Polycaprolactone - Vitamin E TPGS micelles for delivery of paclitaxel: In vitro and in vivo evaluation.

This study aimed to present findings on a paclitaxel (PTX)-loaded polymeric micellar formulation based on polycaprolactone-vitamin E TPGS (PCL-TPGS) and evaluate its in vitro anticancer activity as well as its in vivo pharmacokinetic profile in healthy mice in comparison to a marketed formulation. Micelles were prepared by a co-solvent evaporation method. The micelle's average diameter and polydispersity were determined using dynamic light scattering (DLS) technique. Drug encapsulation efficiency was assessed using an HPLC assay. The in vitro cytotoxicity was performed on human breast cancer cells (MCF-7 and MDA-MB-231) using MTT assay. The in vivo pharmacokinetic profile was characterized following a single intravenous dose of 4 mg/kg to healthy mice. The mean diameters of the prepared micelles were ≤ 100 nm. Moreover, these micelles increased the aqueous solubility of PTX from ∼0.3 µg/mL to reach nearly 1 mg/mL. While the PTX-loaded micelles showed an in vitro cytotoxicity comparable to the marketed formulation (Ebetaxel), drug-free PCL-TPGS micelles did not show any cytotoxic effects on both types of breast cancer cells (∼100% viability). Pharmacokinetics of PTX as part of PCL-TPGS showed a significant increase in its volume of distribution compared to PTX conventional formulation, Ebetaxel, which is in line with what was reported for clinical nano formulations of PTX, i.e., Abraxane, Genexol-PM, or Apealea. The findings of our studies indicate a significant potential for PCL-TPGS micelles to act as an effective system for solubilization and delivery of PTX.

Co-Delivery of Dragon's Blood and Alkanna tinctoria Extracts Using Electrospun Nanofibers: In Vitro and In Vivo Wound Healing Evaluation in Diabetic Rat Model.

The increasing prevalence of diabetic wounds presents a significant challenge due to the difficulty of natural healing and various obstacles. Dragon's blood (DB) and Alkanna tinctoria (AT) are well recognized for their potent healing abilities, which include potent antibacterial and anti-inflammatory activities. In this study, electrospun nanofibers (NFs) based on polyvinyl pyrrolidone (PVP) were co-loaded with both DB and AT, aiming to magnify their efficacy as wound-dressing applications for diabetic wound healing. The evaluation of these NFs as wound dressings was conducted using a streptozotocin-induced diabetic rat model. Electrospun NFs were prepared using the electrospinning of the PVP polymer, resulting in nanofibers with consistent, smooth surfaces. The loading capacity (LC) of AT and DB into NFs was 64.1 and 70.4 µg/mg, respectively, while in the co-loaded NFs, LC was 49.6 for AT and 57.2 µg/mg for DB. In addition, X-ray diffraction (XRD) revealed that DB and AT were amorphously dispersed within the NFs. The loaded NFs showed a dissolution time of 30 s in PBS (pH 7.4), which facilitated the release of AT and DB (25-38% after 10 min), followed by a complete release achieved after 180 min. The antibacterial evaluation demonstrated that the DB-AT mixture had potent activity against Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus). Along with that, the DB-AT NFs showed effective growth inhibition for both P. aeruginosa and S. aureus compared to the control NFs. Moreover, wound healing was evaluated in vivo in diabetic Wistar rats over 14 days. The results revealed that the DB-AT NFs improved wound healing within 14 days significantly compared to the other groups. These results highlight the potential application of the developed DB-AT NFs in wound healing management, particularly in diabetic wounds.

Optimization of cationic nanoparticles stabilized by poloxamer 188: A potential approach for improving the biological activity of Aloeperryi.

