Novel Rhinological Application of Polylactic Acid-An In Vitro Study.

A novel approach to the treatment of sinusitis is the use of nasal stents. The stent is loaded with a corticosteroid, which prevents complications in the wound-healing process. The design is such that it will prevent the sinus from closing again. The stent is 3D printed using a fused deposition modeling printer, which enhances the customization. The polymer utilized for the purpose of 3D printing is polylactic acid (PLA). The compatibility between the drugs and polymers is confirmed by FT-IR and DSC. The drug is loaded onto the polymer by soaking the stent in the drug's solvent, known as the solvent casting method. Using this method, approximately 68% of drug loading is found to be achieved onto the PLA filaments, and a total of 72.8% of drug loading is obtained in terms of the 3D-printed stent. Drug loading is confirmed by the morphological characteristics of the stent by SEM, where the loaded drug is clearly visible as white specks on the surface of the stent. Drug release characterization is conducted by dissolution studies, which also confirm drug loading. The dissolution studies show that the release of drugs from the stent is constant and not erratic. Biodegradation studies were conducted after increasing the rate of degradation of PLA by soaking it in PBS for a predetermined duration of time. The mechanical properties of the stent, such as stress factor and maximum displacement, are discussed. The stent has a hairpin-like mechanism for opening inside the nasal cavity.

Quality-by-Design-Assisted Optimization of Carvacrol Oil-Loaded Niosomal Gel for Anti-Inflammatory Efficacy by Topical Route.

Niosomes are multilamellar vesicles that effectively transfer active ingredients into the skin's layers. To improve the active substance's penetration across the skin, these carriers are frequently utilized as topical drug delivery systems. Essential oils (EOs) have garnered significant interest in the field of research and development owing to their various pharmacological activities, cost-effectiveness, and simple manufacturing techniques. However, these ingredients undergo degradation and oxidation over time, leading to a loss of functionality. Niosome formulations have been developed to deal with these challenges. The main goal of this work was to create a niosomal gel of carvacrol oil (CVC) to improve its penetration into the skin for anti-inflammatory actions and stability. By changing the ratio of drug, cholesterol and surfactant, various formulations of CVC niosomes were formulated using Box Behnken Design (BBD). A thin-film hydration technique using a rotary evaporator was employed for the development of niosomes. Following optimization, the CVC-loaded niosomes had shown: 180.23 nm, 0.265, -31.70 mV, and 90.61% of vesicle size, PDI, zeta potential, and EE%. An in vitro study on drug release discovered the rates of drug release for CVC-Ns and CVC suspension, which were found to be 70.24 ± 1.21 and 32.87 ± 1.03, respectively. The release of CVC from niosomes best fit the Higuchi model, and the Korsmeyer-Peppas model suggests that the release of the drug followed the non-Fickian diffusion. In a dermatokinetic investigation, niosome gel significantly increased CVC transport in the skin layers when compared to CVC-conventional formulation gel (CVC-CFG). Confocal laser scanning microscopy (CLSM) of rat skin exposed to the rhodamine B-loaded niosome formulation showed a deeper penetration of 25.0 µm compared to the hydroalcoholic rhodamine B solution (5.0 µm). Additionally, the CVC-N gel antioxidant activity was higher than that of free CVC. The formulation coded F4 was selected as the optimized formulation and then gelled with carbopol to improve its topical application. Niosomal gel underwent tests for pH determination, spreadability, texture analysis, and CLSM. Our findings imply that the niosomal gel formulations could represent a potential strategy for the topical delivery of CVC in the treatment of inflammatory disease.

Therapeutic Delivery of Tumor Suppressor miRNAs for Breast Cancer Treatment.

