Neurodegenerative disorders: Mechanisms of degeneration and therapeutic approaches with their clinical relevance.

Neurodegenerative disorders (NDs) are expected to pose a significant challenge for both medicine and public health in the upcoming years due to global demographic changes. NDs are mainly represented by degeneration/loss of neurons, which is primarily accountable for severe mental illness. This neuronal degeneration leads to many neuropsychiatric problems and permanent disability in an individual. Moreover, the tight junction of the brain, blood-brain barrier (BBB)has a protective feature, functioning as a biological barrier that can prevent medicines, toxins, and foreign substances from entering the brain. However, delivering any medicinal agent to the brain in NDs (i.e., Multiple sclerosis, Alzheimer's, Parkinson's, etc.) is enormously challenging. There are many approved therapies to address NDs, but most of them only help treat the associated manifestations. The available therapies have failed to control the progression of NDs due to certain factors, i.e., BBB and drug-associated undesirable effects. NDs have extremely complex pathology, with many pathogenic mechanisms involved in the initiation and progression; thereby, a limited survival rate has been observed in ND patients. Hence, understanding the exact mechanism behind NDs is crucial to developing alternative approaches for improving ND patients' survival rates. Thus, the present review sheds light on different cellular mechanisms involved in NDs and novel therapeutic approaches with their clinical relevance, which will assist researchers in developing alternate strategies to address the limitations of conventional ND therapies. The current work offers the scope into the near future to improve the therapeutic approach of NDs.

Supplementation of protease and different nutrient density diets in growing-finishing pigs.

This study was conducted to investigate the effects of protease supplementation and different nutrient density of diets in growing-finishing pigs. A total of one hundred-eight crossbred growing pigs ([Landrace × Yorkshire] × Duroc) with an initial body weight (BW; 18.74 ± 3.46 kg) were used for 15 weeks. Pigs were randomly assigned to six dietary treatments with 6 replicates of 3 pigs per pen in a 3 × 2 factorial through the following arrangement: Three groups of protease (1, Basal diets; 2, Protease A: 125 mg/kg protease derived from Streptomyces sps; 3, Protease B: 100 mg/kg protease derived from Bacillus licheniformis) at two different nutrient density diets (1, Basal requirement; 2, 0.94%-0.98% higher than requirement in dietary protein and 50 kcal/kg in energy). High nutrient (HN) diets showed higher average daily gain (ADG) (p < 0.05) and apparent total tract digestibility (ATTD) of crude protein (CP) (p < .0001) compared to basal nutrient (BN) diets during growing periods. Supplementation of protease showed higher BW (p < 0.05) and ADG (p < 0.05) compared to non-supplementation of protease during growing periods. Also, supplementation of protease showed higher ATTD of CP (p < 0.01), ATTD of gross energy (p < 0.05) and decreased blood urea nitrogen (BUN) level (p = 0.001) compared to non-supplementation of protease during finishing periods. Pigs which fed the protease showed decreased ammonia (NH3) emissions (p < 0.05) during experiment periods and decreased hydrogen sulfide (H2S) emissions (p < 0.01) during finishing periods. Interactions between nutrient density and protease were observed, which decreased the feed conversion ratio (p < 0.05) in HN diets without protease compared to BN diets without protease during weeks 4 to 6. Also, interaction between nutrient density and protease was observed, which resulted in improved ATTD of CP (p < 0.01) in response to PTA supplementation with HN diets during the finishing period. In conclusion, supplementation of protease reduces NH3 in feces and BUN in whole blood by increasing the digestibility of CP and improves growth performance. Also, diets with high nutrient density improved growth performance and nutrient digestibility in growing periods.

Ko au tenei: This is me - Exploring the lived experience of underrepresented groups with pharmacy services to inform the development of pharmacy case-based learning.

