Photothermal Effect and Multi-Modality Imaging of Up-Conversion Nanomaterial Doped with Gold Nanoparticles.

Two key concerns exist in contemporary cancer chemotherapy in clinics: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating revolutionary cancer treatment techniques and photo-thermal therapy (PTT) has been proposed by many scholars. A drug for photothermal cancer treatment was synthesized using the hydrothermal method, which has a high light-to-heat conversion efficiency. It may also be utilized as a clear multi-modality bioimaging platform for photoacoustic imaging (PAI), computed tomography (CT), and magnetic resonance imaging (MRI). When compared to single-modality imaging, multi-modality imaging delivers far more thorough and precise details for cancer diagnosis. Furthermore, gold-doped upconverting nanoparticles (UCNPs) have an exceptionally high target recognition for tumor cells. The gold-doped UCNPs, in particular, are non-toxic to normal tissues, endowing the as-prepared medications with outstanding therapeutic efficacy but exceptionally low side effects. These findings may encourage the creation of fresh effective imaging-guided approaches to meet the goal of photothermal cancer therapy.

Formulation, Optimization, In Vitro and In Vivo Evaluation of Saxagliptin-Loaded Lipospheres for an Improved Pharmacokinetic Behavior.

The development and optimization of controlled release lipospheres (LS) from safe biocompatible behenic acid (BA) was performed for not only enhancing patient's compliance against highly prevailed chronic diabetes but also to vanquish the insufficiencies of traditional methods of drug delivery. The Box-Bhenken design (BBD) was utilized to statistically investigate the impact of formulation variables on percentage yield (Y 1), entrapment efficiency (Y 2), and SG-release (Y 3) from saxagliptin- (SG-) loaded LS, and the chosen optimized LS were subjected to a comparative in vivo pharmacokinetic analysis against commercially available SG brand. The compatibility analysis performed by DSC and FTIR established a complete lack of interaction of formulation components with SG, while p-XRD suggested a mild transformation of crystalline drug to its amorphous form during encapsulation process. The spherical, free flowing smooth surface LS having zeta potential of -32 mV and size range of 11-20 µm were conveniently formulated. The obtained data for Y 1 (30-80%), Y 2 (30-70%), and Y 3 (40-90%) showed a best fit with quadratic model. The pharmacokinetics analysis of LS showed a significantly decreased C max of SG (75.63 ± 3.85) with a sufficiently elevated T max (10.53 h) as compared to commercial brand of SG (99.66 ± 2.97 ng/mL and 3.55 ± 2.18 h). The achievement of greater bioavailability of SG was most probably attributed to higher level of half-life, mean residence time (MRT), and AUC0-24 for SG released from LS. Conclusively, the novel approach of SG-loaded LS had successfully sustained the plasma SG level for a prolonged time without increasing C max which would ultimately bring an effective management of chronic diabetes.

Development of the Binary and Ternary Atorvastatin Solid Dispersions: In Vitro and In Vivo Investigations.

The object of this study was to prepare binary and ternary solid dispersions of atorvastatin (ATR) by the melting method using PEGs and poloxamer 188 (P188) as the carriers, singly and in combination with each other. Dissolution behavior, solubility studies, X-ray diffractometry, differential scanning calorimetry, and Fourier transform infrared spectroscopy were studied. Furthermore, antihyperlipidemic activities of formulations were compared to each other by serum lipid analyses in hyperlipidemic rats. Based on the results, the highest dissolution efficiency (DE30 = 83%) was obtained by binary systems consisted of ATR and P188. Also, no additional improvement was observed in dissolution properties of ternary solid dispersion formulations. Solubility studies showed enhancement of ATR phase solubility in water and a buffer solution containing P188 or PEG 10000. Furthermore, saturated solubility of ATR in the buffer solution improved more than twofold in the optimized ternary dispersion system. No crystalline changes occurred in PEG-based formulations; meanwhile, partial amorphization happened in the ATR-P188 combination. Finally, the in vivo study in hyperlipidemic rats exhibited a rapid decrease in the lipid profile of all formulations compared to ATR (after 7 days). Moreover, reduction of serum triglycerides and total cholesterol on the 14th day in the ATR group (p value < 0.01) was less than solid dispersion or physical mixing preparations (p value < 0.001). These findings proved the appropriate influence of using PEG and P188 in solid dispersion systems for the improvement of the therapeutic efficiency of ATR.