The death rate from breast cancer (BC) has dropped due to early detection and sophisticated therapeutic options, yet drug resistance and relapse remain barriers to effective, systematic treatment. Multiple mechanisms underlying miRNAs appear crucial in practically every aspect of cancer progression, including carcinogenesis, metastasis, and drug resistance, as evidenced by the elucidation of drug resistance. Non-coding RNAs called microRNAs (miRNAs) attach to complementary messenger RNAs and degrade them to inhibit the expression and translation to proteins. Evidence suggests that miRNAs play a vital role in developing numerous diseases, including cancer. They affect genes critical for cellular differentiation, proliferation, apoptosis, and metabolism. Recently studies have demonstrated that miRNAs serve as valuable biomarkers for BC. The contrast in the expression of miRNAs in normal tissue cells and tumors suggest that miRNAs are involved in breast cancer. The important aspect behind cancer etiology is the deregulation of miRNAs that can specifically influence cellular physiology. The main objective of this review is to emphasize the role and therapeutic capacity of tumor suppressor miRNAs in BC and the advancement in the delivery system that can deliver miRNAs specifically to cancerous cells. Various approaches are used to deliver these miRNAs to the cancer cells with the help of carrier molecules, like nanoparticles, poly D, L-lactic-co-glycolic acid (PLGA) particles, PEI polymers, modified extracellular vesicles, dendrimers, and liposomes. Additionally, we discuss advanced strategies of TS miRNA delivery techniques such as viral delivery, self-assembled RNA-triple-helix hydrogel drug delivery systems, and hyaluronic acid/protamine sulfate inter-polyelectrolyte complexes. Subsequently, we discuss challenges and prospects on TS miRNA therapeutic delivery in BC management so that miRNAs will become a routine technique in developing individualized patient profiles.

Nanomaterials-Based Novel Immune Strategies in Clinical Translation for Cancer Therapy.

Immunotherapy shows a lot of promise for addressing the problems with traditional cancer treatments. Researchers and clinicians are working to create innovative immunological techniques for cancer detection and treatment that are more selective and have lower toxicity. An emerging field in cancer therapy, immunomodulation offers patients an alternate approach to treating cancer. These therapies use the host's natural defensive systems to identify and remove malignant cells in a targeted manner. Cancer treatment is now undergoing somewhat of a revolution due to recent developments in nanotechnology. Diverse nanomaterials (NMs) have been employed to overcome the limits of conventional anti-cancer treatments such as cytotoxic, surgery, radiation, and chemotherapy. Aside from that, NMs could interact with live cells and influence immune responses. In contrast, unexpected adverse effects such as necrosis, hypersensitivity, and inflammation might result from the immune system (IS)'s interaction with NMs. Therefore, to ensure the efficacy of immunomodulatory nanomaterials, it is essential to have a comprehensive understanding of the intricate interplay that exists between the IS and NMs. This review intends to present an overview of the current achievements, challenges, and improvements in using immunomodulatory nanomaterials (iNMs) for cancer therapy, with an emphasis on elucidating the mechanisms involved in the interaction between NMs and the immune system of the host.

Prospective Epigenetic Actions of Organo-Sulfur Compounds against Cancer: Perspectives and Molecular Mechanisms.

Major epigenetic alterations, such as chromatin modifications, DNA methylation, and miRNA regulation, have gained greater attention and play significant roles in oncogenesis, representing a new paradigm in our understanding of cancer susceptibility. These epigenetic changes, particularly aberrant promoter hypermethylation, abnormal histone acetylation, and miRNA dysregulation, represent a set of epigenetic patterns that contribute to inappropriate gene silencing at every stage of cancer progression. Notably, the cancer epigenome possesses various HDACs and DNMTs, which participate in the histone modifications and DNA methylation. As a result, there is an unmet need for developing the epigenetic inhibitors against HDACs and DNMTs for cancer therapy. To date, several epigenetically active synthetic inhibitors of DNA methyltransferases and histone deacetylases have been developed. However, a growing body of research reports that most of these synthetic inhibitors have significant side effects and a narrow window of specificity for cancer cells. Targeting tumor epigenetics with phytocompounds that have the capacity to modulate abnormal DNA methylation, histone acetylation, and miRNAs expression is one of the evolving strategies for cancer prevention. Encouragingly, there are many bioactive phytochemicals, including organo-sulfur compounds that have been shown to alter the expression of key tumor suppressor genes, oncogenes, and oncogenic miRNAs through modulation of DNA methylation and histones in cancer. In addition to vitamins and microelements, dietary phytochemicals such as sulforaphane, PEITC, BITC, DADS, and allicin are among a growing list of naturally occurring anticancer agents that have been studied as an alternative strategy for cancer treatment and prevention. Moreover, these bioactive organo-sulfur compounds, either alone or in combination with other standard cancer drugs or phytochemicals, showed promising results against many cancers. Here, we particularly summarize and focus on the impact of specific organo-sulfur compounds on DNA methylation and histone modifications through targeting the expression of different DNMTs and HDACs that are of particular interest in cancer therapy and prevention.

