Loading Capacity For Hydrophobic Drugs Research Articles

Charge reversal yolk-shell liposome co-loaded JQ1 and doxorubicin with high drug loading and optimal ratio for synergistically enhanced tumor chemo-immunotherapy via blockade PD-L1 pathway

Antitumor immunotherapy has become a powerful therapeutic modality to identify and kill various malignant tumors by harnessing the immune system. However, it is hampered by the immunosuppressive microenvironment and poor immunogenicity in malignant tumors. Herein, in order to achieve multi-loading of drugs with different pharmacokinetic properties and targets, a charge reversal yolk-shell liposome co-loaded with JQ1 and doxorubicin (DOX) into the poly (D,L-lactic-co-glycolic acid) (PLGA) yolk and the lumen of the liposome respectively was engineered to increase hydrophobic drug loading capacity and stability under physiological conditions and further enhance tumor chemotherapy via blockade programmed death ligand 1 (PD-L1) pathway. This nanoplatform could release less JQ1 compared to traditional liposomes to avoid drug leakage under physiological conditions due to the protection of liposomes on JQ1 loaded PLGA nanoparticles while the release of JQ1 increased in an acidic environment. In the tumor microenvironment, released DOX promoted immunogenic cell death (ICD), and JQ1 blocked the PD-L1 pathway to strengthen chemo-immunotherapy. The in vivo antitumor results demonstrated the collaborative treatment of DOX and JQ1 in B16-F10 tumor-bearing mice models with minimized systemic toxicity. Furthermore, the orchestrated yolk-shell nanoparticle system could enhance the ICD effect, caspase 3 activation, and cytotoxic T lymphocyte infiltration while inhibiting PD-L1 expression, provoking a strong antitumor effect, whereas yolk-shell liposomes encapsulating only JQ1 or DOX showed modest tumor therapeutic effects. Hence, the cooperative yolk-shell liposome strategy provides a potential candidate for enhancement of hydrophobic drug loading and stability, showing potential for clinic application and synergistic cancer chemo-immunotherapy.

Swellable hollow periodic mesoporous organosilica capsules with ultrahigh loading capacity for hydrophobic drugs.

As a new kind of drug carrier, practical applications of hollow periodic mesoporous organosilica (HPMO) have been greatly limited by their low loading capacity for hydrophobic drugs. In this work, we demonstrated the preparation of HPMO capsules with tunable shell thickness by using 1,2-bis(triethoxysilyl)ethane as the precursor. The capsules with thin shells and thus low Young's modulus showed excellent swellability to organic solvents containing hydrophobic drugs. As a result, hydrophobic drugs, i.e., paclitaxel (PTX) could be loaded into the hollow interior of the HPMO capsules with 4nm shell at an efficiency of ca. 120%. The as-prepared PTX-loaded HPMO capsules were dispersible in aqueous media and showed improved performance in killing cancer cells compared to free PTX.

Timolol-eluting graphene oxide laden silicone contact lens: Control release profile with improved critical lens properties

Glaucoma is a chronic ocular disease characterized by increase in intraocular pressure (IOP). Currently, it is managed by high drug concentration eye drop solutions. The dosage form present <5% ocular bioavailability, due to ocular static and dynamic barriers. Ocular drug delivery using contact lens can ameliorate the disadvantages of conventional eye drop treatment. However, drug loading by traditional method using drug-packaging solution showed low drug uptake, burst released with altered swelling and optical properties. The direct drug loading method during lens fabrication show high drug loss during mandatory extraction and sterilization steps. Graphene oxide (GO), a single monomolecular layer nano-sheets, exhibit high drug loading capacity for hydrophobic drugs due to its π-conjugated stratum. In the present study, GO was incorporated into the contact lenses during fabrication step, to control the release profile of timolol along with improvement in opto-physical properties. These GO-laden contact lenses (SM-GO-TB) as well as blank contact lenses (SM-TB) were soaked in the solution of timolol. Alternatively, direct timolol-GO-lenses (DL-TB-GO) and direct timolol-lenses (DL-TB) were fabricated by adding timolol-GO and timolol during polymerization, respectively. GO improved the swelling of both soaked and direct laden contact lenses due to formation of hydrogen bounds between GO and water molecules. A significant improvement in the transmittance of GO-laden contact lenses was observed because of molecular dispersion of drug on the surface of GO. The addition of GO in the soaked and direct timolol-laden contact lenses showed significant decrease in burst release and improvement in the release profiles compared to respective contact lenses without GO. Thus, the study demonstrated that GO-laden contact lenses could improve the critical lens properties like swelling and transmittance with controlled release of timolol.