ATP-triggered mitochondrial cascade reactions for cancer therapy with nanoscale zeolitic imidazole framework-90.

Goals: Chemotherapy, the most conventional modality for cancer therapy, usually brings serious side effects because of the low cancer-therapeutic specificity and bioavailability. It is of great significance for cancer treatment to develop new effective strategies to regulate biochemical reactions in organelles, enhance the specificity of chemotherapeutic drugs and reduce their side effects. Methods: We report herein a zeolitic imidazole framework-90 (ZIF-90) based nanoplatform, which was used to initiate a series of mitochondrial cascade reactions using ATP as a molecular switch for cancer therapy. The thioketal linked camptothecin (camptothecin prodrug, TK-CPT) and 2-Methoxyestradiol (2-ME) were encapsulated into the pores of ZIF-90 nanoparticles using a simple one-pot method, and the nanoplatform was finally coated with a layer of homologous cell membrane. Results: Mitochondrial ATP can efficiently degrade ZIF-90 and then release the loaded 2-ME and CPT prodrugs. 2-ME can inhibit the activity of superoxide dismutase (SOD), which induces the up-regulation of reactive oxygen species (ROS) in situ. The thioketal linkers in CPT prodrug can respond to ROS, thereby achieving subsequent release of parent CPT drug. This cascade of reactions can lead to prolonged high oxidative stress and cause continuous cancer cell apoptosis, due to the increased ROS level and the liberation of CPT. Conclusion: We constructed an ATP-triggered strategy using nanoscale ZIF-90 to initiate mitochondrial cascade reactions for cancer therapy. The ZIF-90 based nanoplatform exhibited low cytotoxicity, good mitochondria-targeting ability, and excellent therapeutic effect. In vivo experiments demonstrated that the growth of tumor can be efficiently inhibited in a mouse model. This ATP-triggered strategy to induce mitochondrial biochemical reactions offers more possibilities for developing organelle-targeted therapeutic platforms.

Probing the fluorination effect on the self-assembly characteristics, in vivo fate and antitumor efficacy of paclitaxel prodrug nanoassemblies.

Rationale: Small-molecule prodrug nanoassembly is emerging as an efficient platform for chemotherapy. The self-assembly stability plays a vital role on the drug delivery efficiency of prodrug nanoassembly. It is reported that fluoroalkylation could improve the self-assembly stability of amphiphilic polymers by utilizing the unique fluorination effect. But the application of fluoroalkylation on small-molecule prodrug nanoassembly has never been reported. Methods: Here, fluoro-modified prodrug was developed by conjugating paclitaxel with perfluorooctanol (F8-SS-PTX), and the paclitaxel-octanol prodrug (C8-SS-PTX) was used as control. The fluoro-mediated self-assembly mechanisms were illustrated using molecular dynamics simulation. In addition, the impacts of fluoroalkylation on the pharmacy characters, in vivo fate and antitumor effect of small-molecule prodrug nanoassembly were investigated in details. Results: Fluoroalkylation significantly improved the self-assembly stability of F8-SS-PTX NPs both in vitro and in vivo, which could be attributed to the fluoro-mediated hydrophobic force and halogen bonds. The AUC0-24h and tumor accumulation of F8-SS-PTX NPs was 6-fold and 2-fold higher than that of C8-SS-PTX NPs, respectively. As a result, F8-SS-PTX NPs exhibited much better antitumor effect than C8-SS-PTX NPs and Abraxane. Conclusion: Fluoroalkylation could improve the self-assembly stability, in vivo fate, and antitumor efficacy of small-molecule prodrug nanoassemblies, which could be an effective strategy for the rational design of advanced nanomedicines.

Heparin-Tagged PLA-PEG Copolymer-Encapsulated Biochanin A-Loaded (Mg/Al) LDH Nanoparticles Recommended for Non-Thrombogenic and Anti-Proliferative Stent Coating.

