Prevent Drug Release Research Articles

Co-Delivery of Tim-3 Monoclonal Antibody and Sorafenib to Enhance Chemoimmunotherapy of Liver Cancer by Using Silicon Nanosystem

In this study, mesoporous silica nanosystem (ST/SNs) was designed to co-deliver Tim-3 mAb and sorafenib (SF) for combined chemoimmunotherapy of liver cancer. The outer shell of ST/SNs is composed of Tim-3 mAb modified with metalloproteinase 2 (MMP2)-sensitive peptide, which acts as a “gating molecule” in the blood circulation to prevent drug release, and responds to Tim-3 mAb under the action of MMP2 in the tumor microenvironment Shedding enables Tim-3 mAb and SF-triggered drug release for heterotargeted cell delivery to T cells/tumor cells. In vivo tumor inhibition experiments showed that ST/SNs significantly improved tumor inhibition in tumor-bearing mice compared with sequential administration of free SF and Tim-3 mAb. At the same time, ST/SNs significantly up-regulated the expression of anti-tumor cytokines IFN-γ and IL-12 in mouse serum and the proportion of CD3+CD4+ and CD3+CD8+ cells in the tumor, showing a good immune regulation ability. In addition, at the administered dose, the blank vector exhibited low cytotoxicity and hemolysis, and no obvious hemolysis was observed. Provincial People’s Hospital. In conclusion, this study provides a promising chemoimmunotherapy combination drug combination for clinical liver cancer treatment, and provides a potential drug carrier for chemoimmunotherapy combination therapy.

Curcumin-loaded porous particles functionalized with pH-responsive cell-penetrating peptide for colorectal cancer targeted drug delivery.

The anticancer properties of curcumin have been broadly examined in several shapes, such as nanoparticles and nanocomposite structures. Despite its benefits, curcumin also has some disadvantages, including rapid metabolism, poor absorption, and rapid systemic excretion. Therefore, numerous strategies have been used to increase curcumin's bioavailability. One of these approaches is the use of porous particles like aerogels as drug carriers. Aerogels are special due to their peculiar physical structure. They have a high specific surface area, a significant amount of porosity, and a solid composition, which make them a good choice for drug delivery systems. In the present study, a pH-sensitive aerogel was constructed and evaluated for targeted drug delivery of curcumin to colon cancer. To control the release of curcumin, trehalose was used as a coating agent, and PLP (poly(l-lysine isophthalamide)) was used as a targeted drug delivery agent. PLP is a pseudo-peptidic polymer that increases the cell permeability. In order to investigate and compare the synthesized aerogel before and after loading curcumin and coating with trehalose, physicochemical characterization analyses were performed. Finally, the efficacy of the final formulation was evaluated on HT29 colon cells using the cell bioavailability test. The results indicated the successful synthesis of the aerogel with porous structure with solitary cavities. The trehalose coating performed well, preventing drug release at lower pH but allowing the drug to be released at its intended site. The designed curcumin-loaded porous particles functionalized with PLP showed significant efficacy due to increasing penetration of curcumin into cells, and has potential for use as a new drug carrier with dual effectivity in cancer therapy.

Dual pH- and temperature-responsive poly(dimethylaminoethyl methacrylate)-coated mesoporous silica nanoparticles as a smart drug delivery system