INTRODUCTION: Demographic and social characteristics of underrepresented groups are often poorly described in pharmacy case-based learning, leading to poor representation of these groups in the pharmacy curriculum. This research project aimed to understand the lived experience of underrepresented groups with pharmacy services and to use this to inform the development of pharmacy case-based student learning materials. METHODS: This was a single centre, grounded theory, qualitative study. Focus groups were undertaken with six underrepresented groups: Maori, Pacific, Asian, LGBTQIA+ (lesbian, gay, bisexual, transgender, queer/questioning, intersex, asexual), disability, and refugee. These focus groups were conducted in Dunedin, Aotearoa New Zealand from July to August 2022. Focus group sessions were recorded and analysed to identify beliefs, ideas, and themes shared between participants and groups. FINDINGS: Participants in all focus groups had a strong desire to be seen and represented in pharmacy cases, however this was conditional on the learning being delivered in a way that upholds their beliefs, values, and voices. From these lived experiences, cultural, environmental, personal, and social factors were identified as being critical for inclusion in pharmacy case-based learning materials. CONCLUSIONS: The lived experience of underrepresented populations provides critical insights that will enhance pharmacy case-based learning. The key factors that could be included in case-based learning are: ethnicity, personal beliefs, language, disability, gender identity, sexual identity, and family. To achieve health equity and improve cultural awareness and intelligence of our future pharmacy workforce, these experiences need to become more present in curricula.

Effects of stimbiotic supplementation on gut health, immune response, and intestinal microbiota in weaned piglets challenged with E. coli.

In order to make piglet diets more effective, it is necessary to investigate effective methods for breaking down xylan in cereal. The objective of this study was to determine the effects of dietary stimbiotic (STB) supplementation on growth performance, intestinal morphology, immune response and intestinal microbiota in weaned piglets. A total of 24 (Duroc × Yorkshire × Landrace) weaned pigs (initial body weight of 8.01 ± 0.38 kg and 28 ± 3 d old), were assigned to 4 treatments with 6 replicates per treatment. Pigs were housed in individual pens for 17 days, including 5 days adaption period and 12 days after the first Escherichia coli (E. coli) challenge. The experiment was conducted in a 2 × 2 factorial arrangement of treatments consisting of two levels of challenge (challenge and non-challenge) and two levels of STB (0 and 0.5 g/kg diet). Supplementations of STB 0.5 g/kg improved the gain to feed ratio (G:F) (P < 0.05) in piglets challenged with shiga toxigenic E. coli (STEC). STB supplementation decreased (P < 0.05) white blood cells, neutrophils, lymphocytes, and expression levels of tumor necrosis factor-alpha and interleukin-6. Supplementation of STB improved (P < 0.05) the lymphocytes and neutrophils in piglets challenged with STEC on 12 dpi. Supplementation of STB also improved (P < 0.05) the villus height to-crypt depth ratio of ileum in piglets challenged with STEC. Supplementation of STB increased (P < 0.05) the expression levels of claudin-1 of ileum. In genus level, supplementation of STB increased (P < 0.001) the abundance of Prevotella compared to non-supplementation of STB groups in pre-inoculation period. Also, supplementation of STB decreased (P < 0.05) the abundance of Faecalibacterium and Eubacterium_coprostanoligenes_group compared to non-supplementation of STB groups in post-inoculation period. In phylum level, supplementation of STB increased (P < 0.05) the abundance of Desulfobacterota and Fibrobacterota in pre-inoculation period. E. coli challenge increased the abundance of Fibrobacterota compared to non-challenged group in post-inoculation period. In conclusion, these findings indicated that STB supplementation could alleviate a decrease of the performance, immune response, and inflammatory response in piglets induced by the STEC challenge.

Effects of Combinations of Toxin Binders with or without Natural Components on Broiler Breeders Exposed to Ochratoxin A.