Drug-eluting stents have been widely implanted to prevent neointimal hyperplasia associated with bare metal stents. Conventional polymers and anti-proliferative drugs suffer from stent thrombosis due to the non-selective nature of the drugs and hypersensitivity to polymer degradation products. Alternatively, various herbal anti-proliferative agents are sought, of which biochanin A (an isoflavone phytoestrogen) was known to have anti-proliferative and vasculoprotective action. PLA-PEG diblock copolymer was tagged with heparin, whose degradation releases heparin locally and prevents thrombosis. To get a controlled drug release, biochanin A was loaded in layered double hydroxide nanoparticles (LDH), which are further encapsulated in a heparin-tagged PLA-PEG copolymer. LDH nanoparticles are synthesized by a co-precipitation process; in situ as well as ex situ loading of biochanin A were done. PLA-PEG-heparin copolymer was synthesized by esterification reaction, and the drug-loaded nanoparticles are coated. The formulation was characterized by FTIR, XRD, DSC, DLS, and TEM. In vitro drug release studies, protein adhesion, wettability, hemocompatibility, and degradation studies were performed. The drug release was modeled by mathematical models to further emphasize the mechanism of drug release. The developed drug-eluting stent coating is non-thrombogenic, and it offers close to zero-order release for 40 days, with complete polymer degradation in 14 weeks.

Enhanced Dermal Delivery of Flurbiprofen Nanosuspension Based Gel: Development and Ex Vivo Permeation, Pharmacokinetic Evaluations.

PURPOSE: The objective of this study was to optimize the Flurbiprofen (FB) nanosuspension (NS) based gel and to investigate the in vitro release, ex vivo permeation, the plasma concentration-time profile and pharmacokinetic parameters. METHODS: FB-NSs were developed using the wet milling process with the Design of Experiment (DoE) approach. The optimum FB-NS was characterized on the basis of SEM, DSC, XRPD, solubility and permeation studies. The dermal gel was prepared by incorporating FB-NS into HPMC gel. Then the in-vitro release, ex vivo permeation studies were performed, and pharmacokinetic studies were evaluated on rats. RESULTS: The particle size, polydispersity index and zeta potential values of optimum NS were determined as 237.7 ± 6.8 nm, 0.133 ± 0.030 and - 30.4 ± 0.7 mV, respectively. By means of the surfactant content and nanosized particles of the nanosuspension, the solubility of FB was increased about 7-fold. The percentage permeated amount of FB from FB-NS gel (8.40%) was also found to be higher than the physical mixture (5.25%) and coarse suspension (reference) (2.08%) gels. The pharmacokinetic studies showed that the Cmax of FB-NS gel was 2.5 times higher than the reference gel, while AUC0-24 was 2.96 times higher. CONCLUSION: FB-NSs were successfully prepared with a wet milling method and optimized with the DoE approach. The optimized FB nanosuspension gel provided better permeation and pharmacokinetic performance compared to FB coarse suspension gel.

Recent Advancement in Topical Nanocarriers for the Treatment of Psoriasis.

Psoriasis is a life-threatening autoimmune inflammatory skin disease, triggered by T lymphocyte. Recently, the drugs most commonly used for the treatment of psoriasis include methotrexate (MTX), cyclosporine (CsA), acitretin, dexamethasone, and salicylic acid. However, conventional formulations due to poor absorptive capacity, inconsistent drug release characteristics, poor capability of selective targeting, poor retention of drug molecules in target tissue, and unintended skin reactions restrict the clinical efficacy of drugs. Advances in topical nanocarriers allow the development of prominent drug delivery platforms can be employed to address the critical issues associated with conventional formulations. Advances in nanocarriers design, nano-dimensional configuration, and surface functionalization allow formulation scientists to develop formulations for a more effective treatment of psoriasis. Moreover, interventions in the size distribution, shape, agglomeration/aggregation potential, and surface chemistry are the significant aspects need to be critically evaluated for better therapeutic results. This review attempted to explore the opportunities and challenges of current revelations in the nano carrier-based topical drug delivery approach used for the treatment of psoriasis.

Rethinking CRITID Procedure of Brain Targeting Drug Delivery: Circulation, Blood Brain Barrier Recognition, Intracellular Transport, Diseased Cell Targeting, Internalization, and Drug Release.

The past decades have witnessed great progress in nanoparticle (NP)-based brain-targeting drug delivery systems, while their therapeutic potentials are yet to be fully exploited given that the majority of them are lost during the delivery process. Rational design of brain-targeting drug delivery systems requires a deep understanding of the entire delivery process along with the issues that they may encounter. Herein, this review first analyzes the typical delivery process of a systemically administrated NPs-based brain-targeting drug delivery system and proposes a six-step CRITID delivery cascade: circulation in systemic blood, recognizing receptor on blood-brain barrier (BBB), intracellular transport, diseased cell targeting after entering into parenchyma, internalization by diseased cells, and finally intracellular drug release. By dissecting the entire delivery process into six steps, this review seeks to provide a deep understanding of the issues that may restrict the delivery efficiency of brain-targeting drug delivery systems as well as the specific requirements that may guarantee minimal loss at each step. Currently developed strategies used for troubleshooting these issues are reviewed and some state-of-the-art design features meeting these requirements are highlighted. The CRITID delivery cascade can serve as a guideline for designing more efficient and specific brain-targeting drug delivery systems.