A robust drug delivery system was created by grafting poly(dimethylaminoethyl methacrylate) (PDMAEMA) onto silica nanoparticles with two different lengths using an in situ atom transfer radical polymerization, resulting in the formation of a pH- and temperature-sensitive shell. The high molecular weight PDMAEMA demonstrated effective controlled drug release, and prevented drug release in healthy cells. Drug release occurred through polymer shell protonation at pH 5. The critical temperature of 41 °C facilitated rapid solvation of the shell polymers in the blood, preventing tissue accumulation and reducing toxicity compared to systems with lower critical solution temperatures. Field-emission scanning electron microscopy analysis and nitrogen adsorption/desorption analysis showed that the nanoparticles have a fine network, mesoporous structure, and a mean size of around 17 nm that show their excellent capacity for loading drugs. Fourier-transform infrared spectroscopy showed that all the modification steps and polymerization were successfully implemented. Thermogravimetric analysis showed PDMAEMA chains with two different lengths grafted onto the nanoparticles. Transmission electron microscopy analysis also showed grafted polymer chains on the hybrid nanoparticles. The release profile of model cancer drugs (doxorubicin and methotrexate) varied with pH and temperature, with high molecular weight PDMAEMA shells effectively preventing drug release at neutral pH. In vitro analysis using the HeLa cell line showed minimal toxicity in blank samples and significant release profile in acidic environment.

Efficient colonic drug delivery in domestic pigs employing a tablet formulation with dual control concept.

Efficient and reproducible colonic drug delivery remains elusive. The aim of this study was to demonstrate specific colonic delivery in vivo in domestic pigs with a novel tablet formulation based on a dual release control concept using 5-aminosalicylic acid (5-ASA) and caffeine as drug substances. The developed controlled colonic release (CCR) tablet formulation employs a pH-sensitive coating based on Eudragit® FS 30 D to prevent drug release in the upper gastrointestinal tract, and a xyloglucan-based matrix to inhibit drug release after coating removal in the small intestine and to allow microbiome-triggered drug release by enzymatic action in the colon. CCR tablets were administered to domestic pigs and plasma concentration data was analyzed by physiologically based pharmacokinetic modeling to estimate absorbed amounts from small and large intestine and in vivo drug release rates by model-dependent deconvolution using immediate release (IR) tablets and intravenous solutions as reference. Peak concentration times (tmax) and values (cmax) of CCR 5-ASA and caffeine tablets indicated strongly delayed drug absorption and the deduced absorbed amount as a function of time confirmed absorption overwhelmingly from the large intestine. The microbially cleaved marker molecule sulfasalazine administered alone or together with caffeine in CCR tablets reported, in combination with telemetry measurements, gastrointestinal transit times and site of absorption. Drug release from CCR tablets was inferred to take place predominantly at the site of absorption at a release rate of caffeine that was much larger in the colon than in the small intestine indicating enzymatically triggered release by the colonic microbiome. Xyloglucanase activity in rectal and cecal samples was consistent with release data and compound recovery in fecal droppings was consistent with 5-ASA bioavailability. The results provide evidence that the developed formulation can prevent premature drug release and provide targeted colonic drug delivery. Clinical relevance based on the comparability between pig and man is discussed.

(091) Preferred Physical Characteristics of Lidocaine Film for Women with Vestibulodynia