The objective of this study was to investigate the effects of toxin binders on broiler breeders fed an ochratoxin A (OTA)-contaminated diet. A total of 60 45-week-old female Arbor Acres broiler breeder birds with an initial body weight of 3.65 ± 0.35 kg were randomly divided into 6 treatment groups, with 10 replicates per group and 1 bird per replicate. The trial was conducted for 9 weeks (including 1 week of adaptation). Feed additive 1 (FA1) was composed of clay minerals (85% bentonite and 12% clinoptilolite) with 3% charcoal. FA2 was composed of clay minerals (66.1% aluminosilicates) with natural components (0.8% artichoke and rosemary plant extracts), 7% yeast extract, 0.5% beta-glucans, and 25.6% carriers. The dietary treatment groups were as follows: (1) birds fed an OTA-free basal diet (Negative Control; NC); (2) lipopolysaccharide (LPS)-challenged birds fed a diet including OTA (4 mg/kg) (Positive Control, PC); (3) the PC with 0.05% FA1 (Treatment 1, T1); (4) the PC with 0.10% FA1 (Treatment 2, T2); (5) the PC with 0.10% FA2 (Treatment 3, T3); and (6) the PC with 0.20% FA2 (Treatment 4, T4). The LPS challenge (an intramuscular injection of 1 mg E. coli O55:B5 LPS per kg of body weight) was performed on the first day of the experiment. The results of this experiment show that the PC treatment negatively affected (p < 0.05) egg production, hatchability, Haugh unit, bone mineralization, relative organ weight (abdominal fat, liver), the levels of glutamic oxaloacetic transaminase (GOT), high-density lipoprotein (HDL), and total cholesterol in the blood, and OTA accumulation in the liver compared with the NC. However, supplementation with toxin binders mitigated (p < 0.05) the negative effects of the OTA. Specifically, supplementation with 0.10% FA1 and 0.10% FA2 increased (p < 0.05) eggshell strength by week 4, and the Haugh unit and bone mineralization (phosphorous) by week 8, while decreasing (p < 0.05) the relative weight of the liver and the levels of GOT and HDL in the blood. Supplementation with 0.10% FA2 led to greater improvements in various parameters, including laying performance and bone mineralization, than the other treatments. In conclusion, toxin binders with or without natural components can be effective tools in the mitigation of OTA-induced problems due to their synergistic effects.

Effects of dietary supplementation of Pediococcus pentosaceus strains from kimchi in weaned piglet challenged with Escherichia coli and Salmonella enterica.

Escherichia coli (E. coli) and Salmonella enterica (SE) infections in pigs are major source associated with enteric disease such as post weaning diarrhea. The aim of this study was to investigate the effects of Pediococcus pentosaceus in weaned piglets challenged with pathogen bacteria. In Experiment.1 90 weaned piglets with initial body weights of 8.53 ± 0.34 kg were assigned to 15 treatments for 2 weeks. The experiments were conducted two trials in a 2 × 5 factorial arrangement of treatments consisting of two levels of challenge (challenge and non-challenge) with E. coli and SE, respectively and five levels of probiotics (Control, Lactobacillus plantarum [LA], Pediococcus pentosaceus SMFM2016-WK1 [38W], Pediococcus acidilactici K [PK], Lactobacillus reuteri PF30 [PF30]). In Experiment.2 a total of 30 weaned pigs (initial body weight of 9.84 ± 0.85 kg) were used in 4 weeks experiment. Pigs were allocated to 5 groups in a randomized complete way with 2 pens per group and 3 pigs per pen. Supplementation of LA and 38W improved (p < 0.05) growth performance, intestinal pathogen bacteria count, fecal noxious odor and diarrhea incidence. In conclusion, supplementation of 38W strains isolated from white kimchi can act as probiotics by inhibiting E. coli and SE.

Effects of exogenous protease on performance, economic evaluation, nutrient digestibility, fecal score, intestinal morphology, blood profile, carcass trait, and meat quality in broilers fed normal diets and diets considered with matrix value.

