) of various concentrations were prepared. The gels were characterized for transition temperatures, rheological and mechanical properties. FLZ permeability and antifungal effect of the gels were also evaluated. Except for one formulation, all gels exhibited thermosensitive property, i.e. transformed from Newtonian (liquid-like) behavior at 20 °C to non-Newtonian (gel-like) behavior at 37 °C. Transcutol-P increased the transition temperature of the formulations, while the opposite effect was observed for PG. At 37 °C, formulations with high poloxamer concentrations (17%) resulted in high viscosity, compressibility and hardness. Formulations containing 17% poloxamer and 20% Transcutol-P and 10% PG, respectively, exhibited high adhesiveness. No significant differences in the in vitro antifungal activity of FLZ were observed among the formulations suggesting that the gel vehicles did not influence the biological effect of FLZ. FLZ permeability decreased with increasing poloxamer concentration. Formulations containing 17% poloxamer and 20% Transcutol-P and 10% PG seemed to be promising in situ gelling systems for the topical delivery of FLZ.

Characterization and evaluation of 5-fluorouracil-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification technique.

The aim of this research was to advance solid lipid nanoparticle (SLN) preparation methodology by preparing glyceryl monostearate (GMS) nanoparticles using a temperature-modulated solidification process. The technique was reproducible and prepared nanoparticles without the need of organic solvents. An anticancer agent, 5-fluorouracil (5-FU), was incorporated in the SLNs. The SLNs were characterized by particle size analysis, zeta potential analysis, differential scanning calorimetry (DSC), infrared spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), drug encapsulation efficiency, in vitro drug release, and in vitro cell viability studies. Particle size of the SLN dispersion was below 100 nm, and that of redispersed lyophilizates was ~500 nm. DSC and infrared spectroscopy suggested that the degree of crystallinity did not decrease appreciably when compared to GMS. TEM and AFM images showed well-defined spherical to oval particles. The drug encapsulation efficiency was found to be approximately 46%. In vitro drug release studies showed that 80% of the encapsulated drug was released within 1 h. In vitro cell cultures were biocompatible with blank SLNs but demonstrated concentration-dependent changes in cell viability to 5-FU-loaded SLNs. The 5-FU-loaded SLNs can potentially be utilized in an anticancer drug delivery system.

Physico-chemical characterisation, cytotoxic activity, and biocompatibility studies of tamoxifen-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification method.

CONTEXT: Solid lipid nanoparticles (SLNs) can efficiently and efficaciously incorporate anti-cancer agents. OBJECTIVE: To prepare and characterise tamoxifen (TAM)-loaded SLNs. MATERIALS AND METHODS: Glyceryl monostearate, Tween-80, and trehalose were used in SLNs. SLNs were tested via dynamic light scattering (DLS), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). RESULTS: Characterisation studies revealed SLNs of about 540 nm with a negative surface charge and confirmed the entrapment of TAM in the SLNs. The entrapment efficiency was estimated to be 60%. DISCUSSION: The in vitro drug release profile demonstrated a gradual increase followed by a release plateau for several days. A drug concentration-dependent increase in cytotoxic activity was observed when the SLNs were evaluated in cell cultures. CONCLUSION: Biocompatible and stable lyophilised SLNs were successfully prepared and found to possess properties that may be utilised in an anti-cancer drug delivery system.

Nebulized oil-in-water nanoemulsion mists for pulmonary delivery: development, physico-chemical characterization and in vitro evaluation.

CONTEXT: This study presents novel nanostructured oil-in-water (o/w) mists based on self-nanoemulsifying (SNE) mixtures capable of delivering poorly water-soluble drugs into the lungs. OBJECTIVE: Formulation development of an o/w nanoemulsion (NE) capable of being nebulized for pulmonary delivery of poorly water-soluble drugs. MATERIALS AND METHODS: SNE mixtures were prepared and evaluated using Tween 80 and Cremophor RH 40 as surfactants; Transcutol P, Capryol 90 and PEG 400 as cosurfactants; and Labrafac Lipophile Wl 1349 (a medium-chain triglyceride) as an oil. Liquid NEs were analyzed by light scattering, zeta potential, transmission electron microscopy (TEM) and in vitro drug release studies. The aqueous NE was nebulized and assessed by light scattering and TEM. The formulation was aseptically filtered and the sterility validated. In vitro cytotoxicity of the formulations was tested in NIH 3T3 cells. The capability of the formulation to deliver a poorly water-soluble drug was determined using ibuprofen. RESULTS: Ibuprofen was found to be stable in the NEs. The formulations were neutrally charged with a droplet size of about 20 nm. TEM images displayed 100 nm oil droplets. The aseptic filtration method produced sterile NE. The nebulized mist revealed properties ideal for pulmonary delivery. The biocompatible aerosol has a nanostructure consisting of several oil nanodroplets enclosed within each water drop. Solubility and in vitro drug release studies showed successful incorporation and release of ibuprofen. CONCLUSION: The developed formulation could be used as an inhalation for delivering material possessing poor water solubility into the lungs.

Development and characterization of nanostructured mists with potential for actively targeting poorly water-soluble compounds into the lungs.