Abstract Introduction Vestibulodynia (VBD) is the most common cause of sexual pain in the United States, affecting up to 28% of reproductive-aged women during their lifetime. First-line treatment for VBD includes topical lidocaine therapy prior to vulvovaginal manipulation (tampon use, intercourse, tight clothing) to reduce symptoms. Limitations of topical therapy include messy application, inability to apply to the affected area, and transfer of drugs affecting the sexual partner. The purpose of this study was to describe the physical characteristics of a vulvar film designed for insertional sexual pain in women with VBD to optimize the device design. Objective This study explored individuals’ preferred physical characteristics of lidocaine film for women with Vestibulodynia. Methods Participants completed a blend of demographic and sexual history questionnaires followed by focus group discussions. Participants were eligible if they were 1) heterosexual female, 2) aged 18 to 51 years, 3) able and willing to provide written informed consent 4) have vulvodynia, vestibulodynia, or dyspareunia. Women who reported no episodes or attempts of vaginal intercourse in the prior 18 months were excluded. A total of six semi-structured 60-minute focus group discussions with 3-4 participants each, were audio-recorded, transcribed verbatim, and coded for content. All focus groups had participants of varying socioeconomic status, marital status, age, and racial/ethnic background. Women visually examined a new film technology designed for application to the vulvar vestibule prior to penetration. The device is a U-shaped, thin, and flexible short-acting lidocaine 5% film. The strip is clear, smooth, and has a nonslip texture. To apply the film, an easy-to-remove backing is peeled and applied to the vestibule for 5 minutes. After 5 minutes, lidocaine drug delivery into the vulvar tissue is complete and film is removed, preventing drug release onto partner during intercourse like current topical lidocaine therapy. This study was approved by the University of North Carolina Institutional Review Board. Results Twenty women participated in the focus group portion of the study. Across all groups, the mean age for the participants was 33.3 years, most women were educated with at least some college (93%), white (78.6%), married (75%), and had income greater than $100,000 (50%). Across all groups, 75% of women were interested in trying the commercial device. A major common physical theme that emerged across all groups was the desire for ease and accuracy of use, with an interest in multiple sizes or custom sizes. One group of women desired an additional wing-like vaginal flap to deliver lidocaine beyond the hymenal ring and one group of women desired round/oval shape to reach the upper vestibule. Across all groups, women were interested in the film being loaded with other acceptable medications or in combination with lidocaine. Conclusions Additional research and provider education efforts are needed to better communicate about and treat vulvodynia symptoms provoked by penetrative intercourse. Efforts to support and connect patients with symptoms should be considered. Vulvar films may be an acceptable treatment for vulvar pain provoked by penetrative intercourse. Disclosure No

Development of Novel pH-Sensitive Eudragit Coated Beads Containing Curcumin-Mesalamine Combination for Colon-Specific Drug Delivery.

This research aims to develop a drug delivery system that effectively treats colitis while administering curcumin/mesalamine by coating alginate/chitosan beads with Eudragit® S-100 to target the colon. Beads were tested to determine their physicochemical characteristics. Coating with Eudragit® S-100 prevents drug release at a pH of less than 7; this was demonstrated by in-vitro release conducted in a medium with gradually varying pH to mimic circumstances in various regions of the gastrointestinal tract. This study examined the efficacy of the coated beads in treating acetic acid-induced colitis in rats. Results showed that spherical beads were formed with an average diameter of 1.6-2.8 mm, and the obtained swelling ranged from 409.80% to 890.19%. The calculated entrapment efficiency ranged from 87.49% to 97.89%. The optimized formula F13 (which was composed of mesalamine-curcumin active ingredients, Sodium alginate as a gelling agent, chitosan as a controlled release agent, CaCl2 as a crosslinking agent, and Eudragit S-100 as a pH-sensitive coating agent) demonstrated the best entrapment efficiency (97.89% ± 1.66), swelling (890.19% ± 60.1), and bead size (2.7 ± 0.62 mm). In formulation #13, which was coated with Eudragit S 100, curcumin (6.01 ± 0.04%) and mesalamine (8.64 ± 0.7%), were released after 2 h at pH 1.2; 6.36 ± 0.11% and 10.45 ± 1.52% of curcumin and mesalamine, respectively, were then released after 4 h and at pH 6.8. Meanwhile, at pH 7.4, after 24 h, approximately 85.34 ± 2.3% (curcumin) and 91.5 ± 1.2% (mesalamine) were released. Formula #13 significantly reduced the colitis, and this suggests that the developed hydrogel beads can be used for delivering curcumin-mesalamine combinations to treat ulcerative colitis after adequate research.