Endogenous Oleoylethanolamide Crystals Loaded Lipid Nanoparticles with Enhanced Hydrophobic Drug Loading Capacity for Efficient Stroke Therapy.

IntroductionAlthough the preparation of lipid nanoparticles (LNPs) achieves great success, their retention of highly hydrophobic drugs is still problematic.MethodsHerein, we report a novel strategy for efficiently loading hydrophobic drugs to LNPs for stroke therapy. Oleoylethanolamide (OEA), an endogenous highly hydrophobic molecule with outstanding neuroprotective effect, was successfully loaded to OEA-SPC&DSPE-PEG lipid nanoparticles (OSDP LNPs) with a drug loading of 15.9 ± 1.2 wt%. Efficient retention in OSDP LNPs greatly improved the pharmaceutical property and enhanced the neuroprotective effect of OEA.ResultsThrough the data of positron emission tomography (PET) and TTC-stained brain slices, it could be clearly visualized that the acute ischemic brain tissues were preserved as penumbral tissues and bounced back with reperfusion. The in vivo experiments stated that OSDP LNPs could significantly improve the survival rate, the behavioral score, the cerebral infarct volume, the edema degree, the spatial learning and memory ability of the MCAO (middle cerebral artery occlusion) rats.DiscussionThese results suggest that the OSDP LNPs have a great chance to develop hydrophobic OEA into a potential anti-stroke formulation.

Nanocomposite Hydrogels: A Promising Approach for Developing Stimuli-responsive Platforms and their Application in Targeted Drug Delivery

Introduction: With the development of hydrogels from half a century ago, their application in various medical fields, including drug delivery has been widely expanded. Hydrogels used in this field are produced with synthetic polymers such as polyvinylpyrrolidone, polyvinyl alcohol, or natural polymers like chitosan, agarose, and hyaluronic acid to develop biocompatible, biodegradable, and non-immunogenic drug carriers. However, limitations such as inadequate response to stimulation, low homogeneity, and poor loading capacity for hydrophobic drugs have limited the use of hydrogels for drug delivery due to the hydrophilic nature of the hydrogel. The use of nanoparticles in the structure of hydrogels to produce hydrogel nanocomposites leads to more diverse interactions such as hydrogen and electrostatic bonds in addition to covalent interactions between hydrogel polymers. In addition to enhancing the mechanical properties of the hydrogel and further homogeneity, these interactions lead to the formation of platforms responsive to various stimuli, attaining sustained release, and ameliorating the poor loading of hydrophobic drugs used in cancer treatment and wound dressing.&#x0D; Conclusion: A review of a research conducted in the last 20 years represents that the application of nanocomposite hydrogels in drug delivery includes a wide range of production methods, nanoparticles to create various stimulation mechanisms, and therapeutic applications. Indeed, research has been focused on developing smart systems for controlled release with stimuli to reduce side effects of conventional cancer treatment methods, such as chemotherapy, by targeting drug delivery and reducing drug administration frequency and mitigating chronic wound complications by the release of growth factors.

Preparation and In Vitro Cytotoxicity Assessments of Spherical Silica-Encapsulated Liposome Particles for Highly Efficient Drug Carriers.