A novel RP-HPLC method development and validation for simultaneous quantification of gefitinib and resveratrol in polymeric hybrid lipid nanoparticles and glioma cells.

Resveratrol and Gefitinib are adjunct therapies for various cancers; however, both have been limited by low solubility, low cellular uptake, and bioavailability issues. As a result, this research aimed to develop an accurate, precise, selective, and sensitive reverse-phase high-performance liquid chromatography (RP-HPLC) method to simultaneously determine both compounds in nanoformulation and Glioma cells. The phenomenex luna C8 column, a mobile phase (80: 20 ratios of acetonitrile: 200 mM ammonium acetate) with a flow rate of 1 mL. min-1, 40 ± 0.2 °C as a column temperature, and the injection volume was 20 µl were selected as optimized chromatographic conditions. Retention time (RT) of resveratrol (1.80 min) and gefitinib (2.56 min) were identified using an optimized analytical method and detected at 345 nm (isosbestic point). The approach was proven to be specific for resveratrol and gefitinib analysis in the existence of PHLNPs, precise (RSD 2 %), and accurate (>90 %). The simultaneous analytical method was successfully developed to identify percentage drug entrapment efficiency (% DEE), % drug loading (% DL) of resveratrol and gefitinib in PHLNPs, and secondary estimates of in-vitro drug release profile and percentage cellular uptake studies. The in-vitro results revealed that the developed analytical method could simultaneously detect and quantify these drugs in other nanoformulations and in-vivo studies.

Novel Drug Delivery Systems as an Emerging Platform for Stomach Cancer Therapy.

Cancer has long been regarded as one of the world's most fatal diseases, claiming the lives of countless individuals each year. Stomach cancer is a prevalent cancer that has recently reached a high number of fatalities. It continues to be one of the most fatal cancer forms, requiring immediate attention due to its low overall survival rate. Early detection and appropriate therapy are, perhaps, of the most difficult challenges in the fight against stomach cancer. We focused on positive tactics for stomach cancer therapy in this paper, and we went over the most current advancements and progressions of nanotechnology-based systems in modern drug delivery and therapies in great detail. Recent therapeutic tactics used in nanotechnology-based delivery of drugs aim to improve cellular absorption, pharmacokinetics, and anticancer drug efficacy, allowing for more precise targeting of specific agents for effective stomach cancer treatment. The current review also provides information on ongoing research aimed at improving the curative effectiveness of existing anti-stomach cancer medicines. All these crucial matters discussed under one overarching title will be extremely useful to readers who are working on developing multi-functional nano-constructs for improved diagnosis and treatment of stomach cancer.

Anti-Proliferative Potential of Quercetin Loaded Polymeric Mixed Micelles on Rat C6 and Human U87MG Glioma Cells.

Quercetin (Qu) is a natural flavonoid present in many commonly consumed food items and is also identified as a potential anticancer agent. The present study evaluates the Qu-loaded polymeric mixed micelles (Qu-PMMs) against C6 and U87MG glioma cell lines. The Box-Behnken Design (BBD) was employed to study the influence of independent variables such as Soluplus, Vitamin-E polyethyleneglycol-1000 succinate (E-TPGS), and poloxamer 407 concentrations on dependent variables including particle size (PS), polydispersity index (PDI), and percentage entrapment efficiency (%EE) of the prepared Qu-PMMs. The Qu-PMMs were further characterized by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Scanning Electron Microscope (SEM), and were assessed for in vitro drug release, effect on cell viability, migration, cellular uptake, and apoptosis assays. The PS, PDI, and % EE of the optimized PMMs were 107.16 ± 1.06 nm, 0.236 ± 0.053, and 77.46 ± 1.94%, respectively. The FTIR and XRD revealed that the Qu was completely entrapped inside the PMMs. The SEM analysis confirmed the spherical shape of micelles. The in vitro cell viability study showed that the Qu-PMMs had 1.7 times higher cytotoxicity against C6 and U87MG cells than Qu pure drug (Qu-PD). Furthermore, Qu-PMMs demonstrated superior cellular uptake, inhibited migration, and induced apoptosis when tested against C6 and U87MG cells than pure Qu. Thus, the polymeric mixed micelle (PMMs) enhanced the therapeutic effect of Qu and can be considered an effective therapeutic strategy to treat Glioma.