Tablet formulation with dual control concept for efficient colonic drug delivery

Aim of this study was to develop a tablet formulation for targeted colonic drug release by implementing two control mechanisms: A pH-sensitive coating layer based on Eudragit® FS 30 D to prevent drug release in the upper gastrointestinal tract, combined with a matrix based on plant-derived polysaccharide xyloglucan to inhibit drug release after coating removal in the small intestine and to allow microbiome triggered drug release in the colon. In vitro dissolution tests simulated the passage through the entire gastrointestinal tract with a four-stage protocol, including microbial xyloglucanase addition in physiologically relevant concentrations as microbiome surrogate to the colonic dissolution medium. Matrix erosion was monitored in parallel to drug release by measurement of reducing sugar equivalents resulting from xyloglucan hydrolysis. Limited drug release in gastric and small intestinal test stages and predominant release in the colonic stage was achieved. The xyloglucan matrix controlled drug release after dissolution of the enteric coating through the formation of a gummy polysaccharide layer at the tablet surface. Matrix degradation was dependent on enzyme concentration in the colonic medium and significantly accelerated drug release resulting in erosion-controlled release process. Drug release at physiologically relevant enzyme concentration was completed within the bounds of colonic transit time. The dual control concept was applicable to two drug substances with different solubility, providing similar release rates in colonic environment containing xyloglucanase. Drug solubility mechanistically affected release, with diffusion of caffeine, but not of 5-ASA, contributing to the overall release rate out of the matrix tablet.

Dual responsive block copolymer coated hollow mesoporous silica nanoparticles for glucose-mediated transcutaneous drug delivery

A self-regulated anti-diabetic drug release device mimicking pancreatic cells is highly desirable for the therapy of diabetes. Herein, a glucose-mediated dual-responsive drug delivery system, which combines pH- and H 2 O 2 -responsive block copolymer grafted hollow mesoporous silica nanoparticles (HMSNs) with microneedle (MN) array patch, has been developed to achieve self-regulated administration. The poly[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate]- b -poly[2-(dimethylamino)ethyl methacrylate] (PPBEM- b -PDM) polymer serves as gate keeper to prevent drug release from the cavity of HMSNs at normoglycemic level. In contrast, the drug release rate is significantly enhanced upon H 2 O 2 and pH stimuli due to the chemical change of H 2 O 2 sensitive PPBEM block and acid responsive PDM block. Therefore, incorporation of anti-diabetic drug and glucose oxidase (GOx, which can oxidize glucose to gluconic acid and in-situ produce H 2 O 2 ) into stimulus polymer coated HMSNs results in a glucose-mediated MN device after depositing the drug-loaded nanoparticles into MN array patch. Both in vitro and in vivo results show this MN device presents a glucose mediated self-regulated drug release characteristic, which possesses a rapid drug release at hyperglycemic level but retarded drug release at normoglycemic level. The result indicates that the fabricated smart drug delivery system is a good candidate for the therapy of diabetes.

Black phosphorus-incorporated titanium dioxide nanotube arrays for near-infrared–triggered drug delivery

Inflammatory reaction after implantation is a serve complication of medical implants. Here, we propose a near-infrared (NIR) light stimulus-responsive drug-eluting platform based on titanium dioxide nanotube (TNT) arrays. Nano-sized black phosphorus (BP) prepared using a liquid exfoliation method served as a photothermal agent and were incorporated with TNTs, imparting TNTs NIR stimulus-responsive activity. The combination of BP and TNTs exhibited excellent photothermal conversion performance. Ibuprofen, a commonly used anti-inflammatory drug, was selected as the model drug and loaded on the NIR-responsive functional TNTs. A coating of 1-tetradecanol (TD) was used as a thermosensitive gatekeeper to prevent drug release at normal body temperature. Upon exposure to NIR light, the NIR-responsive drug delivery system transformed light energy to thermal energy that melted the TD layer and led to drug release from the reservoir. Furthermore, the combination of BP and TNTs showed enhanced biomineralization performance because of the degradation of BP into phosphate. Moreover, BP-modified TNTs showed no obvious cytotoxicity to MC3T3-E1 cells. Thus, this NIR light-responsive drug delivery system shows potential for controlled drug delivery in Ti-based orthopedic implants to overcome the challenges of tissue inflammation after implantation.

Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases

Critical cancer pathways often cannot be targeted because of limited efficiency crossing cell membranes. Here we report the development of a Salmonella-based intracellular delivery system to address this challenge. We engineer genetic circuits that (1) activate the regulator flhDC to drive invasion and (2) induce lysis to release proteins into tumor cells. Released protein drugs diffuse from Salmonella containing vacuoles into the cellular cytoplasm where they interact with their therapeutic targets. Control of invasion with flhDC increases delivery over 500 times. The autonomous triggering of lysis after invasion makes the platform self-limiting and prevents drug release in healthy organs. Bacterial delivery of constitutively active caspase-3 blocks the growth of hepatocellular carcinoma and lung metastases, and increases survival in mice. This success in targeted killing of cancer cells provides critical evidence that this approach will be applicable to a wide range of protein drugs for the treatment of solid tumors.

Colon targeted dosage form of Capecitabine using folic acid anchored modified carbon nanotube: in vitro cytotoxicity, apoptosis and in vivo roentgenographic study

Objective Development of dosage form comprising of Capecitabine loaded carbon nanotubes for its targeted delivery to the colon. Method Single walled carbon nanotubes (SWCNT) were functionalized by -COOH and Chitosan along with Folic acid. Capecitabine was loaded in these SWCNT’s, and the system was analyzed by FTIR, SEM and Raman spectroscopy. Percent drug loading was assessed and the cytotoxicity (COLO320DM and HT29) was verified by using MTT and SRB assay. The apoptosis study was carried out by flowcytometry. The system was enclosed in an enteric coated capsule with pH sensitive polymers and characterized for invitro disintegration, dissolution and invivo roentgenographic studies. Results FTIR, Raman and XRD studies indicated the confirmation of attachments, whereas SEM exhibited size range of 200-500 nm. Drug loading capacity was observed to be 94.63 ± 1.07%. Cytotoxicity studies of Capecitabine and FA–CHI-F-SWCNT-Capecitabine against COLO320DM by using MTT assay showed that FA–CHI-F-SWCNT- Capecitabine exhibited 86.45 ± 0.5788% inhibition whereas pure Capecitabine showed 50.52 ± 0.3106% inhibition. Against HT29, the % inhibition was observed to be 82.76 ± 0.4668% and 56.41 ± 0.2316% respectively for FA–CHI-F-SWCNT-Capecitabine and pure Capecitabine. In case of SRB assay of COLO320DM, the FA–CHI-F-SWCNT-Capecitabine exhibited 89.62 ± 0.4095% inhibition and Capecitabine showed 84.36 ± 0.2559% inhibition, whereas against HT29, FA–CHI-F-SWCNT-Capecitabine showed 81.36 ± 0.2958% inhibition and Capecitabine exhibited 90.62 ± 0.4196% inhibition. Conclusion FA–CHI-F-SWCNT loaded system revealed better cytotoxicity as compared with pure Capecitabine against two different cell lines. Invivo studies revealed that the prepared capsule formulation remained intact in the stomach thereby preventing drug release in the gastric milieu.

Design, Formulation and Characterization of Microspheres containing Mesalamine for the Treatment of Ulcerative Colitis

The purpose of the present study was to prepare, characterize and evaluate the colon-targeted microspheres of mesalamine for the treatment and management of ulcerative colitis (UC). Microspheres were prepared by the ionic-gelation emulsification method using tripolyphosphate (TPP) as cross linking agent. The microspheres were coated with Eudragit S-100 by the solvent evaporation technique to prevent drug release in the stomach. The prepared microspheres were evaluated for surface morphology, entrapment efficiency, drug loading, micromeritic properties and in-vitro drug release. The microspheres formed had rough surface as observed in scanning electron microscopy. The entrapment efficiency of microspheres ranged from 43.72% - 82.27%, drug loading from 20.28% - 33.26%. The size of the prepared microspheres ranged between 61.22-90.41μm which was found to increase with increase in polymer concentration. All values are statistically significant as p<0.05. The release profile of mesalamine from eudragit-coated chitosan micro-spheres was found to be pH dependent. It was observed that Eudragit S100 coated chitosan microspheres gave no release in the simulated gastric fluid, negligible release in the simulated intestinal fluid and maximum release in the colonic environment. It was concluded from the study that Eudragit-coated chitosan microspheres were promising carriers for colon-targeted delivery of Mesalamine.