This study was conducted to estimate the effects of exogenous protease on performance, economic evaluation, nutrient digestibility, fecal score, intestinal morphology, blood profile, carcass traits, and meat quality in broilers fed normal diets and diets considered with matrix value. A total of 90, one-day-old Arbor Acres broiler chickens were randomly allocated to 3 dietary treatments with 6 replicates and each replicate of 5 broiler chickens. Treatments were as follows: 1) Basal diet (positive control, PC), 2) Basal diet formulated with full ProAct 360 matrix at 50 g/MT without addition of ProAct 360 (negative control, NC), 3) NC + 50 g/MT ProAct 360 (PA). Supplementation of exogenous protease to nutrient deficient NC diet by matrix values (PA) tended to increase growth performance and significantly improved intestinal morphology compared with the NC group. The PA group had significantly lower fecal score, and higher ATTD of crude protein and amino acids than those of the NC group. Furthermore, supplementation of exogenous protease to NC diet decreased feed cost, resulting in improved profit margin. However, there was no significant difference on carcass yield and relative organ weight. In conclusion, supplementation of exogenous protease using matrix value could be used as economic additive to improve growth, profit margin, digestibility, and gut health in broiler chickens.

Topical Cream Carrying Drug-Loaded Nanogels for Melanoma Treatment.

In this study, nanogel creams carrying paclitaxel (PTX) and temozolomide (TMZ) were prepared for the topical treatment of melanoma. PTX and TMZ were first loaded in poly-(D,L-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(D,L-lactide-co-glycolide) (PLAG-b-PEG-b-PLGA) thermosensitive nanogels, which made a transition from a free-flowing sol (formation of micellar network) at 25°C with the z-average particle size of c.a. 96 nm to a gel (aggregation of micelles) at 33°C with the z-average particle size of c.a. 427 nm. An anhydrous absorption ointment base, aquaphor, was then added to drug-loaded nanogels to form nanogel creams carrying PTX and TMZ. Nanogel creams permitted controlled release of the payloads and improved the penetration of the payloads through the rodent skin compared to drug(s)-loaded nanogels. PTX and TMZ in a combination were synergistically effective in inhibiting SK-MEL28, A375, and B16-F10 melanoma cancer cells in vitro. Topically applied nanogel creams carrying TMZ/PTX (4 mg/1.5 mg/dose) showed a trend of tumor volume inhibition on B16-F10-bearing xenograft mice in vivo.

Effects of supplemental different clay minerals in broiler chickens under cyclic heat stress.

The objective of this study was to investigate the effect of supplementing clay minerals and organic chromium in feed on broiler chicken under heat stress (HS). A total of 90 one-day-old broiler chicken (Arbor Acres) with an initial body weight of 45.0 ± 0.2 g were assigned to five treatment groups (six replications, three birds each cage): 1) NC group, basal diet under room temperature environment; 2) PC group, basal diet under high temperature (HT) environment; 3) ILT group, basal diet + 1% illite + HT; 4) ZLT group, basal diet + 1% zeolite + HT; 5) OC group, basal diet + 400 ppb/kg organic chromium + HT. The ILT and ZLT groups had significantly higher body weight than the PC group in 4 weeks. Apparent total tract digestibility of gross energy was increased in the ILT, ZLT, and OC groups compared to the PC group. The NC group had lower foot-pad dermatitis score than other groups. Escherichia coli population in the cecum and feces was decreased in the ZLT group than in the PC group. Lactobacillus in cecum and feces was significantly increased in the ZLT group than in the PC group. Regarding blood profiles, blood cortisol was decreased in the NC and ILT groups compared to the PC group. Water holding capacity and pH were increased in the ZLT group than the PC group. In conclusion, according to the results of growth performance, nutrients digestibility, bacteria counts, and meat characteristics, supplementation of the ZLT in broiler diet can alleviate HS.

Effects of different levels of organic chromium and selenomethionine cocktails in broilers.