Aloe perryi (AP) has gained considerable interest as a medicinal herb in various biological applications due to its rich phytochemical composition. However, the therapeutic benefits of AP could be potentiated by utilizing nanotechnology. Moreover, cationic solid lipid nanoparticles (CSLNs) possess remarkable characteristics that can greatly enrich a variety of biological uses. An optimization approach was used to achieve high-quality CSLNs to maximize the therapeutic efficacy of AP. Therefore, a factorial design was used to investigate the influence of various variables on the attributes of CSLNs quality. In this study, the factors under investigation were compritol 888 ATO (C-888, X1), poloxamer 188 (PL188, X2), and chitosan (CS, X3), which served as independent variables. The parameters measured as dependent variables included particle size (Y1), zeta potential (Y2), and encapsulation efficiency EE (Y3). The relationship among these variables was determined by Analysis of Variance (ANOVA) and response surface plots. The results revealed that PL188 played a significant role in reducing the particle size of CSLNS (ranging from 207 to 261 nm with 1 % PL188 to 167-229 nm with 3 % PL188). Conversely, an increase in the concentration of CS led to a rise in the particle size. The magnitude of positive zeta potential values was dependent on the increased concentration of CS. Moreover, the higher amounts of C-888 and PL188 improved the EE% of the CSLNs from 42 % to 86 %. Furthermore, a concentration-dependent antioxidant effect of the optimized AP-CSLNs was observed. The antioxidant activity of the optimized AP-CSLNs at 100 µg/mL was 75 % compared to 62 % and 60 % for AP-SLNs and AP solution, respectively. A similar pattern of improvement was also observed with antimicrobial, and anticancer activities of the optimized AP-CSLNs. These findings demonstrated the potential of AP-CSLNs as a carrier system, enhancing the biological activities of AP, opening new possibilities in herbal medicines.

Role of Polymeric Micelles in Ocular Drug Delivery: An Overview of Decades of Research.

Local drug delivery to the eye through conventional means has faced many challenges due to three essential barriers: (a) the complex structure of the cornea limiting drug absorption, (b) the capacity of ocular absorptive cells in drug metabolism, and (c) the washing effect of eye tears. Polymeric micelles (PMs) have been the focus of much interest for ocular drug delivery due to several advantages they provide for this application, including the capacity for the solubilization of hydrophobic drugs, nonirritability, nanoscopic diameter, and the clarity of their aqueous solution not interfering with vision. The potential to increase the release and residence time of incorporated medication at the site of absorption is also a bonus advantage for these delivery systems. This Review covers research conducted on single or mixed micelles prepared from small amphiphilic molecules, copolymers (diblock, triblock, and graft), and gel systems containing micelles. The purpose of this review is to provide an update on the status of micellar ocular delivery systems for different indications, with a focus on preclinical and clinical drug development. In this context, we are discussing the anatomy of the eye, various ocular barriers, different micellar formulations, and their benefits in ocular drug delivery, as well as the role of PMs in the management of ocular diseases both in preclinical models and in clinic. The encouraging preclinical effectiveness findings from experiments conducted in both laboratory settings and live animals have paved the way for the advancement of micellar systems in clinical trials for ocular administration and the first nanomicallar formulation approved for clinical use by the United States Food and Drug Administration (marketed as Cequa by Sun Pharmaceuticals).

Novel Metoprolol-Loaded Chitosan-Coated Deformable Liposomes in Thermosensitive In Situ Gels for the Management of Glaucoma: A Repurposing Approach.

Glaucoma is a long-term eye disease associated with high intraocular pressure (IOP), which seriously damages the eyes, causing blindness. For successful therapy, potent drugs and delivery systems are required. Metoprolol (MT) is believed to help reduce elevated IOP. The paradigm of ocular therapeutics may be changed by the integration of chitosan-coated liposomes (CLPs) with thermosensitive in situ gel (ISG). Therefore, MT-CLPs were developed and characterized and compared to uncoated ones (MT-LPs). Furthermore, MT-LP- and MT-CLP-loaded ISGs were prepared and characterized in in vitro, ex vivo, and in vivo studies. MT-LPs and MT-CLPs displayed spherical shapes with nanosize range, reasonable EE%, and significant bioadhesion. The zeta potential changed from negative to positive after CS coating. The extended in vitro drug release of MT-CLPs showed significant mucin mucoadhesion. The formed ISGs were homogeneous with a pH range of 7.34 to 7.08 and a rapid sol-gel transition at physiological temperature. MT-ISG1 (MT-LP) and MT-ISG2 (MT-CLPs-0.5) could increase ocular permeability by 2-fold and 4.4-fold compared to MT-ISG (pure MT). MT-ISG2 demonstrated significantly reduced IOP in rabbits without causing any irritation. In conclusion, MT-ISG2 markedly enhanced corneal permeability and reduced IOP. They would be promising carriers for MT for glaucoma management.