Development and Characterization of Oral Raft Forming In Situ Gelling System of Neratinib Anticancer Drug Using 32 Factorial Design.

Neratinib (NTB) is an irreversible inhibitor of pan-human epidermal growth factor receptor (HER-2) tyrosine kinase and is used in the treatment of breast cancer. It is a poorly aqueous soluble drug and exhibits extremely low oral bioavailability at higher pH, leading to a diminishing of the therapeutic effects in the GIT. The main objective of the research was to formulate an oral raft-forming in situ gelling system of NTB to improve gastric retention and drug release in a controlled manner and remain floating in the stomach for a prolonged time. In this study, NTB solubility was enhanced by polyethylene glycol (PEG)-based solid dispersions (SDs), and an in situ gelling system was developed and optimized by a two-factor at three-level (32) factorial design. It was analyzed to study the impact of two independent variables viz sodium alginate [A] and HPMC K4M [B] on the responses, such as floating lag time, percentage (%) water uptake at 2 h, and % drug release at 6 h and 12 h. Among various SDs prepared using PEG 6000, formulation 1:3 showed the highest drug solubility. FT-IR spectra revealed no interactions between the drug and the polymer. The percentage of drug content in NTB SDs ranged from 96.22 ± 1.67% to 97.70 ± 1.89%. The developed in situ gel formulations exhibited a pH value of approximately 7. An in vitro gelation study of the in situ gel formulation showed immediate gelation and was retained for a longer period. From the obtained results of 32 factorial designs, it was observed that all the selected factors had a significant effect on the chosen response, supporting the precision of design employed for optimization. Thus, the developed oral raft-forming in situ gelling system of NTB can be a promising and alternate approach to enhance retention in the stomach and to attain sustained release of drug by floating, thereby augmenting the therapeutic efficacy of NTB.

Characterization of cisplatin-loaded chitosan nanoparticles and rituximab-linked surfaces as target-specific injectable nano-formulations for combating cancer.

The present study was carried out to develop cisplatin-loaded chitosan nanoparticles (CCNP) and cisplatin-loaded chitosan nanoparticle surface linked to rituximab (mAbCCNP) as targeted delivery formulations. The two formulations (CCNP and mAbCCNP) exhibited significant physicochemical properties. The zetapotential (ZP) values of CCNP and mAbCCNP were 30.50 ± 5.64 and 26.90 ± 9.09 mV, respectively; while their particle sizes were 308.10 ± 1.10 and 349.40 ± 3.20 z.d.nm, respectively. The poly dispersity index (PDI) of CCNP was 0.257 ± 0.030 (66.6% PDI), while that of mAbCCNP was 0.444 ± 0.007 (57.60% PDI). Differential scanning calorimetry (DSC) revealed that CCNP had endothermic peaks at temperatures ranging from 135.50 to 157.69 °C. A sharp exothermic peak was observed at 95.79 °C, and an endothermic peak was observed at 166.60 °C. The XRD study on CCNP and mAbCCNP revealed distinct peaks at 2θ. Four peaks at 35.38°, 37.47°, 49.29°, and 59.94° corresponded to CCNP, while three distinct peaks at 36.6°, 49.12°, and 55.08° corresponded to mAbCCNP. The in vitro release of cisplatin from nanoparticles followed zero order kinetics in both CCNP and mAbCCNP. The profile for CCNP showed 43.80% release of cisplatin in 6 h (R2 = 0.9322), indicating linearity of release with minimal deviation. However, the release profile of mAbCCNP showed 22.52% release in 4 h (R2 = 0.9416), indicating linearity with sustained release. In vitro cytotoxicity studies on MCF-7 ATCC human breast cancer cell line showed that CCNP exerted good cytotoxicity, with IC50 of 4.085 ± 0.065 µg/mL. However, mAbCCNP did not elicit any cytotoxic effect. At a dose of 4.00 µg/mL cisplatin induced early apoptosis and late apoptosis, chromatin condensation, while it produced secondary necrosis at a dose of 8.00 µg/mL. Potential delivery system for cisplatin CCNP and mAbCCNP were successfully formulated. The results indicated that CCNP was a more successful formulation than mAbCCNP due to lack of specificity of rituximab against MCF-7 ATCC human breast cancer cells.