Selenium (Se) is an essential trace mineral that plays an important role in physiological processes by regulating the antioxidant defense system and enhancing immunity. Chromium is an essential mineral involved in carbohydrate and lipid metabolism and also plays a role in maintaining normal insulin function. Based on these advantages, we hypothesized that the addition of selenomethionine (SeMet) and organic chromium (OC) to broiler diets would increase Se deposition, antioxidant capacity and immune response in meat. Therefore, this study analyzed the effects of OC and SeMet on growh performance, nutrients digestibility, blood profiles, intestinal morphology, meat quality characteristics, and taxonomic analysis of broilers. A total of 168 one-day-old broiler chicken (Arbor Acres) were randomly allotted to 3 groups based on the initial body weight of 37.33 ± 0.24 g with 7 replicate per 8 birds (mixed sex). The experiments period was 28 days. Dietary treatments were folloewd: Basal diets based on corn-soybean meal (CON), basal diet supplemented with 0.2 ppm OC and 0.2 ppm SeMet (CS4), and basal diet supplemented with 0.4 ppm OC and 0.4 ppm SeMet (CS8). Supplementation of OC and SeMet did not affect on growth performance, nutrient digestibility. However, CS8 supplementation increased in duodenum villus height and villus height : crypt depth, and increased in breast meat Se deposition. In addition, CS8 group showed higher uric acid and total antioxidant status than CON group. Taxonomic analysis at phylum level revealed that Proteobacteria and Firmicutes of CS4 and CS8 were lower than CON group. In genus level, the relative abundance of fecal Lactobacillus and Enterococcus of CS4 and CS8 groups were higher than CON group. In short, 0.4 ppm OC and 0.4 ppm SeMet supplementation to broiler diet supporitng positive gut microbiome change, also enhancing antioxidant capacity, and Se deposition in breast meat.

Effect of black soldier fly larvae as substitutes for fishmeal in broiler diet.

This study investigated the effect of processed forms (defatted or hydrolyzed) of black soldier fly larvae (Hermetia illucens L., BSFL) as a protein substitute on broilers. Experiment 1 was a feeding experiment, and Experiment 2 was a metabolism experiment. In Experiment 1, a total of 120 day-old Arbor Acres broilers (initial body weight 39.52 ± 0.24 g) were used for 28 days. There were 8 replicate pens, and 5 broilers were assigned to each pen. In Experiment 2, a total of 36 day-old broilers (initial body weight 39.49 ± 0.21 g) were used for the metabolism trial. There were 2 broilers in a metabolism cage and six replicate cages per treatment. The dietary treatments were as follows: a basal diet (CON), a basal diet without fishmeal and substitute with defatted BSFL (T1), a basal diet without fishmeal and a substitute with hydrolyzed BSFL (T2). In Experiment 1, during the entire experimental period, the T2 group significantly increased (p < 0.05) body weight gain and feed intake compared to the CON and T1 groups. The feed conversion ratio showed a lower tendency (p = 0.057) in the T2 group than in the CON and T1 groups. At 2 weeks, the CON and T2 groups were significantly higher (p < 0.05) crude protein (CP) digestibility than the T1 group. At 4 weeks, the total protein level significantly increased (p < 0.05) in the CON and T2 groups compared to the T1 group. In Experiment 2, the CP digestibility significantly increased (p < 0.05) in the T2 group compared to the CON and T1 group at weeks 2 and 4. At week 4 amino acid digestibility, the T2 group significantly increased (p < 0.05) lysine, methionine, tryptophan, and glycine digestibility compared to the T1 group. There was no difference in fecal microbiota among the treatment groups. In conclusion, feeding hydrolyzed BSFL as a fishmeal substitute in broiler diets improved growth performance, CP digestibility, and specific amino acid digestibility. Therefore, it is considered that hydrolyzed BSFL in broiler diets can be sufficiently used as a new protein source.

Effect of loading density and weather conditions on animal welfare and meat quality of slaughter pigs.