Development and Characterization of PEGylated Fatty Acid-Block-Poly(ε-caprolactone) Novel Block Copolymers and Their Self-Assembled Nanostructures for Ocular Delivery of Cyclosporine A.

Low aqueous solubility and membrane permeability of some drugs are considered major limitations for their use in clinical practice. Polymeric micelles are one of the potential nano-drug delivery systems that were found to ameliorate the low aqueous solubility of hydrophobic drugs. The main objective of this study was to develop and characterize a novel copolymer based on poly (ethylene glycol) stearate (Myrj™)-block-poly(ε-caprolactone) (Myrj-b-PCL) and evaluate its potential as a nanosystem for ocular delivery of cyclosporine A (CyA). Myrj-b-PCL copolymer with various PCL/Myrj ratios were synthesized via ring-opening bulk polymerization of ε-caprolactone using Myrj (Myrj S40 or Myrj S100), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. The co-solvent evaporation method was used to prepare CyA-loaded Myrj-b-PCL micelles. The prepared micelles were characterized for their size, polydispersity, and CMC using the dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Transmission electron microscopy (TEM) images of the prepared micelles showed spherical shapes with diameters in the nano range (<200 nm). Ex vivo corneal permeation study showed sustained release of CyA from the developed Myrj S100-b-PCL micelles. In vivo ocular irritation study (Draize test) showed that CyA-loaded Myrj S100-b-PCL88 was well tolerated in the rabbit eye. Our results point to a great potential of Myrj S100-b-PCL as an ocular drug delivery system.

Design and Development of D‒α‒Tocopheryl Polyethylene Glycol Succinate‒block‒Poly(ε-Caprolactone) (TPGS-b-PCL) Nanocarriers for Solubilization and Controlled Release of Paclitaxel.

The objective of this study was to synthesize and characterize a set of biodegradable block copolymers based on TPGS-block-poly(ε-caprolactone) (TPGS-b-PCL) and to assess their self-assembled structures as a nanodelivery system for paclitaxel (PAX). The conjugation of PCL to TPGS was hypothesized to increase the stability and the drug solubilization characteristics of TPGS micelles. TPGS-b-PCL copolymer with various PCL/TPGS ratios were synthesized via ring opening bulk polymerization of ε-caprolactone using TPGS, with different molecular weights of PEG (1-5 kDa), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. Assembly of block copolymers was achieved via the cosolvent evaporation method. The self-assembled structures were characterized for their size, polydispersity, and CMC using dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Only copolymers that consisted of TPGS with PEG molecular weights ≥ 2000 Da were able to self-assemble and form nanocarriers of ≤200 nm in diameter. Moreover, TPGS2000-b-PCL4000, TPGS3500-b-PCL7000, and TPGS5000-b-PCL15000 micelles enhanced the aqueous solubility of PAX from 0.3 µg/mL up to 88.4 ug/mL in TPGS5000-b-PCL15000. Of the abovementioned micellar formulations, TPGS5000-b-PCL15000 showed the slowest in vitro release of PAX. Specifically, the PAX-loaded TPGS5000-b-PCL15000 micellar formulation showed less than 10% drug release within the first 12 h, and around 36% cumulative drug release within 72 h compared to 61% and 100% PAX release, respectively, from the commercially available formulation (Ebetaxel®) at the same time points. Our results point to a great potential for TPGS-b-PCL micelles to efficiently solubilize and control the release of PAX.

Crosstalk of low density lipoprotein and liposome as a paradigm for targeting of 5-fluorouracil into hepatic cells: cytotoxicity and liver deposition.