Effect of Altitude Level on Surgical Outcomes of Laparoscopic Sleeve Gastrectomy for Patients With Morbid Obesity: A Multicentre Prospective Study.

BACKGROUND: This study aimed to evaluate the impact of altitude level on surgical outcomes of laparoscopic sleeve gastrectomy (LSG) for patients with morbid obesity. METHODS: At the normal altitude level, 808 patients underwent LSG, and 467 patients underwent LSG in high-altitude regions. The primary outcome was evaluated based on the postoperative morbidity rate. Secondary outcomes were evaluated based on operating time, mortality, hospital stay, percentage of total weight loss (TWL), and comorbidities improvement. RESULTS: No significant differences were noted in-hospital stay, time to start oral intake, gastric leakage, overall complications, and hospital mortality between the 2 groups. Deep vein thrombosis, pulmonary embolism, and mesenteric vascular occlusion were significantly higher in high altitude [11 (1.3%) vs. 14 (3%), P=0.04; 8 (0.7%) vs. 11 (2.4%), P=0.01; 4 (0.5%) vs. 8 (1.7%), P=0.03, respectively]. Patients with normal altitude recorded a better %TWL than those at high altitude after 12 months (41±9 vs. 39±9.6, P=0.002) and after 24 months (41±8 vs. 40±9, P=0.009). In both groups, a significant improvement was noted in comorbidity after LSG. CONCLUSION: The %TWL significantly achieved with LSG in normal and high altitudes. After 12 and 24 months, the %TWL is significantly higher with LSG at normal altitudes. High altitude is associated with a high incidence of deep vein thrombosis, pulmonary embolism, and superior mesenteric vascular occlusion with LSG.

Carbon Nanotubes: Current Perspectives on Diverse Applications in Targeted Drug Delivery and Therapies.

Current discoveries as well as research findings on various types of carbon nanostructures have inspired research into their utilization in a number of fields. These carbon nanostructures offer uses in pharmacy, medicine and different therapies. One such unique carbon nanostructure includes carbon nanotubes (CNTs), which are one-dimensional allotropes of carbon nanostructure that can have a length-to-diameter ratio greater than 1,000,000. After their discovery, CNTs have drawn extensive research attention due to their excellent material properties. Their physical, chemical and electronic properties are excellent and their composites provide great possibilities for enormous nanometer applications. The current study provides a systematic review based on prior literature review and data gathered from various sources. The various research studies from many research labs and organizations were systematically retrieved, collected, compiled and written. The entire collection and compilation of this review concluded the use of CNT approaches and their efficacy and safety for the treatment of various diseases such as brain tumors or cancer via nanotechnology-based drug delivery, phototherapy, gene therapy, antiviral therapy, antifungal therapy, antibacterial therapy and other biomedical applications. The current review covers diverse applications of CNTs in designing a range of targeted drug delivery systems and application for various therapies. It concludes with a discussion on how CNTs based medicines can expand in the future.

Solubility Determination, Hansen Solubility Parameters and Thermodynamic Evaluation of Thymoquinone in (Isopropanol + Water) Compositions.