Development of an In Vivo Predictive Dissolution Methodology of Topiroxostat Immediate-Release Tablet Using In Silico Simulation.

The main objective of this study was to develop an in vivo predictive dissolution (IVPD) model for topiroxostat immediate-release (IR) formulation by the combination of mechanistic absorption model (MAM) deconvolution method with time shifting factor (TSF) adjustment. The in vitro dissolution profiles in different biorelevant dissolution media containing different concentrations of sodium lauryl sulfate (SLS) were obtained from dissolution testing with the paddle method of the US Pharmacopeia, while the human pharmacokinetic profile was taken from the published experimental results. The GastroPlus™ software was used to observe the linear relationship between in vitro drug dissolution and in vivo absorption. The pharmacokinetic profile of topiroxostat IR tablet was first deconvoluted through the MAM method to obtain the fraction absorbed in vivo. Next, Levy plot was constructed to estimate the TSF, and the time scale for both processes of dissolution and absorption was then adjusted to be superimposable. The IVPD modelling was subsequently established with data between in vitro dissolution profiles and fraction absorbed in vivo. Finally, the dissolution profiles of topiroxostat IR tablet were translated into a pharmacokinetic curve in terms of convolution method. The comparison between translated and observed pharmacokinetic data will validate the performance of the developed IVPD model. This new linear IVPD model with high predictive power for the tablet can predict the in vivo pharmacokinetic differences through in vitro dissolution data, and it can be utilized as a risk-control tool for the formulation development of the topiroxostat IR tablet and the quality control of product batches.

Formulation, Pharmacokinetics evaluation, and IVIVC Assessment of Gliclazide Multiparticulates in Rat Model.

In vitro and in vivo studies of gliclazide (GLZ)-loaded freeze-dried alginate-gelatin (AL-GL) beads were carried out, aiming to modify its oral bioavailability. Crosslinked freeze-dried GLZ AL-GL beads (particle size: 1.5- and 3.0-mm) were prepared. In vitro evaluation of GLZ AL-GL beads included SEM, DSC, FT-IR, and release rate study in gradient media. In vivo study was single-dose (4 mg/kg), randomized, parallel-group design, two-treatment (T: test GLZ AL-GL beads and R: reference product Diamicron® 30-mg MR tablet) conducted in 96 healthy rats. Each group was subdivided into 2 sub-groups (G1 and G2) having different blood sampling schemes for up to 72 h. Assessment of level A in-vitro-in-vivo correlation (IVIVC) model was carried out. AL-GL beads successfully increased GLZ release rate compared to R. GLZ percent released (Q4h) was 109.34, 86.85, and 43.43% for 1.5-mm and 3.0-mm beads and R, respectively. DSC analysis confirmed the interaction of AL-GL via crosslinking. No chemical interaction of GLZ has occurred as proved by FT-IR. Relative bioavailability (T/R) for AUC0-∞ was 132.45% for G1 and 146.16% for G2. No significant differences between T and R in the primary pharmacokinetic parameters were determined. Tmax values were found to be earlier in the case of G1 than those of G2. A secondary absorption peak of GLZ was clearly detected in the case of R while its sharpness was minimized in T. High IVIVC was established, and hence, the proposed in vitro release model perfectly correlated with the in vivo study. The current study design might be a platform to enable panoramic view for GLZ variability in vivo.

Nerve conduit based on HAP/PDLLA/PRGD for peripheral nerve regeneration with sustained release of valproic acid.