There are several factors that affect the welfare and meat quality of pigs during pre-slaughter transport. Among various factors, the effects of weather conditions and loading density were studied. A total of 3,726 finishing pigs were allotted to one of nine groups arranged in a 3 × 3 factorial design according to the weather conditions (low temperature [LT], under 10°C; normal temperature [NT], 10°C-24°C; high temperature [HT], upper 24°C), and loading density (low density [LD], upper 0.43 m2/100 kg; normal density [ND], 0.37-0.43 m2/100 kg; high density [HD], under 0.37 m2/100 kg). Each treatment group follow as: LTLD, LTND, LTHD, NTLD, NTND, NTHD, HTLD, HTND, HTHD. In terms of carcass composition, pigs had the highest carcass weight and backfat thickness at LT. Comparing the HD transport to the ND transport, the meat quality indicated a lower pH and more drip loss. The incidence rate of pale, soft, exudative (PSE) pork was high in the order of the HD, LD, and the ND transport (20%, 9%, and 2%, respectively). The HT transport showed the lowest pH and greatest L* value under the given weather conditions. Pigs transported under the HTHD and LTLD conditions had the greatest rates of PSE pork (40% and 20%, respectively). Pigs exposed to HD transport had the shortest laying time and the highest overplap behavior. The LDLT transport pigs had a shorter laying time than the LDNT and LDHT transport pigs. In conclusion, too high or too low density transport is generally not excellent for meat quality or animal welfare, however it is preferable to transport at a slightly low density at high temperature and at a slightly high density at low temperature.

Stimbiotic Supplementation Alleviates Poor Performance and Gut Integrity in Weaned Piglets Induced by Challenge with E. coli.

The aim of this study was to investigate the effects of stimbiotic (STB), a xylanase and xylo-oligosaccharide complex. A total of 36 male weaned pigs with initial body weights of 8.49 ± 0.10 kg were used in a 3-week experiment. The experiment was conducted in a 2 × 3 factorial arrangement (six replicates/treatment) of treatments consisting of two levels of challenge (challenge and non-challenge) and three levels of STB (0, 0.5, and 1 g/kg diet). Supplementations STB 0.5 g/kg (STB5) and STB 1 g/kg (STB10) improved the G:F (p = 0.04) in piglets challenged with STEC. STB supplementation, which also decreased (p < 0.05) the white blood cells, neutrophils, lymphocytes, and expression levels of tumor necrosis factor-alpha and interleukin-6. Supplementations STB5 and STB10 improved (p < 0.01) the lymphocytes and neutrophils in piglets challenged with STEC on 14 dpi. Additionally, supplementations STB5 and STB10 improved (p < 0.01) the tumor necrosis factor-alpha in piglets challenged with STEC on 3 dpi. Supplementations STB5 and STB10 also improved the villus height-to-crypt depth ratio (p < 0.01) in piglets challenged with STEC. Supplementation with STB reduced (p < 0.05) the expression levels of calprotectin. In conclusion, STB could alleviate a decrease of the performance, immune response, and inflammatory response induced by the STEC challenge.

Nanogels as a Versatile Drug Delivery System for Brain Cancer.

Chemotherapy and radiation remain as mainstays in the treatment of a variety of cancers globally, yet some therapies exhibit limited specificity and result in harsh side effects in patients. Brain tissue differs from other tissue due to restrictions from the blood-brain barrier, thus systemic treatment options are limited. The focus of this review is on nanogels as local and systemic drug delivery systems in the treatment of brain cancer. Nanogels are a unique local or systemic drug delivery system that is tailorable and consists of a three-dimensional polymeric network formed via physical or chemical assembly. For example, thermosensitive nanogels show promise in their ability to incorporate therapeutic agents in nano-structured matrices, be applied in the forms of sprays or sols to the area from which a tumor has been removed, form adhesive gels to fill the cavity and deliver treatment locally. Their usage does come with complications, such as handling, storage, chemical stability, and degradation. Despite these limitations, the current ongoing development of nanogels allows patient-centered treatment that can be considered as a promising tool for the management of brain cancer.

