Drug Loading Ratio Research Articles

Dramatically Increased Binding Constant of Water-Soluble Cyclodextrin Hyperbranched Polymers: Explored with Diffusion Ordered NMR Spectroscopy (DOSY).

We report that the polymerization of cyclodextrin (CD) with epichlorohydrin (ECH) dramatically increases the binding constant of CD to vanillin, from 55 to 8.4 × 103 M–1, by approximately 100 times, as determined by diffusion ordered spectroscopy (DOSY)–1H NMR. The binding constant increased with an increase of the ECH content of the polymer, although ECH polymers without CDs showed no affinity at all, suggesting that the hydrophobicity of the ECH network outside of CDs helps to enhance the binding. This increased binding constant allows CD–ECH polymers to increase the drug loading ratio, which may be one of the most critical issues for drug delivery systems.

Drug-grafted DNA as a novel chemogene for targeted combinatorial cancer therapy.

Combinatorial therapy based on chemotherapeutic drugs and gene agents to achieve synergistic antitumor effects has emerged as a new direction for cancer treatment. However, simple and efficient co-delivery of those two drug categories remains a key challenge in this hot area owing to their substantially different pharmacodynamics, impeding the translational potentials of combinatorial approaches. To address this issue, herein we propose a simple strategy to site-specifically graft camptothecins (CPTs, a representative chemodrug) onto a DNA with dual functional segments, including an AS1411 aptamer sequence to target the cancer cell and a BCL-2 antisense sequence to down-regulate the anti-apoptotic gene. The obtained DNA-drug conjugate possesses precise chemical composition, controllable drug loading ratio, and responsive disulfide linkage, which can serve as a novel type of chemogene for combinatorial cancer therapy. In both in vitro and in vivo evaluations, our CPT-bearing chemogene exhibit the targeted co-delivery of chemo and gene agents to tumor site, efficient BCL-2 gene knockdown, and strong induced apoptosis of cancer cells, together leading into an enhanced antitumor efficacy. With simple and precise structure as well as facile synthetic procedure, the new chemogene may turn into a promising drug formulation for combinatorial antitumor treatment.

Antibacterial and antioxidant chitosan nanoparticles improve the preservation effect for donor kidneys in vitro

Hypothermic machine perfusion (HMP) is a preferable measure to preserve kidneys from donation after cardiac death (DCD), while the current standard perfusate is imperfect. We synthesized amphiphilic chitosan, N-alkylated-O-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (N-alkyl-O-HTCC) as additive in the perfusate, which can self-assembly into micelles in water (size 133 ± 8.48 nm) (ζ-potential 43.9 ± 2.06 mV), with good antibacterial activity for Escherichia coli and Staphylococcus aureus. The derivates can also deliver hydrophobic drug Alda-1 into kidneys through HMP, with drug loading ratio (~42.14%). The delivery system specifically activated mitochondrial acetaldehyde dehydrogenase 2 in kidneys and reduced the ischemic injury. What's more, the addition of N-alkyl-O-HTCC in HMP also activated mitochondria superoxide dismutase 2, presented nice antioxidant activity. These all helped to improve the quality of DCD kidneys. This study provides a feasible amphiphilic carrier for hydrophobic drugs, and provides efficient guidance for perfusate improvement.

Aptamers Entirely Built from Therapeutic Nucleoside Analogues for Targeted Cancer Therapy.

Owing to the specific and high binding affinity of aptamers to their targets, aptamer-drug conjugates (ApDCs) have emerged as a promising drug delivery system for targeted cancer therapy. However, in a conventional ApDC, the aptamer segment usually just serves as a targeting moiety, and only a limited number of drug molecules are sequentially conjugated to the oligonucleotide, giving a relatively low drug loading capacity. To address this challenge, herein we employ four clinically approved nucleoside analogues, including clofarabine (Clo), ara-guanosine (AraG), gemcitabine (Ge), and floxuridine (FdU), to replace all natural nucleosides in aptamer sequences, generating a series of whole drug-constituted DNA-like oligomers that are termed drugtamers. Similar to their parent aptamers, the obtained drugtamers maintain the targeting capability and can specifically bind to the target receptors overexpressed on the cancer cell surface. With 100% drug loading ratio, active targeting capability, and enzyme-mediated release of active therapeutics, our drugtamers can strongly induce the apoptosis of cancer cells and inhibit the tumor progression, which enables a new potential for a better targeted cancer therapy.