This work reports the formation of spherical solid silica-encapsulated liposome particles (SLPs) as functions of the concentration of silica precursor, reaction time, temperature, and volume ratios of solvent, respectively. The solid SLPs are more robust and have better drug-loading-efficiency liquid liposomes in carrier formulations. The liquid-state liposomes are hard to handle and have a lower drug-loading efficiency because they are fragile to external stimuli and have narrow hydrophobic phospholipid bilayers. The SLPs were obtained by silicification with tetraethyl orthosilicate (TEOS) in the hydrophilic region of phospholipid bilayers by a sol-gel process. These SLPs were characterized by scanning electron microscopy (SEM), focused ion beam (FIB)-SEM, confocal laser scanning microscopy (CLSM), thermogravimetric analysis (TGA), ζ-potential, X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and UV-vis spectroscopy. The obtained SLPs were spherical with an average size of 2-3 μm. The hydrophilic region of the SLP phospholipid bilayers was confirmed using CLSM with green fluorescent fluorescein isothiocyanate (FITC) labeling and FIB-SEM. Furthermore, the drug-loading capacity and in vitro cytotoxicity assessments were performed using several drug compounds and L929 cells. The drug-loading capacity of the SLPs was >95%, and in particular, the hydrophobic drug-loading capacity was 2.3 times higher than that of general liposomes. Moreover, the result of an in vitro cytotoxicity assessment of the SLPs was good, about 99% of cell viability.

Sonochemical preparation of folic acid-decorated reductive-responsive ε-poly-L-lysine-based microcapsules for targeted drug delivery and reductive-triggered release.

In this work, a versatile folic acid (FA) decorated reductive-responsive ε-poly-l-Lysine (ε-PL)-based microcapsules (FA-ε-PLMCs) were designed and facilely assembled by using sonochemical technique. Cellular uptake experiment of FA-ε-PLMCs loaded with Coumarin 6 (C6) as a model of hydrophobic drugs implied that hydrophobic drugs encapsulated inside FA-ε-PLMCs could be delivered selectively into Hela cells via folate-receptor (FR)-mediated endocytosis due to FA decorated on microcapsules. Furthermore, the shells of FA-ε-PLMCs cross-linked by disulfide bonds were derived from sulfhydryl groups (-SH) under ultrasonication. Under reductive environment, the hydrophobic drugs loaded in FA-ε-PLMCs would be easily released due to the cleavage of disulfide bonds. Benefiting from their suitable particle size, good loading capacity for hydrophobic drugs, remarkable targetability and reductive-triggered release, the obtained FA-ε-PLMCs could be a promising hydrophobic drugs carrier for the cancer treatment.

Role of zein incorporation on hydrophobic drug-loading capacity and colloidal stability of phospholipid nanoparticles.

Liposome, phosphatidylcholine nanoparticle (PC-NP), is an attractive colloidal carrier of hydrophobic drugs but its clinical development is often limited by low drug-loading capacity and the physical instability. Zein is a water-insoluble amphiphilic protein obtained from the corn. We herein investigated a possibility to develop zein-phosphatidylcholine hybrid nanoparticle (Z/PC-NP) as an advanced hydrophobic drug carrier. By employing the conventional liposome preparation method with the addition of zein, Z/PC-NP were produced. The extent of zein incorporation in PC-NP was affected by PC composition. DSC demonstrated the lowered phase transition temperature of PC by zein and FTIR showed the appearance of weakened but clear amide bonds of zein as well as increased levels of heterogeneous hydrogen bonding of Z/PC-NP compared to PC-NP. DLS, TEM and cryo-TEM studies suggested Z/PC-NP to be spherical nanoparticles composed of a zein core and a zein-PC hybrid shell. Z/PC-NP exhibited a higher loading capacity for hydrophobic model drugs (paclitaxel, docetaxel, celecoxib and curcumin), than did the zein nanoparticle and PC-NP, while exhibiting an intermediate drug release rate. The serum stability and the storage stability of Z/PC-NP were greater than those of PC-NP. Zein functioned as a cryoprotectant of PC-NP during freeze-drying. Z/PC-NP may provide a promising nanoparticle carrier of hydrophobic drugs.