Development polymeric micellar system for targeted delivery of antitumor drugs

Asymmetric block copolymers PAAc-b-PAAm (DBC) and PAAm-b-PAAc-b-PAAm (TBC) comprised poly(acrylic acid) and polyacrylamide have been evaluated as potential vehicles for doxorubicin (Dox) targeted delivery. The processes of Dox release from the DBC and TBC micelles under the influence of the drug’s concentration gradient and various surrounding medium, such as NaCl solution and aqueous medium at pH= 5.75 and 9, were examined. The previously established tendency to significantly reduce the Dox encapsulation degree by the DBC and TBC micelles at the increase of the size of their “corona” was fully confirmed (Kunitskaya et al. 2018). Noticed that PAAm block’s lengthening complicated the Dox release against all environments under study. It was revealed that micelles which easily and effectively encapsulate Dox as easily "give away" the drug during dialysis. Increasing pH of the DBC and TBC solutions to 9 prevented drug release. It can be stipulated by enhancing interaction between Dox and micellar “core” caused by the ionization of –COOH groups contained in PAAc blocks. Preliminary biological investigations in vitro against human T-leukemia cells demonstrate essential anticancer activity of Dox/DBC and Dox/TDC compositions, as compared to pure Dox.

DEVELOPMENT AND EVALUATION OF A NOVEL TIME AND PH-DEPENDENT COLON TARGETED DRUG DELIVERY OF ORNIDAZOLE

Objective: The anti-amoebic drug Ornidazole was developed in this study as a novel colon-specific drug delivery method for the treatment of colonic diseases such as diverticulitis, inflammatory bowel syndrome, and Crohn’s disease. Pectin forms a matrix with a pH-sensitive polymeric coating that prevents drug release in the upper gastrointestinal tract, thereby addressing solubility issues. Pectin is sometimes used as an adsorbent, bulk-forming agent.
 Methods: Ornidazole-containing core tablets were directly compressed. Ornidazole compression coated tablets were formulated with varying polymer proportions in the coat. All the tablets were studied for weight uniformity, hardness, friability, drug content, and in vitro dissolution tests
 Results: All formulations demonstrated good Fourier-transform infrared compliance and no interaction between drug, polymer, and other excipients. The study’s findings show that the formulation F6 coated with Eudragit RS 100 had a drug release of 99.230.8 for 24 h.
 Conclusion: As a result, (F6) is regarded as the optimal formulation. The pH in the colon causes the release of Ornidazole from tablets.

Preparation of Novel Functional Drug Particles Embedded in a Gelling-Swelling Layer (PEGS) for Taste Masking and Subsequent Rapid Drug Release.

The purpose of this research was to develop novel functional drug particles embedded in a gelling-swelling layer (PEGS) which are capable of achieving both taste-masking of unpalatable drugs and rapid drug elution. The functional particles had a three-layer structure consisting of a core drug layer, a gelling-swelling layer and an outer water-penetration control layer containing a water-insoluble polymer. The concept of formulation design was as follows: when water reaches the gelling-swelling layer, pulverized fine gelling-swelling particles gellate and swell from water absorption to form a rigid layer, thereby preventing drug release. After a defined lag time, the increased volume of the gelling-swelling layer breaks down the outer water-penetration control layer, leading to rapid drug release. In order to adapt this system for use in orally disintegrating tablets, PEGS were prepared at a size of about 250 µm using a fine particle-coating method. Ambroxol hydrochloride was used as a model drug for bitterness and the effects of different gelling-swelling agents and water-insoluble polymers on drug release characteristics from PEGS were examined. In in vitro dissolution tests, it was shown that the drug dissolution rate from PEGS could be suppressed to about 5% after 2 min and increased to more than 85% after 30 min by adjusting the composition and thickness of the outer layer. The PEGS expanded about 1.5-fold and the outer layer was ruptured after 5 min in water.