Development of 3D-Printed Layered PLGA Films for Drug Delivery and Evaluation of Drug Release Behaviors.

3D printing has been widely used to rapidly manufacture a variety of solid dosage forms on-demand, without sacrificing precision. This study used extrusion-based 3D printing to prepare single-layered, tri-layered, and core-in-shell poly(lactic-co-glycolic acid) (PLGA) films carrying paclitaxel and rapamycin in combination or lidocaine alone. Each layer was composed of either low molecular weight (MW) PLGA or high MW PLGA. In vitro drug release kinetics of paclitaxel, rapamycin, and lidocaine for PLGA films were assessed and compared with PLGA-polyethylene glycol (PEG)-PLGA hydrogel discs. Regardless of the structure of PLGA film, paclitaxel (half-time: 54-63 days) was released faster than when compared with rapamycin (half-time: 74-80 days). In contrast, single-layered PLGA-PEG-PLGA discs released rapamycin (half-time 5.7 h) at a more rapid rate than paclitaxel (half-time: 7.3 h). Single-layered PLGA-PEG-PLGA discs enabled a faster drug release than PLGA films, noting that the disc matrices dissolve in water in 24 h. Similarly, lidocaine incorporated in PLGA films (half-time: 13-36 days) exhibited slower release patterns than that in PLGA-PEG-PLGA discs (half-time: 2.6 h). In vitro drug release patterns were explained using molecular models that simulate drug-polymer interactions. Analysis of models suggested that drug-polymer interactions, location of each drug in the polymeric matrix, and solubility of drugs in water were major factors that determine drug release behaviors from the polymeric films and discs.

Preparations of Rectal Suppositories Containing Artesunate.

Rectal artesunate suppositories are a useful option for pre-referral treatment of severe malaria, specifically in children under 6 years of age in remote malaria-endemic areas. The main challenges are to improve the solubility of drugs in the rectal fluids and prevent the product from turning rancid or melting in a tropical climate. In this short proof-of-concept study, three types of rectal suppositories of artesunate were prepared: (i) polyethylene glycol (PEG)-based suppositories carrying free artesunate (non-modified artesunate), (ii) PEG-based suppositories carrying artesunate-loaded micelles and (iii) 3D-printed suppositories carrying a PEG/artesunate mixture. Physical parameters of suppositories, release profiles of artesunate (the fastest to the slowest: ii≥i>iii) and thermostability (the most stable to the least stable: iii>ii>i) of suppositories at increased temperature were assessed to determine the advantages and disadvantages of each formulation.

3D Printing of Poloxamer 407 Nanogel Discs and Their Applications in Adjuvant Ovarian Cancer Therapy.

Nanogels are attractive biocompatible materials that enable local delivery of multiple drugs. In this study, we demonstrated that 3D printing technology could be used to precisely construct nanogel discs carrying paclitaxel and rapamycin. 3D-printed nanogel disc rounds (12 mm diameter × 1 mm thickness) carrying paclitaxel and rapamycin evaded premature gelation during storage and the initial burst release of the drugs in the dissolution medium. In vivo 3D-printed nanogel discs permitted successful intraperitoneal delivery of paclitaxel and rapamycin in ES-2-luc ovarian-cancer-bearing xenograft mice. They were also shown to be therapeutically effective and capable of preventing postsurgical peritoneal adhesions in the treated xenograft mice.

Nanogels for Pharmaceutical and Biomedical Applications and Their Fabrication Using 3D Printing Technologies.