The nerve conduits have been developed for nerve defect repair. However, no artificial conduits have obtained comparable results to autografts to bridge the large gaps. A possible reason for this poor performance may be a lack of sustainable neurotrophic support for axonal regrowth. Previous studies suggested nanocomposite conduits can be used as a carrier for valproic acid (VPA), a common drug that can produce effects similar to the neurotrophic factors. Here, we developed the novel bioabsorbable conduits based on hydroxyapatite/poly d-l-lactic acid (PDLLA)/poly{(lactic acid)-co-[(glycolic acid)-alt-(l-lysine)]} with sustained release of VPA. Firstly, the sustained release of VPA in this conduit was examined by high-performance liquid chromatography. Then Schwann cells were treated with the conduit extracts. The cell metabolic activity and proliferation were assayed by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide and bromodeoxyuridine staining. A 10-mm segment of rat sciatic nerve was resected and then repaired, respectively, using the VPA conduit (Group A), the PDLLA conduit (Group B), or the autografts (Group C). Nerve conduction velocities (NCVs), compound muscle action potentials (CMAPs), and histological staining were assayed following the surgery. The cell metabolic activity and proliferation were significantly increased (p < .05) by the extracts from VPA-conduit extract compared to others. NCVs and CMAPs were significantly higher in Groups A and C than Group B (p < .05). The nerve density of Groups A and C was higher than Group B. There was no significant difference between Groups A and C. Taken together, this study suggested the sustained-release VPA conduit promoted peripheral nerve regeneration that was comparable to the autografts. It holds potential for future use in nerve regeneration.

Effect of Surface Property on the Release and Oral Absorption of Solid Sirolimus-Containing Self-microemulsifying Drug Delivery System.

The combination of self-microemulsifying drug delivery system (SMEDDS) and mesoporous silica materials favors the oral delivery of poorly water-soluble drugs (PWSD). However, the influence of the surface property of the mesopores towards the drug release and in vivo pharmacokinetics is still unknown. In this study, SBA-15 with hydroxyl groups (SBA-15-H), methyl groups (SBA-15-M), amino groups (SBA-15-A), or carboxyl groups (SBA-15-C) was combined with SMEDDS containing sirolimus (SRL). The diffusion and self-emulsifying of SMEDDS greatly improved the drug release over the raw SRL and SRL-SBA-15-R (R referred to as the functional groups). Results of drug absorption and X-ray photoelectron spectroscopy (XPS) showed strong hydrogen binding between SRL and the amino groups of SBA-15-A, which hindered the drug release and oral bioavailability of SRL-SMEDDS-SBA-15-A. The favorable release of SRL-SMEDDS-SBA-15-C (91.31 ± 0.57%) and SRL-SMEDDS-SBA-15-M (91.76 ± 3.72%) contributed to enhancing the maximum blood concentration (Cmax) and the area under the concentration-time curve (AUC0→48). In conclusion, the release of SRL-SMEDDS-SBA-15-R was determined by the surface affinity of the SBA-15-R and the interaction between the SRL molecules and the surface of SBA-15-R. This study suggested that the SMEDDS-SBA-15 was a favorable carrier for PWSD, and the surface property of the mesopores should be considered for the optimization of the SMEDDS-SBA-15.

Galactose-Modified PH-Sensitive Niosomes for Controlled Release and Hepatocellular Carcinoma Target Delivery of Tanshinone IIA.

Increasing the drug tumor-specific accumulation and controlling their release is considered one of the most effective ways to increase the efficacy of drugs. Here, we developed a vesicle system that can target hepatoma and release drugs rapidly within tumor cells. This non-ionic surfactant vesicle is biodegradable. Galactosylated stearate has been used to glycosylate the vesicles to achieve liver targeting; replacement of a portion (Chol:CHEMS = 1:1) of cholesterol by cholesteryl hemisuccinate (CHEMS) allows for a rapid release of drugs in an acidic environment. In vitro release experiments confirmed that galactose-modified pH-sensitive niosomes loaded with tanshinone IIA had excellent drug release performance in acid medium. In vitro experiments using ovarian cancer cells (A2780), colon cancer cells (HCT8), and hepatoma cell (Huh7, HepG2) confirmed that the preparation had specific targeting ability to hepatoma cells compared with free drugs, and this ability was dependent on the galactose content. Furthermore, the preparation also had a more substantial inhibitory effect on tumor cells, and subsequent apoptosis assays and cell cycle analyses further confirmed its enhanced anti-tumor effect. Results of pharmacokinetic experiments confirmed that the vesicle system could significantly extend the blood circulation time of tanshinone IIA, and the larger area under the curve indicated that the preparation had a better drug effect. Thus, the results of biodistribution experiments confirmed the in vivo liver targeting ability of this preparation. Niosomes designed in this manner are expected to be a safe and effective drug delivery system for liver cancer therapy.

Development of Nanonized Nitrendipine and Its Transformation into Nanoparticulate Oral Fast Dissolving Drug Delivery System.