This study aimed to utilize cholesterol conjugation of 5-fluorouracil (5-FUC) and liposomal formulas to enhance the partitioning of 5-FU into low density lipoprotein (LDL) to target hepatocellular carcinoma (HCC). Thus, 5-FU and 5-FUCwere loaded into liposomes. Later, the direct loading and transfer of 5-FU, and 5-FUC from liposomes into LDL were attained. The preparations were characterized in terms of particle size, zeta potential, morphology, entrapment efficiency, and cytotoxicity using the HepG2 cell line. Moreover, the drug deposition into the LDL and liver tissues was investigated. The present results revealed that liposomal preparations have a nanosize range (155 - 194 nm), negative zeta potential (- 0.82 to - 16 mV), entrapment efficiency of 69% for 5-FU, and 66% for 5-FUC. Moreover, LDL particles have a nanosize range (28-49 nm), negative zeta potential (- 17 to -27 mV), and the entrapment efficiency is 11% for 5-FU and 85% for 5-FUC. Furthermore, 5-FUC loaded liposomes displayed a sustained release profile (57%) at 24 h compared to fast release (92%) of 5-FU loaded liposomes. 5-FUC and liposomal formulas enhanced the transfer of 5-FUC into LDL compared to 5-FU. 5-FUC loaded liposomes and LDL have greater cytotoxicity against HepG2 cell lines compared to 5-FU and 5-FUC solutions. Moreover, the deposition of 5-FUC in LDL (26.87ng/mg) and liver tissues (534 ng/gm tissue) was significantly increased 5-FUC liposomes compared to 5-FU (11.7 ng/g tissue) liposomal formulation. In conclusion, 5-FUC is a promising strategy for hepatic targeting of 5-FU through LDL-mediated gateway.

Improved pharmacokinetic and biodistribution of 5-fluorouracil loaded biomimetic nanoerythrocytes decorated nanocarriers for liver cancer treatment.

Nanoerythrocytes membrane (NEs) has recently been used to improve pharmacokinetics and biodistribution for successful drug therapy. NEs intended to enhance the drug targeting due to immune evasion and long circulation. In this work, NEs could serve as efficient 5- fluorouracil (5-FU) carriers to target liver cells. NEs decorated 5-FU-loaded chitosan coated-poly (lactide-co-glycolic acid) nanoparticles (5-FU-C-NPs-NEs), chitosomes (5-FU-C-LPs-NEs) and 5-FU-NEs were prepared by hypotonic lysis and extrusion procedures. Moreover, 5-FU loaded-chitosan coated 5-FU-NPs (5-FU-C-NPs) and chitosomes (5-FU-C-LPs) for the compared issues were prepared. They were characterized in terms of particle size, encapsulation efficiency (EE), membrane protein content, phosphatidylserine exposure, surface morphology, and in vitro release profiles. Also, their cytotoxic efficacy was determined. Furthermore, pharmacokinetics and biodistribution studies were investigated for optimized formulation. The results revealed that 5-FU-C-NPs-NEs have narrow particle size distribution, desirable EE%, and retained the erythrocyte membrane properties as confirmed by polyacrylamide gel electrophoresis (SDS-PAGE). Additionally, it displayed a sustained release profile up to 72 h of 5-FU-C-NPs-NEs compared to other formulations. In comparison to 5-FU solution and 5-FU-C-NPs, 5-FU-C-NPs-NEs extended the drug release time in vivo with highly uptake by the liver. These results suggest that the 5-FU-C-NPs-NEs could be used to deliver 5-FU and enhance its targetability to liver cancer.

Chitosan-Coated Flexible Liposomes Magnify the Anticancer Activity and Bioavailability of Docetaxel: Impact on Composition.