This article studies the solubility, Hansen solubility parameters (HSPs), and thermodynamic behavior of a naturally-derived bioactive thymoquinone (TQ) in different binary combinations of isopropanol (IPA) and water (H2O). The mole fraction solubilities (x3) of TQ in various (IPA + H2O) compositions are measured at 298.2-318.2 K and 0.1 MPa. The HSPs of TQ, neat IPA, neat H2O, and binary (IPA + H2O) compositions free of TQ are also determined. The x3 data of TQ are regressed by van't Hoff, Apelblat, Yalkowsky-Roseman, Buchowski-Ksiazczak λh, Jouyban-Acree, and Jouyban-Acree-van't Hoff models. The maximum and minimum x3 values of TQ are recorded in neat IPA (7.63 × 10-2 at 318.2 K) and neat H2O (8.25 × 10-5 at 298.2 K), respectively. The solubility of TQ is recorded as increasing with the rise in temperature and IPA mass fraction in all (IPA + H2O) mixtures, including pure IPA and pure H2O. The HSP of TQ is similar to that of pure IPA, suggesting the great potential of IPA in TQ solubilization. The maximum molecular solute-solvent interactions are found in TQ-IPA compared to TQ-H2O. A thermodynamic study indicates an endothermic and entropy-driven dissolution of TQ in all (IPA + H2O) mixtures, including pure IPA and pure H2O.

Clinically Significant Fatigue in Adult Leukemia Patients: Prevalence, Predictors, and Impact on Quality of Life.

Background Cancer-related fatigue (CRF) is a common distressing symptom in leukemia patients. CRF becomes clinically significant fatigue (CSF) when adversely affects health-related quality of life (HRQoL) and warrants further workup, referrals, and treatment. Objective: To assess the prevalence and predictors of CSF and assesses its impact on HRQoL in adult leukemia patients. Method Analysis was performed on 168 leukemia patients. The primary study outcomes were CSF (score ≥4) as measured by the fatigue numerical rating scale and HRQoL using a validated Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) scale. Result The prevalence of CSF was 89 (53%), with a mean score of 6.66±2.02. About 106 (63.1%) of leukemia patients had poor Health-related quality of life (HRQoL) (102.61±23.50). Overall, FACT-Leu mean score indicated that study participants had poor HRQoL (114.70±29.67). There was a statistically significant difference in HRQoL between the patients with CSF 104.89±28.82 and Non-CSF 125.76±26.71, p<0.001. Poor appetite (odd ratio: 3.02 [95% CI: 1.33-6.85]) was statistically significant predictors (p<0.010) of CSF. Dependence on caregiver (odd ratio: 3.31 [95% CI: 0.41-0.75]) and having non-CSF (odd ratio: 5.22 [95% CI: 2.44-11.19]) were found statistically significant predictors of good HRQoL. Conclusion CSF is prevalent among leukemia patients, and adversely affects their HRQoL. Holistic assessment and supportive care are needed to reduce the burden of CSF and improve leukemia patients HRQoL.

Effective co-delivery of doxorubicin and dasatinib using a PEG-Fmoc nanocarrier for combination cancer chemotherapy.

A simple PEGylated peptidic nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-Cbz-lysine)2 (PLFCL), was developed for effective co-delivery of doxorubicin (DOX) and dasatinib (DAS) for combination chemotherapy. Significant synergy of DOX and DAS in inhibition of cancer cell proliferation was demonstrated in various types of cancer cells, including breast, prostate, and colon cancers. Co-encapsulation of the two agents was facilitated by incorporation of 9-Fluorenylmethoxycarbonyl (Fmoc) and carboxybenzyl (Cbz) groups into a nanocarrier for effective carrier-drug interactions. Spherical nanomicelles with a small size of ∼30 nm were self-assembled by PLFCL. Strong carrier/drug intermolecular π-π stacking was demonstrated in fluorescence quenching and UV absorption. Fluorescence study showed more effective accumulation of DOX in nuclei of cancer cells following treatment with DOX&DAS/PLFCL in comparison with cells treated with DOX/PLFCL. DOX&DAS/PLFCL micelles were also more effective than other treatments in inhibiting the proliferation and migration of cultured cancer cells. Finally, a superior anti-tumor activity was demonstrated with DOX&DAS/PLFCL. A tumor growth inhibition rate of 95% was achieved at a respective dose of 5 mg/kg for DOX and DAS in a murine breast cancer model. Our nanocarrier may represent a simple and effective system that could facilitate clinical translation of this promising multi-agent regimen in combination chemotherapy.

The self-assembling camptothecin-tocopherol prodrug: An effective approach for formulating camptothecin.