Nanogels are hydrogels formed by connecting nanoscopic micelles dispersed in an aqueous medium, which give an opportunity for incorporating hydrophilic payloads to the exterior of the micellar networks and hydrophobic payloads in the core of the micelles. Biomedical and pharmaceutical applications of nanogels have been explored for tissue regeneration, wound healing, surgical device, implantation, and peroral, rectal, vaginal, ocular, and transdermal drug delivery. Although it is still in the early stages of development, due to the increasing demands of precise nanogel production to be utilized for personalized medicine, biomedical applications, and specialized drug delivery, 3D printing has been explored in the past few years and is believed to be one of the most precise, efficient, inexpensive, customizable, and convenient manufacturing techniques for nanogel production.

Triolimus: A Multi-Drug Loaded Polymeric Micelle Containing Paclitaxel, 17-AAG, and Rapamycin as a Novel Radiosensitizer.

Triolimus is a multi-drug loaded polymeric micelle containing paclitaxel (PTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin (RAP). This study examines the radiosensitizing effect of Triolimus in vitro and in vivo. Radiosensitizing effects of Triolimus on A549 cells are dose dependent and at 2 × 10-9 m, Triolimus shows significant radiosensitization even at low radiation doses (2 Gy). By sensitivity enhancement ratio, PTX alone, dual drug combinations, and Triolimus treatment at 2 × 10-9 m have radiosensitizing effects with potency as follows: PTX alone (PTX) > PTX and RAP (P/R) > Triolimus (TRIO) > PTX and 17-AAG (P/17) >17-AAG and RAP (17/R). In vivo, fractionated radiation of 15 Gy preceded by infusion of PTX alone, dual drug combinations, or an intermediate dose of Triolimus (Int. TRIO: PTX/17-AAG/RAP at 15/15/7.5 mg kg-1 ) strongly inhibits A549 tumor growth. Notably, pretreatment with high dose of Triolimus (High TRIO: PTX/17-AAG/RAP at 60/60/30 mg kg-1 ) before the fractionated radiation leads to tumor control for up to 24 weeks. An enhanced radiosensitizing effect is observed without an increase in acute toxicity compared to PTX alone or radiation alone. These results suggest that further investigations of Triolimus in combination with radiation therapy are merited.

Proof-of-Concept of Polymeric Sol-Gels in Multi-Drug Delivery and Intraoperative Image-Guided Surgery for Peritoneal Ovarian Cancer.

PURPOSE: The purpose of this study is to investigate a sol-gel transition property and content release profiles for thermosensitive poly-(D,L-lactide-co-glycolide)-block-poly-(ethylene glycol)-block-poly-(D,L-lactide-co-glycolide) (PLGA-b-PEG-b-PLGA) hydrogels carrying paclitaxel, rapamycin, and LS301, and to present a proof-of-concept that PLGA-b-PEG-b-PLGA hydrogels carrying paclitaxel, rapamycin, and LS301, called TheranoGel, exhibit excellent theranostic activity in peritoneal ES-2-luc ovarian cancer xenograft mice. METHODS: Thermosensitive PLGA-b-PEG-b-PLGA hydrogels carrying paclitaxel, rapamycin, and LS301, individually or in combination, were prepared via a lyophilization method, characterized with content release kinetics, and assessed with theranostic activity in ES-2-luc xenograft mice. RESULTS: A thermosensitive PLGA-b-PEG-b-PLGA sol-gel system was able to entrain 3 poorly water-soluble payloads, paclitaxel, rapamycin, and LS301 (TheranoGel). TheranoGel made a sol-to-gel transition at 37°C and slowly released 3 drugs at a simultaneous release rate in response to the physical dissociation of hydrogels in vitro. TheranoGel enabled loco-regional delivery of multi-drugs by forming a gel-depot in the peritoneal cavity of ES-2-luc xenograft mice. An intraperitoneal (IP) administration of TheranoGel resulted in excellent therapeutic and diagnostic activities, leading to the improved peritoneal surgery in ES-2-luc xenograft mice. CONCLUSIONS: TheranoGel prepared via a facile lyophiliation method enabled successful IP delivery of multi-drugs and exhibited excellent theranostic activity in vivo.