Polymer-grafted hollow mesoporous silica nanoparticles integrated with microneedle patches for glucose-responsive drug delivery

A glucose-mediated drug delivery system would be highly satisfactory for diabetes diagnosis since it can intelligently release drug based on blood glucose levels. Herein, a glucose-responsive drug delivery system by integrating glucose-responsive poly(3-acrylamidophenylboronic acid) (PAPBA) functionalized hollow mesoporous silica nanoparticles (HMSNs) with transcutaneous microneedles (MNs) has been designed. The grafted PAPBA serves as gatekeeper to prevent drug release from HMSNs at normoglycemic levels. In contrast, faster drug release is detected at a typical hyperglycemic level, which is due to the change of hydrophilicity of PAPBA at high glucose concentration. After transdermal administration to diabetic rats, an effective hypoglycemic effect is achieved compared with that of subcutaneous injection. These observations indicate that the designed glucose-responsive drug delivery system has a potential application in diabetes treatment.

Effect of chemical linkers of curcumin conjugated hyaluronic acid on nanoparticle properties and in vitro performances in various cancer cells

Chemical linkers play an important role in determining the physicochemical properties, stability and cytotoxic activities of nanoparticles for cancer treatment. Herein, curcumin (CUR) and hyaluronic acid (HA) conjugate nanoparticles with two different chemical linkers were compared in terms of their physicochemical properties and cytotoxicity to various cancer cells. CUR (10–50 mol%) was grafted onto HA backbones using ester (non-pH-sensitive) and hydrazone (pH-sensitive) bonds. All CUR-HA conjugates were able to self-assemble in aqueous medium to form nanoparticles. The conjugates with the hydrazone bonds showed lower critical aggregation concentration (CAC) values than those with the ester bonds. Particle sizes decreased when the loading of CUR increased from 10 mol% to 30 mol% but increased from 30 mol% to 50 mol% CUR. The 30 mol% CUR-HA nanoparticles with the hydrazone bonds (30ChH) showed the smallest particle size, which was slightly smaller than those with the ester bonds (30CeH). The stability of 30ChH was better than that of 30CeH, as observed by the unchanged particle size and zeta potential over 14 days. The in vitro CUR release from 30ChH at pH 7.4 was lower than that of 30CeH, suggesting that 30ChH would remain stable in blood circulation. The in vitro cytotoxicity study demonstrated that both CUR-HA conjugates significantly induced higher cytotoxicity and inhibition of cell proliferation than CUR solution in all cell lines tested (A549, PANC-1, HCT116 and Caco-2). In summary, the chemical linkers of the CUR-HA conjugates affected the physicochemical properties of the nanoparticles. The CUR-HA conjugates with pH-sensitive linkers showed greater stability and prevented drug release at physiological pH but showed high CUR release in the acidic environment of cancer cells, which indicates the potential for cancer therapy.

Preparation of responsive "dual-lock" nanoparticles and their application in collaborative therapy based on CuS coordination.