Dual-responsive nano-prodrug micelles for MRI-guided tumor PDT and immune synergistic therapy.

Micelles as nanocarriers not only offer new opportunities for early diagnosis and treatment of malignant cancers but also encounter numerous barriers in the path of efficient delivery of drugs to diseased areas in the body. To address these issues, we developed a pH/GSH responsive nano-prodrug micelle (NLG919/PGA-Cys-PPA@Gd) with a high drug-loading ratio and controlled drug release performance for MRI-guided tumor photodynamic therapy (PDT) and immune synergistic therapy. Under normal conditions, theranostic nanomicelles remained stable and in a photo-quenched state. Upon accumulation in the tumor site, however, the micelles demonstrated tumor microenvironment (TME) triggered photoactive formed-PPA (a photosensitizer) and NLG919 (an indoleamine 2,3-dioxygenase (IDO) inhibitor) release because the amide bonds of PGA-Cys-PPA and the disulfide linkage of Cys were sensitive to pH and GSH, respectively. More importantly, these micelles could avoid the undesired PPA leakage in blood circulation due to the conjugation between PPA and polymers. Furthermore, the obtained micelles could also enhance the contrast of T1-weighted MRI of tumors by virtue of their high relaxivity (r1 = 29.85 mM-1 s-1). In vitro and in vivo results illustrated that the micelles had good biocompatibility and biosafety. On the basis of the efficient drug delivery strategies in PDT and IDO pathway inhibition, this intelligent dual-drug delivery system could serve as an effective approach for MRI guided combination therapy of cancer.

Mechanism Study of Thermally Induced Anti-Tumor Drug Loading to Engineered Human Heavy-Chain Ferritin Nanocages Aided by Computational Analysis

Diverse drug loading approaches for human heavy-chain ferritin (HFn), a promising drug nanocarrier, have been established. However, anti-tumor drug loading ratio and protein carrier recovery yield are bottlenecks for future clinical application. Mechanisms behind drug loading have not been elaborated. In this work, a thermally induced drug loading approach was introduced to load anti-tumor drug doxorubicin hydrochloride (DOX) into HFn, and 2 functionalized HFns, HFn-PAS-RGDK, and HFn-PAS. Optimal conditions were obtained through orthogonal tests. All 3 HFn-based proteins achieved high protein recovery yield and drug loading ratio. Size exclusion chromatography (SEC) and transmission electron microscopy (TEM) results showed the majority of DOX loaded protein (protein/DOX) remained its nanocage conformation. Computational analysis, molecular docking followed by molecular dynamic (MD) simulation, revealed mechanisms of DOX loading and formation of by-product by investigating non-covalent interactions between DOX with HFn subunit and possible binding modes of DOX and HFn after drug loading. In in vitro tests, DOX in protein/DOX entered tumor cell nucleus and inhibited tumor cell growth.

Sequential Release of Paclitaxel and Imatinib from Core-Shell Microparticles Prepared by Coaxial Electrospray for Vaginal Therapy of Cervical Cancer.