Importance of Encapsulation Stability of Nanocarriers with High Drug Loading Capacity for Increasing in Vivo Therapeutic Efficacy.

Current drug delivery systems are hampered by poor delivery to tumors, in part reflecting poor encapsulation stability of nanocarriers. Although nanocarriers such as polymeric micelles have high colloidal stability and do not aggregate or precipitate in bulk solution, nanocarriers with low encapsulation stability can lose their cargo during circulation in blood due to interactions with blood cells, cellular membranes, serum proteins, and other biomacromolecules. The resulting premature drug release from carriers limits the therapeutic efficacy at target sites. Herein, we report a simple and robust technique to improve encapsulation stability of drug delivery systems. Specifically, we show that installation of disulfide cross-linked noncovalent polymer gatekeepers onto mesoporous silica nanoparticles with a high loading capacity for hydrophobic drugs enhances in vivo therapeutic efficacy by preventing premature release of cargo. Subsequent release of drug cargos was triggered by cleavage of disulfide cross-linking by glutathione, leading to improved antitumor activity of doxoroubicin in mice. These findings provide novel insights into the development of nanocarriers with high encapsulation stability and improved in vivo therapeutic efficacy.

Application of a simple desolvation method to increase the formation yield, physical stability and hydrophobic drug encapsulation capacity of chitosan-based nanoparticles

As one of the classical nano drug carriers, chitosan-based nanoparticles (CsNps) are getting increasing attentions for their non-toxicity, biocompatibility and biodegradability. The ionotropic gelation is the most favorable method for CsNps preparation, while it’s beset by some issues, i.e. low particle formation yield, poor physical stability and low hydrophobic drug loading capacity. To solve these problems, a simple desolvation method was attempted in this study for CsNps preparation. Using this method, an increased formation yield of CsNps (about 100%) could be obtained, and after diluting the particles by various buffers (PBS 7.0, 7.4 and 8.0, DMEM medium and 1640 medium), an improved stability in diameter could be observed. The drug loading results showed paclitaxel loading efficiency of 9.8% could be obtained when the ratio of paclitaxel to Cs was set at 0.2, higher than the ionotropic gelation method (0.43%). The particles formation mechanisms were studied by the molecular dynamics simulation, and the results showed the Lennard-Jones interaction of Cs-Cs, which could be adjusted by the pH value of system, played a great role in formation of particles with the desolvation method. This study provided an alternative preparation technology for CsNps with high process yield, physical stability and hydrophobic drug encapsulation capacity.

Facile Synthesis of Yolk-Shell-Structured Triple-Hybridized Periodic Mesoporous Organosilica Nanoparticles for Biomedicine.

The synthesis of mesoporous nanoparticles with controllable structure and organic groups is important for their applications. In this work, yolk-shell-structured periodic mesoporous organosilica (PMO) nanoparticles simultaneously incorporated with ethane-, thioether-, and benzene-bridged moieties are successfully synthesized. The preparation of the triple-hybridized PMOs is via a cetyltrimethylammonium bromide-directed sol-gel process using mixed bridged silsesquioxanes as precursors and a following hydrothermal treatment. The yolk-shell-structured triple-hybridized PMO nanoparticles have large surface area (320 m(2) g(-1) ), ordered mesochannels (2.5 nm), large pore volume (0.59 cm(3) g(-1) ), uniform and controllable diameter (88-380 nm), core size (22-110 nm), and shell thickness (13-45 nm). In vitro cytotoxicity, hemolysis assay, and histological studies demonstrate that the yolk-shell-structured triple-hybridized PMO nanoparticles have excellent biocompatibility. Moreover, the organic groups in the triple-hybridized PMOs endow them with an ability for covalent connection of near-infrared fluorescence dyes, a high hydrophobic drug loading capacity, and a glutathione-responsive drug release property, which make them promising candidates for applications in bioimaging and drug delivery.