Flexible liposomes (FLs) were developed as promising nano-carriers for anticancer drugs. Coating them with chitosan (CS) could improve their drug delivery properties. The aim of this study was to investigate the physicochemical characteristics, pharmacokinetics behavior, and cytotoxic efficacy of docetaxel (DTX)-loaded CS-coated FLs (C-FLs). DTX-loaded FLs and C-FLs were produced via thin-film evaporation and electrostatic deposition methods, respectively. To explore their physicochemical characterization, the particle size, zeta potential, encapsulation efficiency (EE%), morphology, and DTX release profiles were determined. In addition, pharmacokinetic studies were performed, and cytotoxic effect was assessed using colon cancer cells (HT29). Various FLs, dependent on the type of surfactant, were formed with particle sizes in the nano-range, 137.6 ± 6.3 to 238.2 ± 14.2 nm, and an EE% of 59⁻94%. Moreover, the zeta potential shifted from a negative to a positive value for C-FL with increased particle size and EE%, and the in vitro sustained-release profiles of C-FL compared to those of FL were evident. The optimized C-FL containing sodium deoxycholate (NDC) and dicetyl phosphate (DP) elicited enhanced pharmacokinetic parameters and cytotoxic efficiency compared to those of the uncoated ones and Onkotaxel®. In conclusion, this approach offers a promising solution for DTX delivery.

Novel docetaxel chitosan-coated PLGA/PCL nanoparticles with magnified cytotoxicity and bioavailability.

In the present study, docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) nanoparticles were successfully prepared and coated with chitosan (CS). The prepared nanoparticles (NPs) were evaluated for their particle size, zeta potential, particle morphology, drug entrapment efficiency (EE%), and in vitro drug release profile. The anticancer activity of DTX-loaded NPs was assessed in human HT29 colon cancer cell line utilizing MTT assay. The pharmacokinetics of DTX-loaded NPs was monitored in Wistar rats in comparison to DTX solution. The prepared NPs exhibited particle sizes in the range 177.1 ± 8.2-287.6 ± 14.3 nm. CS decorated NPs exhibited a significant increase in particle size and a switch of zeta potential from negative to positive. In addition, high EE% values were obtained for CS coated PCL NPs and PLGA NPs as 67.1 and 76.2%, respectively. Moreover, lowering the rate of DTX in vitro release was achieved within 48 h by using CS coated NPs. Furthermore, a tremendous increase in DTX cytotoxicity was observed by CS-decorated PLGA NPs compared to all other NPs including DTX-free-NPs and pure DTX. The in vivo study revealed significant enhancement in DTX bioavailability from CS-decorated PLGA NPs with more than 4-fold increase in AUC compared to DTX solution. In conclusion, CS-decorated PLGA NPs are a considerable DTX-delivery carrier with magnificent antitumor efficacy.

Flexosomes for transdermal delivery of meloxicam: characterization and antiinflammatory activity.

The study aims to investigate the impact of flexosomes (FLs) on transdermal delivery of meloxicam (MLX). FLs are composed of phospholipid, Tween 80, and ethanol which were prepared by film hydration method. The prepared FLs were characterized for particle size, zeta potential, and entrapment efficiency (EE). Ex vivo skin penetration studies were perfomed, and the best formulation was further evaluated using in vivo antiinflammatory activity test. FLs were in nano-size scale carring negative charge and observed high EE% and enhanced skin penetration of MLX compared to conventional liposomes (CLs). The best formula was FL4 which was composedof phospholipid (10%), Tween 80 (1.5%), and ethanol (40%). FL4 showed 143.4 nm vesicle size, 84% EE, and 31-fold ex vivo permeation enhancement through skin compared to CLs. The antiinflammatory activity of FL4 gel showed significant increase compared to control. This study observed the effectiveness of using FLs as carriers for transdermal delivery of MLX.

Simvastatin-loaded nanostructured lipid carriers attenuate the atherogenic risk of erythrocytes in hyperlipidemic rats.