The present research focuses on the development of a nanoparticulate (nanocrystals-loaded) rapidly dissolving (orodispersible) tablet with improved solubility and bioavailability. The nanosuspension (NS) was prepared by antisolvent sonoprecipitation technique and the optimized NS was lyophilized to obtain nanocrystals (NCs), which were evaluated for various parameters. The nitrendipine (NIT) nanoparticulate orodispersible tablet (N-ODT) was prepared by direct compression method. The optimized N-ODT was evaluated for pre and post compression characteristics, in vivo pharmacokinetic and stability profile. The optimized NS showed a particle size of 505.74 ± 15.48 nm with a polydispersity index (PDI) of 0.083 ± 0.006. The % NIT content in the NCs was found to be 78.4 ± 2.3%. The saturation solubility of NIT was increased remarkably (26.14 times) in comparison to plain NIT, post NCs development. The DSC and p-XRD analysis of NCs revealed the perseverance of the integrity and crystallinity of NIT on lyophilization. The results of micromeritic studies revealed the good flow-ability and compressibility of NCs blend. All the post-compression properties of N-ODT were observed within the standard intended limit. The dispersion, wetting, and disintegration time of the optimized batch of N-ODT was found to be 39 ± 1.13 s, 44.66 ± 1.52 s, and 33.91 ± 0.94 s respectively. The in vitro dissolution study displayed 100.28 ± 2.64% and 100.61 ± 3.3% of NIT released from NCs (in 8 min) and N-ODT (in 6 min) respectively, while conventional NIT tablet took 30 min to release 99.94 ± 1.57% of NIT. The in vivo pharmacokinetic study in rabbits demonstrated significantly (p < 0.05) higher bioavailability of NIT on release from N-ODT than the conventional NIT tablet. Thus, N-ODT could be a promising tool for improving the solubility and bioavailability of NIT and to treat cardiovascular diseases effectively.

Paclitaxel and naringenin-loaded solid lipid nanoparticles surface modified with cyclic peptides with improved tumor targeting ability in glioblastoma multiforme.

The present work describes the systematic development of paclitaxel and naringenin-loaded solid lipid nanoparticles (SLNs) for the treatment of glioblastoma multiforme (GBM). So far only temozolomide therapy is available for the GBM treatment, which fails by large amount due to poor brain permeability of the drug and recurrent metastasis of the tumor. Thus, we investigated the drug combination containing paclitaxel and naringenin for the treatment of GBM, as these drugs have individually demonstrated significant potential for the management of a wide variety of carcinoma. A systematic product development approach was adopted where risk assessment was performed for evaluating the impact of various formulation and process parameters on the quality attributes of the SLNs. I-optimal response surface design was employed for optimization of the dual drug-loaded SLNs prepared by micro-emulsification method, where Percirol ATO5 and Dynasan 114 were used as the solid lipid and surfactant, while Lutrol F188 was used as the stabilizer. Drug loaded-SLNs were subjected to detailed in vitro and in vivo characterization studies. Cyclic RGD peptide sequence (Arg-Gly-Asp) was added to the formulation to obtain the surface modified SLNs which were also evaluated for the particle size and surface charge. The optimized drug-loaded SLNs exhibited particle size and surface charge of 129 nm and 23 mV, drug entrapment efficiency >80% and drug loading efficiency >7%. In vitro drug release study carried out by micro dialysis bag method indicated more than 70% drug was release observed within 8 h time period. In vivo pharmacokinetic evaluation showed significant improvement (p < 0.05) in drug absorption parameters (Cmax and AUC) from the optimized SLNs over the free drug suspension. Cytotoxicity evaluation on U87MG glioma cells indicated SLNs with higher cytotoxicity as compared to that of the free drug suspension (p < 0.05). Evaluation of uptake by florescence measurement indicated superior uptake of SLNs tagged with dye over the plain dye solution. Overall, the dual drug-loaded SLNs showed better chemoprotective effect over the plain drug solution, thus construed superior anticancer activity of the developed nanoformulation in the management of glioblastoma multiforme.

Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs.

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment.Graphical abstract.

In vitro anti-leukemic assessment and sustained release behaviour of cytarabine loaded biodegradable polymer based nanoparticles.