It is difficult for drug delivery systems to release drugs as expected, often leading to undesired side effects. To solve this problem, a CuS@MSN/DOX@MnO2@membrane (CMDMm) was reasonably designed. It was introduced to release the drug by a double response, similar to using two keys to open two locks at the same time for one door. CuS@MSN was used as a photothermal therapy (PTT) material and carrier, and then the surface of CuS@MSN/DOX was sealed by MnO2 to prevent drug release in advance. MnO2 could be reduced and degraded in a tumor microenvironment. It was applied in MR imaging due to the T1 magnetism of Mn2+ following the reduction of MnO2. Finally, the 4T1 cell membrane was extracted and coated onto the surface of CuS@MSN/DOX@MnO2, which served as a target for 4T1 tumor cells. A noteworthy phenomenon was that the fluorescence of DOX was quenched by the coordination between DOX and CuS, and this greatly improved the interaction between DOX and CuS@MSN. However, the coordination was weakened when DOX was protonated in a tumor microenvironment (∼pH 5.0), leading to the release of DOX and fluorescence recovery. The drug release experiments showed that the release efficiency was higher at pH 5.0 with 10 mmol L-1 GSH. Through in vitro laser confocal imaging, it was successfully observed that DOX was reliably released in specific tumor cells according to the fluorescence recovery, and that there was no leakage in other cells. In short, effective double response drug release was successfully confirmed.

Colitis-targeted hybrid nanoparticles-in-microparticles system for the treatment of ulcerative colitis

Nanoparticle (NP)-based drug delivery systems accumulate in the disrupted epithelium of inflamed colon tissue in ulcerative colitis. However, premature early drug release and uptake or degradation of NPs during their passage through the harsh gastric or intestinal environment compromise their therapeutic outcomes. This study aimed to develop an advanced colitis-targeted hybrid nanoparticles-in-microparticles (NPsinMPs) drug delivery system to overcome the aforementioned challenges. First, sustained drug releasing poly(lactic-co-glycolic acid) NPs were generated and further encapsulated in pH-sensitive Eudragit FS30D MPs to ensure complete drug protection in a gastric-like pH and for selective delivery of NPs to the colon. SEM and confocal microscopy for the NPsinMPs revealed successful NP encapsulation. NPsinMPs prevented drug release in an acidic gastric-like and intestinal-like pH and presented a sustained release thereafter at an ileal and colonic pH, indicating the degradation of the outer pH-sensitive MPs and release of NPs. Furthermore, in vivo imaging of gastrointestinal tract of a colitis mouse orally administered with fluorescent NPsinMPs revealed higher fluorescence intensities selectively in the colon, demonstrating the release of loaded NPs and their concomitant accumulation at the site of colon inflammation. NPsinMPs markedly mitigated experimental colitis in mice indicated by improved histopathological analysis, decreased myeloperoxidase activity, neutrophils and macrophage infiltration, and expression of proinflammatory cytokines in colonic tissues compared with NP-treated mice. The present results show the successful formulation of an NPsinMP-based drug delivery system and provide a platform to improve NP-based colon-targeted drug delivery through improved protection of encapsulated NPs and their payload in the early small intestine.

Formulation and evaluation of lansoprazole loaded enteric coated microspheres

The research focuses on the development of multiparticulate delivery system for acid-labile Lansoprazole to prevent its degradation in the acidic environment of the stomach and enhance its bioavailability via intestinal absorption. This problem can be solved by enteric coating. In this project, cellulose acetate phthalate a polymer usually utilized for gastrointestinal film coating of tablets, was used to prepare enteric microspheres of lansoprazole with solvent evaporation technique in various formulations such as F1, F2, F3, F4, F5 with drug: polymer ratios of 1:1, 1:2, 1:3, 1:4, 1:5 respectively. FTIR study indicated compatibility between drug and polymer. Increase in concentration of polymer increased spheriocity and mean diameter of the microspheres. The drug entrapment efficiency was in the range of 72.23% to 88.64%. SEM revealed that microspheres were found spherical and porous. In-vitro study proves that drug release slowly increases as the pH of the medium increased and prevents degradation of drug in acidic pH. In-vitro drug release was found to be 92.80%, 94.55%, 92.72%, 96.34%, 98.65% in all 5 formulations. All 5 formulations showed gastric resistance around 80-90%. So it is concluded that the developed enteric coated microspheres of Lansoprazole prevented drug release in the stomach which would lead to significant improvement in its bioavailability through enhanced intestinal absorption.