Hydrophobic Cysteine Poly(disulfide)‐based Redox‐Hypersensitive Nanoparticle Platform for Cancer Theranostics

AbstractSelective tumor targeting and drug delivery are critical for cancer treatment. Stimulus‐sensitive nanoparticle (NP) systems have been designed to specifically respond to significant abnormalities in the tumor microenvironment, which could dramatically improve therapeutic performance in terms of enhanced efficiency, targetability, and reduced side‐effects. We report the development of a novel L‐cysteine‐based poly (disulfide amide) (Cys‐PDSA) family for fabricating redox‐triggered NPs, with high hydrophobic drug loading capacity (up to 25 wt % docetaxel) and tunable properties. The polymers are synthesized through one‐step rapid polycondensation of two nontoxic building blocks: L‐cystine ester and versatile fatty diacids, which make the polymer redox responsive and give it a tunable polymer structure, respectively. Alterations to the diacid structure could rationally tune the physicochemical properties of the polymers and the corresponding NPs, leading to the control of NP size, hydrophobicity, degradation rate, redox response, and secondary self‐assembly after NP reductive dissociation. In vitro and in vivo results demonstrate these NPs’ excellent biocompatibility, high selectivity of redox‐triggered drug release, and significant anticancer performance. This system provides a promising strategy for advanced anticancer theranostic applications.

Hydrophobic Cysteine Poly(disulfide)-based Redox-Hypersensitive Nanoparticle Platform for Cancer Theranostics.

Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus-sensitive nanoparticle (NP) systems have been designed to specifically respond to significant abnormalities in the tumor microenvironment, which could dramatically improve therapeutic performance in terms of enhanced efficiency, targetability, and reduced side-effects. We report the development of a novel L-cysteine-based poly (disulfide amide) (Cys-PDSA) family for fabricating redox-triggered NPs, with high hydrophobic drug loading capacity (up to 25 wt% docetaxel) and tunable properties. The polymers are synthesized through one-step rapid polycondensation of two nontoxic building blocks: L-cystine ester and versatile fatty diacids, which make the polymer redox responsive and give it a tunable polymer structure, respectively. Alterations to the diacid structure could rationally tune the physicochemical properties of the polymers and the corresponding NPs, leading to the control of NP size, hydrophobicity, degradation rate, redox response, and secondary self-assembly after NP reductive dissociation. In vitro and in vivo results demonstrate these NPs' excellent biocompatibility, high selectivity of redox-triggered drug release, and significant anticancer performance. This system provides a promising strategy for advanced anticancer theranostic applications.

Effects of triglycerides on the hydrophobic drug loading capacity of saturated phosphatidylcholine-based liposomes

A high drug-loading capacity is a critical factor for the clinical development of liposomal formulations. The accommodation of hydrophobic drugs within the liposomal membrane is often limited in saturated phosphatidylcholine (PC)-based liposomes owing to the rigidity of the lipid acyl chain. In the current study, we explored the possibility of improving the hydrophobic drug loading capacity of liposomes by incorporating triglyceride into liposomal membranes. Incorporation of Captex 300, a medium chain triglyceride, into liposomes composed of dimyristoylphosphatidylcholine and cholesterol greatly increased the fluidity and lamellarity of the resultant liposomes. Liposomal incorporation of medium or long chain, but not short chain, triglycerides greatly enhanced the concentration of loaded paclitaxel (PTX) in saturated PC-based liposomes. The enhancing effect of triglyceride saturated at a triglyceride content corresponding to the amount required to fluidize the liposome structure. In addition, the enhancing effect was not observed in unsaturated PC-based liposomes and was not associated with the solubility of PTX in each triglyceride. Triglycerides also enhanced the loading of docetaxel, another hydrophobic drug. Taken together, our results suggest that triglyceride incorporation in saturated PC-based liposomes provide an improved dosage form that enables increased hydrophobic drug loading by altering the fluidity and structure of liposomal membranes.