PURPOSE: To formulate nanoemulsions (NE) with potential for delivering poorly water-soluble drugs to the lungs. METHOD: A self nanoemulsifying composition consisting of cremophor RH 40, PEG 400 and labrafil M 2125 CS was selected after screening potential excipients. The solubility of carbamazepine, a poorly water-soluble drug, was tested in the formulation components. Oil-in-water (o/w) NEs were characterized using dynamic light scattering, electrophoretic light scattering, transmission electron microscopy (TEM) and differential scanning calorimetry. NEs were nebulized into a mist using a commercial nebulizer and characterized using laser diffraction and TEM. An aseptic method was developed for preparing sterile NEs. Biocompatibility of the formulation was evaluated on NIH3T3 cells using MTT assay. In vitro permeability of the formulation was tested in zebra fish eggs, HeLa cells, and porcine lung tissue. RESULTS: NEs had neutrally charged droplets of less than 20 nm size. Nebulized NEs demonstrated an o/w nanostructure. The mist droplets were of size less than 5 µm. Sterility testing and cytotoxicity results validated that the NE was biocompatible and sterile. In vitro tests indicated oil nanodroplets penetrating intracellularly through biological membranes. CONCLUSION: The nanoemulsion mist has the potential for use as a pulmonary delivery system for poorly water-soluble drugs.

Preparation, characterization, sterility validation, and in vitro cell toxicity studies of microemulsions possessing potential parenteral applications.

CONTEXT: Water-in-oil microemulsions (w/o ME) are ideal for parenteral drug delivery. However, no such formulations have been tested for biocompatibility in in vitro cell cultures. Furthermore, sterilization of w/o MEs is a challenging process that has not been previously developed and validated. PURPOSE: To formulate pharmaceutically relevant water-in-oil (w/o) microemulsion's systems suitable for use as a parenteral formulation. METHODS: w/o MEs were prepared using dioctyl sodium sulfosuccinate (DOSS), ethyl oleate (EO), and water. Formulations were characterized using polarized light microscopy, electrical conductivity, rheology, and dynamic light scattering. An aseptic filtration method for sterilization was developed using membrane filtration. The biocompatibility of selected MEs were evaluated in NIH3T3 cell cultures. Dissolution studies were performed on microemulsions containing methylene blue to evaluate the drug release profile. RESULTS: The maximum amount of water incorporated in the formulations was 14% w/w. DOSS/EO/water microemulsions exhibited Newtonian flow. Particle sizes for these MEs were less than 30 nm in size. Formulations filtered aseptically were free of bacteria when gram-stained and visualized under a microscope. All MEs showed no toxicity to NIH 3T3 cells. DISCUSSION: The absence of birefringence and low conductivity values indicated that the formulations were w/o microemulsions. The filtration method of sterilization was validated by the absence of microbial growth on blood agar plates over a 14-day period. In vitro dye release studies demonstrate sustained release of the model drug over a 72-h time period. CONCLUSION: Characteristics delineated in this study demonstrate the potential for these formulations to be used as parenteral preparations.

Calcium alginate nanoparticles synthesized through a novel interfacial cross-linking method as a potential protein drug delivery system.

The goal of this research work was to develop a novel technique to synthesize calcium alginate nanoparticles using pharmaceutically relevant microemulsions. Stable microemulsion-based reactors were prepared using aqueous sodium alginate, aqueous calcium chloride, dioctyl sodium sulfosuccinate (DOSS), and isopropyl myristate. The reactor microemulsions were characterized via conductivity and dynamic light scattering (DLS) experiments. The conductivity data indicated composition- and reagent-dependent variations in electrical conductivity when the aqueous phase containing reagents were present at or above a Wo (Wo = [DOSS]/[water]) value of 14. The reactor microemulsions were of approximately 6 nm sized droplets. When the reactor microemulsions were mixed and sonicated for 1 h approximately, 350-nm-sized calcium alginate nanoparticles were produced, as indicated by DLS measurements. The particles were isolated and characterized via low-vacuum scanning electron microscopy. The electron micrographs corroborate the DLS results. The nanoparticles were evaluated as a drug delivery system by incorporating bovine serum albumin (BSA) and performing in vitro release and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies. The BSA release profile was characterized by an initial burst release followed by a sustained-release phase. SDS-PAGE studies indicated that the incorporated protein did not suffer covalent aggregation or degradation via fragmentation.

IPM/DOSS/water microemulsions as reactors for silver sulfadiazine nanocrystal synthesis.

The first goal of this work was the preparation of a water-in-oil microemulsion from components generally regarded as safe for use in humans. Stable formulations without need of a co-surfactant were prepared from isopropyl myristate (IPM), dioctyl sodium sulfosuccinate (DOSS), and water. A ternary phase diagram was prepared for the IPM/DOSS/water system. The IPM/DOSS/water microemulsions were characterized by conductivity and dynamic laser light scattering (DLS). The results obtained from conductivity experiments indicate conductivity values of less than 1 muS/cm and were consistent with the formation of w/o microemulsions. The DLS results showed that the emulsified water droplets had an average diameter range of 9.2 to 19.7 nm, depending on composition. Modulation of the droplet size is possible by varying the water to DOSS molar ratio and DOSS to IPM ratio. The second goal of this work was the preparation of silver sulfadiazine (AgSD) nanoparticles. It was hypothesized that two separate microemulsions containing dispersed aqueous droplets of either sodium sulfadiazine or silver nitrate would react when mixed. The DLS results are consistent with the successful formation of submicron AgSD crystals.

Delivery of insulin from hydroxyapatite ceramic microspheres: preliminary in vivo studies.

The major limiting factor in utilizing protein drugs for sustained delivery is the lack of suitable delivery systems. Ceramic hydroxyapatite microspheres are biocompatible and utilized for the purification of proteins. As a preliminary study, we have investigated the possibility of using hydroxyapatite ceramic microspheres loaded with insulin as an implantable delivery system in rats. With this limited test, it was shown that the loaded insulin was active and able to suppress the blood glucose level in normal rats.