This study aimed to investigate the effect of simvastatin (SV) loaded nanostructured lipid carriers (SV loaded NLCs) on atherogenic index (AI), erythrocytes membrane lipid and antioxidant/pro-oxidant status in hyperlipidemic rats. SV loaded NLCs were successfully prepared with desired nano-particles size, spherical shape, high encapsulation efficiency (EE %) and sustained SV release. The results of biological studies revealed that administration of SV loaded NLCs to rats increased SV bioavailability compared to SV suspension. Intraperitoneal injection of tyloxapol as hyperlipidemic agent induces a significant increase of plasma AI, uric acid, lipid peroxidation and protein oxidation. While, plasma total antioxidant capacity and paraoxonase-1 activity were significantly decreased. Moreover, tyloxapol induced-hyperlipidemia increases erythrocyte's membrane cholesterol and deteriorates erythrocyte's antioxidant enzyme activity, GSH/GSSG ratio and NO level However, the propagation of erythrocyte's pro-oxidant activity and hemolysis was observed. On the contrast, the treatment of these rats with SV loaded NLCs improved the measured parameters compared to rats received SV suspension and hyperlipidemic rats. The predominant effect of SV loaded NLCs may be attributed to the enhancement of absorption, prolonged duration and improvement of bioavailability of SV. Accordingly, SV loaded NLCs showed advantageous effects on the blood lipid levels and atherogenic risk of erythrocytes in hyperlipidemic conditions compared to SV suspension.

Itraconazole-hydroxypropyl-ß-cyclodextrin loaded deformable liposomes: in vitro skin penetration studies and antifungal efficacy using Candida albicans as model.

The study aimed to develop novel ITZ-loaded deformable liposomes (DL) in presence of hydroxypropyl-ß-cyclodextrin (HPßCD) (DL-CD) to enhance antifungal activity. These formulations have been reported as conceivable vesicles to deliver drug molecules to the skin layers. The efficiency of the prepared systems was compared with conventional liposomes (CL) and ITZ solution. The developed liposomes were characterized for particle size, entrapment efficiency (EE %), deformability, stability, and morphology of the vesicles. In addition, ex vivo penetration and antifungal activity were evaluated. It was found that the presence of HPßCD played a significant role in reducing the vesicle size to nano range. The deformability study and TEM images revealed that membrane deformability of DL and DL-CD was much higher than that of CL. Moreover, DL-CD enhanced the amount of ITZ in SC and deeper skin layers compared to DL and CL. The antifungal activity of ITZ-loaded deformable liposomes remained intact compared to ITZ solution. It can be concluded that deformable liposomes in the presence of HPßCD may be a promising carrier for effective cutaneous delivery of ITZ.

Novel sulpiride-loaded solid lipid nanoparticles with enhanced intestinal permeability.

BACKGROUND: Solid lipid nanoparticles (SLN), novel drug delivery carriers, can be utilized in enhancing both intestinal permeability and dissolution of poorly absorbed drugs. The aim of this work was to enhance the intestinal permeability of sulpiride by loading into SLN. METHODS: A unique ultrasonic melt-emulsification method with minimum stress conditions was used for the preparation of SLN. The mixture of the drug and the melted lipids was simply dispersed in an aqueous solution of a surfactant at a temperature that was 10°C higher than the melting points of the lipids using probe sonication, and was then simultaneously dispersed in cold water. Several formulation parameters were optimized, including the drug-to-lipid ratio, and the types of lipids and surfactants used. The produced SLN were evaluated for their particle size and shape, surface charge, entrapment efficiency, crystallinity of the drug and lipids, and the drug release profile. The rat everted sac intestine model was utilized to evaluate the change in intestinal permeability of sulpiride by loading into SLN. RESULTS: The method adopted allowed successful preparation of SLN with a monodispersed particle size of 147.8-298.8 nm. Both scanning electron microscopic and atomic force microscopic images showed uniform spherical particles and confirmed the sizes determined by the light scattering technique. Combination of triglycerides with stearic acid resulted in a marked increase in zeta potential, entrapment efficiency, and drug loading; however, the particle size was increased. The type of surfactant used was critical for particle size, charge, drug loading, and entrapment efficiency. Generally, the in vitro release profile demonstrated by all formulations showed the common biphasic mode with a varying degree of burst release. The everted sac model showed markedly enhanced sulpiride permeability in the case of the SLN-loaded formulation. The in situ results showed a very good correlation with the in vitro release data. CONCLUSION: Incorporation of sulpiride into SLN results in enhanced intestinal permeability of sulpiride, that may in turn increase overall oral absorption of the drug. The superior attributes of the prepared SLN, specifically the high particle size uniformity and drug loading capacity, is considered novel, especially given the simplicity and modest nature of the sonication method used.