To optimize the anti-tumor efficacy of combination therapy with paclitaxel (PTX) and imatinib (IMN), we used coaxial electrospray to prepare sequential-release core–shell microparticles composed of a PTX-loaded sodium hyaluronate outer layer and an IMN-loaded PLGA core. The morphology, size distribution, drug loading, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, PLGA degradation, cellular growth inhibition, in vivo vaginal retention, anti-tumor efficacy, and local irritation in a murine orthotopic cervicovaginal tumor model after vaginal administration were characterized. The results show that such core–shell microparticles were of spherical appearance, with an average size of 14.65 μm and a significant drug-loading ratio (2.36% for PTX, 19.5% for IMN, w/w), which might benefit cytotoxicity against cervical-cancer-related TC-1 cells. The DSC curves indicate changes in the phase state of PTX and IMN after encapsulation in microparticles. The FTIR spectra show that drug and excipients are compatible with each other. The release profiles show sequential characteristics in that PTX was almost completely released in 1 h and IMN was continuously released for 7 days. These core–shell microparticles showed synergistic inhibition in the growth of TC-1 cells. Such microparticles exhibited prolonged intravaginal residence, a >90% tumor inhibitory rate, and minimal mucosal irritation after intravaginal administration. All results suggest that such microparticles potentially provide a non-invasive local chemotherapeutic delivery system for the treatment of cervical cancer by the sequential release of PTX and IMN.

PH/ROS Dual-Responsive Polymer–Drug-Based Nanocarriers: Click-Reaction Preparation and Fluorescence Imaging-Guided Chemotherapy and Photodynamic Therapy

In the past decades, polymer-drug conjugates of anticancer agents have gained much attention due to their enhanced aqueous solubility, improved pharmacokinetics, and better drug utilization than their conventional insoluble counterparts. Several polymer-drug conjugates have entered the third phase of clinical trials yet suffer from inherent deficiencies, including uncontrolled drug release and unclear degradation mechanisms. In this study, a pH/reactive oxygen species (ROS) dual-responsive PEG-doxorubicin (DOX) conjugate (denoted as TPD) was synthesized through acyl alkynyl-amine click reaction by PEG dipropiolate (PEGB), amine-terminated thioketal (TKL), and doxorubicin (DOX). Due to the generated ene-amine and thioketal in the backbone, the prepared amphiphilic TPD not only has a high drug loading ratio for photosensitizer chlorin e6 (Ce6) but also has the sensitivity to the acidic tumor microenvironment (TME) and ROS. Considering the complex conditions of TME, the prepared TPD@Ce6 nanoparticles (NPs) might respond to the relatively low pH and release Ce6 initially, and upon laser radiation, Ce6 produces abundant singlet oxygen (1O2) to achieve a programmable accelerated release of DOX and more Ce6 at the tumor site. In addition, the NIR fluorescence of DOX could monitor drug delivery and controlled release. The developed TPD@Ce6 NPs can realize the targeted tumor in combination therapy with negligible cytotoxicity on normal tissues.

Construction polyprodrugs by click-reactions and metal-coordination: pH-responsive release for magnetic resonance imaging guided chemotherapy

It is a long-pursued goal to construct various smart theranostics nanoplatforms by facile and repeatable method for personalized tumor treatment. Herein, we employed novel alkyne-phenol and alkyne-amine click-reaction to fabricate responsively biodegradable and multimodal polymeric nanoplatforms for magnetic resonance imaging (MRI) guided effective chemotherapy. The antitumor drug doxorubicin (DOX) and some essential amino acid such as lysine could react with trimethylolpropane tripropiolate (TMP) in a quite mild conditions (room temperature and weak alkaline) by facile click-reactions to give polyprodrugs, the carboxyl and excess amino groups on LTD tended to further coordinate with Mn2+ to afforded metal-coordinated-polyprodrugs (termed as LTD@Mn2+). The resulting LTD@Mn2+ nanoparticles have high covalently drug loading ratio (up to 35%), and could effectively and responsively release DOX and Mn2+ in the acidic environment of tumor cells (extracellular pH ~6.8, endosomes and lysosomes pH ~5.0), because the resulting vinyl-ether and vinyl-amino bonds in LTD@Mn2+ are stable in neutral physiological environment but tend to be broken in acidic conditions. The smart LTD@Mn2+ nanoplatforms not only showed significant tumor inhibit efficiency and negligible damage to normal tissues both in vitro and in vivo due to the high drug loading ratio and controlled release properties, but also provided satisfied MRI quality for assessment the treatment effect because of the magnetic nature of Mn2+. Thus, the metal-ligated polyprodrug suggests a new strategy for the simple and repeatable preparation of polyprodrugs for precise and personalized treatment of tumors.