Microfluidic assembly of multistage porous silicon-lipid vesicles for controlled drug release.

A reliable microfluidic platform for the generation of stable and monodisperse multistage drug delivery systems is reported. A glass-capillary flow-focusing droplet generation device was used to encapsulate thermally hydrocarbonized porous silicon (PSi) microparticles into the aqueous cores of double emulsion drops, yielding the formation of a multistage PSi-lipid vesicle. This composite system enables a large loading capacity for hydrophobic drugs.

Amphoteric calix[8]arene-based complex for pH-triggered drug delivery

Amphoteric calix[8]arene with negatively charged upper rim and positively charged lower rim was synthesized based on water-soluble p-sulfonato-calix[8]arene. The pH-sensitive amphoteric calix[8]arenes exhibit not only a good hydrophobic drug loading capacity but also a pH-triggered drug releasing behavior. The in vitro release studies demonstrated that release of ciprofloxacin from amphoteric calix[8]arene complexes was highly pH-sensitive. More efficient drug release was observed at mildly acidic pH 5.0 and basic pH 8.5 compared to physiological pH. The amphoteric calix[8]arene complexes hold out great promise of being pH-sensitive drug carrier.

Mesoporous Biocompatible and Acid-Degradable Magnetic Colloidal Nanocrystal Clusters with Sustainable Stability and High Hydrophobic Drug Loading Capacity

Fabrication of magnetic particles (MPs) with high magnetization and large surface area simultaneously is critical for the application of MPs in bioseparation and drug delivery but remains a challenge. In this article, we describe an unprecedented approach to synthesize mesoporous magnetic colloidal nanocrystal clusters (MCNCs) stabilized by poly(γ-glutamic acid) (PGA) with high magnetization, large surface area (136 m(2)/g) and pore volume (0.57 cm(3)/g), excellent colloidal stability, prominent biocompatibility, and acid degradability. This result provides the important step toward the construction of a new family of MCNCs and demonstrates its capacity in a "magnetic motor" drug delivery system. Here, as an example, we explore the applicability of as-prepared mesoporous MCNCs as hydrophobic drug delivery vehicles (paclitaxel as model drug), and the resultant loading capacity is as high as 35.0 wt %. The antitumor efficacy measured by MTT assay is significantly enhanced, compared with free drugs. Thus, combined with their inherent high magnetization, the mesoporous MCNCs pave the way for applying magnetic targeting drug carriers in antitumor therapeutics.

The preparation of liposomes using compressed carbon dioxide: strategies, important considerations and comparison with conventional techniques

Numerous strategies are currently available for preparing liposomes, although no single method is ideal in every respect. Two methods for producing liposomes using compressed carbon dioxide in either its liquid or supercritical state were therefore investigated as possible alternatives to the conventional techniques currently used. The first technique used modified compressed carbon dioxide as a solvent system. The way in which changes in pressure, temperature, apparatus geometry and solvent flow rate affected the size distributions of the formulations was examined. In general, liposomes in the nano-size range with an average diameter of 200 nm could be produced, although some micron-sized vesicles were also present. Liposomes were characterized according to their hydrophobic drug-loading capacity and encapsulated aqueous volumes. The latter were found to be higher than in conventional techniques such as high-pressure homogenization. The second method used compressed carbon dioxide as an anti-solvent to promote uniform precipitation of phospholipids from concentrated ethanolic solutions. Finely divided solvent-free phospholipid powders of saturated lipids could be prepared that were subsequently hydrated to produce liposomes with mean volume diameters of around 5 microm.