Camptothecin (CPT) is a potent antitumor agent and functions via inhibiting the activity of topoisomerase I during DNA replication. However, the clinical application of CPT has been greatly hindered by its extremely poor solubility, the instability of its active lactone ring in blood stream, as well as the non-specific toxicity to normal tissues. In addition, most of the formulations developed so far are not applicable for formulating CPT. In this study, two novel CPT prodrugs were developed by conjugating CPT to α-tocopherol via a carbonate ester bond (CPT-VE) or disulfide linkage (CPT-S-S-VE). Both CPT prodrugs were able to self-assemble into nanofibers with the facilitation of a PEG5K-Fmoc-VE2-based nanomicellar carrier. Both prodrug nanoassemblies exhibited excellent stability. Fluorescence quenching, UV absorbance, and FT-IR studies demonstrated strong interactions between carrier and prodrugs, including hydrophobic interaction, π-π stacking, as well as hydrogen bonding. NMR studies suggested that prodrugs were successfully incorporated into PEG5K-Fmoc-VE2 during self-assembly process. In vitro, PEG5K-Fmoc-VE2/CPT-S-S-VE presented significantly higher level of cytotoxicity on tumor cells compared to PEG5K-Fmoc-VE2/CPT-VE. Biodistribution study showed that CPT-S-S-VE formulated in PEG5K-Fmoc-VE2 micelles was effectively converted to parent CPT following delivery to tumor tissues. Finally, PEG5K-Fmoc-VE2/CPT-S-S-VE nanofibers showed superior tumor growth inhibition in an aggressive murine breast cancer model (4T1.2).

Tunable pH-Responsive Polymeric Micelle for Cancer Treatment.

The development of bioresponsive polymers is important in drug delivery systems. Herein, we reported the construction of a series of pH-sensitive micelles by conjugating the hydrophilic polyethylene glycol (PEG) segment to a hydrophobic farnesylthiosalicylate derivative, FTS-hydrazide (FTS-H), with a hydrazone linker, whose cleavability can be conveniently modulated by choosing various lengths of the carbon chain or appropriate electron-withdrawing groups with different steric environment around the hydrazone linker. We examined the hydrolysis rates of these pH-sensitive micelles in both neutral and acidic conditions. One of the pH-sensitive micelles (PHF-2) was found to be highly sensitive to acidic conditions while being fairly stable in neutral conditions. Furthermore, PHF-2 micelles well retained the antitumor activity of free FTS-H. We further evaluated the use of PHF-2 micelles as a carrier for delivering paclitaxel (PTX) and the triggered release of PTX under the acidic environment. PTX-loaded PHF-2 micelles showed enhanced antitumor activity compared with free PTX, likely because of the combinational effect between PHF-2 micelles and loaded PTX.

Anti-fibrotic effect of thymoquinone on hepatic stellate cells.

Hepatic stellate cells (HSCs) are the major cell type involved in the production of extracellular matrix in liver. After liver injury, HSCs undergo transdifferentiation process from quiescent state to activated state, which plays an important role in liver fibrosis. Previous studies have shown that thymoquinone (TQ) might have protective effect against liver fibrosis in animal models; however, the underlying mechanism of action is not fully understood. The aim of this study is to examine whether TQ has any direct effect on HSCs. Our results showed that pretreatment of mice with TQ has protective effect against CCl4-induced liver injury compared to control group (untreated), which is consistent with previous studies. Moreover, our in vivo study showed that COL1A1 and α-SMA mRNA levels were significantly downregulated by TQ treatment. Similarly, in vitro study confirmed that TQ downregulated COL1A1, COL3A1 and α-SMA mRNA levels in activated rat HSCs and LX2 cells, an immortalized human hepatic stellate cell line. Pretreatment with TQ also inhibited the LPS-induced proinflammatory response in LX2 cells as demonstrated by reduced mRNA expression of IL-6 and MCP-1. Mechanistically, inactivation of NF-κB pathway is likely to play a role in the TQ-mediated inhibition of proinflammatory response in HSCs. Finally, we have shown that TQ inhibited the culture-triggered transdifferentiation of freshly isolated rat HSCs as shown by significant downregulation of mRNA expression of several fibrosis-related genes. In conclusion, our study suggests that TQ has a direct effect on HSCs, which may contribute to its overall antifibrotic effect.