A small molecule nanodrug consisting of pH-sensitive ortho ester–dasatinib conjugate for cancer therapy

The main objective of this paper is to develop a self-delivered prodrug system with nanoscale characteristics to enhance the efficacy of tumor therapy. The pH-sensitive prodrug was composed of ortho ester-linked dasatinib (DAS-OE), which was further self-assembled with or without doxorubicin (DOX) to obtain two carrier-free nanoparticles (DOX/DAS-OE NPs or DAS-OE NPs). The prodrug-based nanoparticles united the superiorities of small molecules and nano-assemblies together and displayed well-defined structure, uniform spherical shape, high drug loading ratio and on-demand drug release behavior. The drug loading content of DAS and DOX was 61.6% and 21.9%, respectively, and more than 80.2% of DAS and 60.2% DOX were released from DOX/DAS-OE NPs within 20 h at pH 5.0. Both in vitro and in vivo studies demonstrated that the pH-sensitive ortho ester bonds in the prodrug underwent hydrolysis to release DAS and DOX simultaneously after cellular internalization, resulting in remarkable antitumor effect. Tumor growth inhibition rate was 19.9% (free DAS), 35.5% (free DOX), 66.3% (DAS-OE NPs) and 82.8% (DOX/DAS-OE NPs), respectively. Thus, the ortho ester-linked prodrug system shows great potentials in cancer therapy.

Facile preparation of pH/redox dual-responsive biodegradable polyphosphazene prodrugs for effective cancer chemotherapy

In order to maximize the therapeutic effect and and minimize the systemtic side effect of the small molecule anticancer drugs, biodegradable drug delivery systems (DDSs) that respond to tumor microenvironment (TME) have attracted significant attention. Herein, a novel redox/pH dual-responsive and biodegradable polyphosphazene (PPZ) nano-prodrugs have been prepared via one-pot crosslinking of vanillin modified DOX (VMD, acid-sensitive) and 4,4′-dihydroxydiphenyl disulfide (HPS, GSH-responsive) with hexachlorocyclotriphosphazene (HCCP). The phenol groups of the as-synthesized VMD and HPS have high nucleophilic substitution activity towards HCCP under base catalyst and afforded PPZ nano-prodrugs, denoted as HCCP-VMD-HPS, with a high drug loading ratio of up to 56.4 %. As expected, the skeleton of the PPZ consisting of imine bonds in VMD and the disulfide bonds in HPS and cyclotriphosphazenes inclined to be decomposed in low pH conditions and high level of GSH environments. The antitumor drug DOX was found to be controlled released in TME conditions (extracellular, pH∼6.8 and endosomes, lysosomes pH∼5.0 with ∼10 mM GSH), rather than neutral physiological conditions (pH 7.4 with ∼20 μM GSH). Moreover, the resulting HCCP-VMD-HPS nano-prodrug have obvious cytotoxicity to cancer cells while a negligible side effect to normal cells. We therefore believe that the prepared redox/pH dual-responsive and biodegradable PPZ DDSs have great potential in various field.

Construction of a Mesoporous Polydopamine@GO/Cellulose Nanofibril Composite Hydrogel with an Encapsulation Structure for Controllable Drug Release and Toxicity Shielding.