AIMS: The study aimed to develop, characterize, and evaluate poly (ɛ-caprolactone) (PCL) based nanoparticles for the sustained release behaviour of cytarabine and to investigate the in vitro anti-cancer influence on KG-1 leukemic cell line. MATERIALS AND METHODS: Nanoprecipitation method was used for the preparation of cytarabine loaded PCL nanoparticles. The developed nanoparticles were characterized for physicochemical properties and the anti-leukemic effect on the KG-1 cell line was evaluated. KEY FINDINGS: A total number of five formulations were prepared with size range from 120.5 ± 1.18 to 341.5 ± 3.02, entrapment efficiency (41.31 ± 0.49 to 62.28 ± 0.39%), spherical morphology, negative zeta potentials, considerable particle size distribution, compatibility between the drug and excipients and thermal stability. X-ray diffraction analysis confirmed the successful incorporation of cytarabine in PCL polymer. In vitro drug release in phosphate buffer saline (pH 7.4) showed initial burst release followed by sustained release up to 48 h. The sustained release behaviour efficiently increased the toxicity of cytarabine-loaded PCL nanoparticles to KG-1 (leukemic) and MCF-7 (breast cancer) cell lines in time dependent manner with lower IC50 values than that of drug solution. The flow cytometry study revealed the better apoptotic activity of cytarabine loaded PCL nanoparticle against treated KG-1 cell line. The western blot analysis confirmed the upregulation of cleaved caspase-3 and downregulation of Bcl-2 protein. SIGNIFICANCE: The experimental results suggest that cytarabine loaded PCL nanoparticles is an efficient carrier to prevent the dose associated toxicity while providing sustained release pattern to ensure maximum anti-cancer influence.

Multi-functionalized micro-helical capsule robots with superior loading and releasing capabilities.

The functionalization of microrobots is essential for realizing their biomedical application in targeted cargo delivery, but the multifunctional integration of microrobots and controllable cargo delivery remains an enormous challenge at present. This work reports a kind of multi-functionalized micro-helical robot with superior loading capabilities for the controlled release of encapsulants. The magnetic microrobot, with a multilayer capsule helical structure, was developed via multifunctional strategies, including microfluidic synthesis, polyelectrolyte complexation, and surface coating with magnetic nanoparticles. The microrobot is constructed of a helical structure from a calcium alginate microfiber via a co-axial capillary microfluidic system. Then, it is coated with a polyelectrolyte complexation membrane and decorated with magnetic nanoparticles. After multi-step layer-by-layer (LbL) assembly with functionalized units, the structure is converted to a helical capsule possessing a soft and biocompatible polysaccharide alginate/chitosan/alginate shell with Fe3O4 nanoparticles decorated on the surface. The functionalized microrobot not only enables wireless steering with rotational locomotion under the control of a six degrees of freedoms (6-DOFs) electromagnetic system at different frequencies, but it also possesses stimuli-responsive abilities owing to the semi-permeable membrane, which can trigger the controllable release of encapsulants in response to ions in the environment. This work provides an efficient strategy for the superior multi-functionalization of microrobots to achieve enhanced locomotion and encapsulation performance for the loading, transport, and targeted delivery of cargo.

Multi-region finite element modelling of drug release from hydrogel based ophthalmic lenses.

Understanding the way in which drug is released from drug carrying hydrogel based ophthalmic lenses aids in the development of efficient ophthalmic drug delivery. Various solute-polymer interactions affect solute diffusion within hydrogels as well as hydrogel-bulk partitioning. Additionally, surface modifications or coatings may add to resistance of mass transfer across the hydrogel interface. It is necessary to consider both interfacial resistances as well as the appropriate driving force when characterizing interface flux. Such a driving force is induced by a difference in concentration which deviates from equilibrium conditions. We present a Galerkin finite element approach for solute transport in hydrogels which accounts for diffusion within the gel, storage effects due to polymer-solute interaction, as well as partitioning and mass transfer resistance effects at the interface. The approach is formulated using a rotational symmetric model to account for realistic geometry. We show that although the resulting global system is not symmetric in the case of partitioning, it is similar to a symmetric negative semidefinite system. Thus, it has non-positive real eigenvalues and is coercive, ensuring the validity of the finite element formulation as well as the numerical stability of the implicit backward Euler time integration method employed. Two models demonstrating this approach are presented and verified with release experimental data. The first is the release of moxifloxacin from intraocular lenses (IOLs) plasma grafted with different polyacrylates. The second accounts for both loading as well as the release of diclofenac from disc shaped IOL material loaded for varied time periods and temperature.