The development of intelligent and multifunctional hydrogels having photothermal properties, good mechanical properties, sustained drug release abilities with low burst release, antibacterial properties, and biocompatibility is highly desirable in the biomaterial field. Herein, mesoporous polydopamine (MPDA) nanoparticles wrapped with graphene oxide (GO) were physically cross-linked in cellulose nanofibril (CNF) hydrogel to obtain a novel MPDA@GO/CNF composite hydrogel for controllable drug release. MPDA nanoparticles exhibited a high drug loading ratio (up to 35 wt %) for tetracycline hydrochloride (TH). GO was used to encapsulate MPDA nanoparticles for extending the drug release time and reinforcing the physical strength of the obtained hydrogel. The mechanical strength of the as-fabricated MPDA@GO/CNF composite hydrogel was five times greater compared to that of the pure CNF hydrogel. Drug release experiments demonstrated that burst release behavior was significantly reduced by adding MPDA@GO. The drug release time of the MPDA@GO/CNF composite hydrogel was 3 times and 7.2 times longer than that of the polydopamine/CNF hydrogel and pure CNF hydrogel, respectively. The sustained and controlled drug release behaviors of the composite hydrogel were highly dependent on the proportion of MPDA and GO. Moreover, the rate of drug release could be accelerated by near-infrared (NIR) light irradiation and pH value change. The drug release kinetics of the as-prepared composite hydrogel was well described by the Korsmeyer-Peppas model, and the drug release mechanism of TH from the composite hydrogel was anomalous transport. Importantly, this carefully designed MPDA@GO/CNF composite hydrogel showed good biocompatibility through an in vitro cytotoxicity test. In particular, the toxicity of GO was well shielded by the CNF hydrogel. Therefore, this novel MPDA@GO/CNF composite hydrogel with an encapsulation structure for controllable drug release and toxicity shielding of GO could be used as a very promising controlled drug delivery carrier, which may have potential applications for chemical and physical therapies.

Preparation, Biosafety, and Cytotoxicity Studies of a Newly Tumor-Microenvironment-Responsive Biodegradable Mesoporous Silica Nanosystem Based on Multimodal and Synergistic Treatment.

Patients with triple negative breast cancer (TNBC) often suffer relapse, and clinical improvements offered by radiotherapy and chemotherapy are modest. Although targeted therapy and immunotherapy have been a topic of significant research in recent years, scientific developments have not yet translated to significant improvements for patients with TNBC. In view of these current clinical treatment shortcomings, we designed a silica nanosystem (SNS) with Nano-Ag as the core and a complex of MnO2 and doxorubicin (Dox) as the surrounding mesoporous silica shell. This system was coated with anti-PD-L1 to target the PD-L1 receptor, which is highly expressed on the surface of tumor cells. MnO2 itself has been shown to act as chemodynamic therapy (CDT), and Dox is cytotoxic. Thus, the full SNS system presents a multimodal, potentially synergistic strategy for the treatment of TNBC. Given potential interest in the clinical translation of SNS, the biological safety and antitumor activity of SNS were evaluated in a series of studies that included physicochemical characterization, particle stability, blood compatibility, and cytotoxicity. We found that the particle size and zeta potential of SNS were 94.6 nm and -22.1 mV, respectively. Ultraviolet spectrum analysis showed that Nano-Ag, Dox, and MnO2 were successfully loaded into SNS, and the drug loading ratio of Dox was about 10.2%. Stability studies found that the particle size of SNS did not change in different solutions. Hemolysis tests showed that SNS, at levels far exceeding the anticipated physiologic concentrations, did not induce red blood cell lysis. Further in vitro and in vivo experiments found that SNS did not activate platelets or cause coagulopathy and had no significant effects on the total number of blood cells or hepatorenal function. Cytotoxicity experiments suggested that SNS significantly inhibited the growth of tumor cells by damaging cell membranes, increasing intracellular ROS levels, inhibiting the release of TGF-β1 cytokines by macrophages, and inhibiting intracellular protein synthesis. In general, SNS appeared to have favorable biosafety and antitumor effects and may represent an attractive new therapeutic approach for the treatment of TNBC.

Preparation and Evaluation of Recombinant Human Erythropoietin Loaded Tween 80-Albumin Nanoparticle for Traumatic Brain Injury Treatment.

ObjectiveTraumatic brain injury (TBI) is a serious health problem with few available treatment options. Rh-erythropoietin (rh-EPO) is a potential therapeutic drug for TBI, but it cannot cross the blood–brain barrier (BBB) directly. In this regard, a novel strategy to deliver rh-EPO for enhanced TBI treatment is via the development of Tween 80 modified albumin nanoparticles using electrostatic spray technology.MethodsThe rh-EPO loaded Tween 80 modified albumin nanoparticles (rh-EPO-Tw-ABNPs) were prepared by electrostatic spray technology, while the process parameters were optimized via a single factor design. Investigation of physicochemical properties, bioactivity and stability of rh-EPO-Tw-ABNPs was carried out. The in vitro release and biocompatibility with nerve cells were also analyzed. The in vivo brain targeting efficiency, brain edema relieving effect and the expression of aquaporin 4 (AQP4) and glial fibrillary acidic protein (GFAP) in the brain were evaluated in TBI model rats.ResultsThe particle size of optimal rh-EPO-Tw-ABNPs was about 438 ± 45 nm, with a zeta potential of −25.42 ± 0.8 mv. The average drug loading ratio of rh-EPO-Tw-ABNPs was 21.3± 3.7 IU/mg with a relative bioactivity of 91.6 ± 4.1%. The in vitro release of rh-EPO from the nanoparticles was rather slow, while neither the blank Tw-ABNPs nor rh-EPO-Tw-ABNPs exhibited toxicity on the microglia cells. Furthermore, in vivo experiments indicated that the rh-EPO-Tw-ABNPs could enhance the distribution of EPO in the brain and relieve brain edema more effectively. Moreover, compared with an rh-EPO injection, the rh-EPO-Tw-ABNPs could increase the AQP4 level but reduced GFAP expression in the brain with more efficiency.ConclusionThe rh-EPO-Tw-ABNPs could enhance the transport of rh-EPO into the brain with superior therapeutic effect for TBI.

Study of pH-Responsive and Polyethylene Glycol-Modified Doxorubicin-Loaded Mesoporous Silica Nanoparticles for Drug Delivery.

Tumor-targeted drug delivery systems represent challenging and widely investigated strategies to enhance cancer chemotherapy. In this study, we introduce a novel high-hydrophilic mesoporous silica nanoparticle system with a pH-sensitive drug release. The resultant composite nanoparticles appear as spheres of uniform size (450±25 nm) with a porous structure, which enables a high drug-loading ratio. Through modification of chitosan and polyethylene glycol monomethyl ether, the modified mesoporous silica was non-toxic to normal cells, but effective at inducing tumor cell death. With regard to the characteristics of drug release, the modified mesoporous silica clearly displayed a pH-stimulated release of the model drug doxorubicin hydrochloride in an acidic phosphate buffer solution (pH 4.0 and 6.0). The release was much greater than that observed in neutral or alkaline phosphate buffer solutions (pH 7.3 and 8.0). Furthermore, the release behavior was in accordance with the Higuchi model, indicating that this modified mesoporous silica drug delivery system can exhibit controlled release. The above results imply that the modified mesoporous silica is an effective drug delivery system for cancer therapy.

The toxicity performance of pH-responsive doxorubicin nanocarrier with different drug loading strategy

To improve the water solubility, keep drug loading rate and reduce toxic side effects of chemotherapeutic drugs, two kinds of pH–responsive nanoparticles (denoted as HDOX and PDOX) were prepared to achieve controlled release of drugs and their toxicity against tumor cells were studied. The HDOX was synthesized to incorporate doxorubicin (DOX) via a pH-responsive chemical hydrazone bond, while the PDOX was a pH-responsive polymer-coated nanoparticle to load DOX. The drug loading was measured by fluorescence spectroscopy. The drug release performances in vitro were investigated under different simulated conditions, as well as the toxicity of two NPs were evaluated by the MTT assay. In vitro experiments showed that HDOX (∼15 wt %) has a superior drug-loading ratio compared to PDOX (∼10 wt %). Besides, HDOX and PDOX also displayed a higher stability in normal physiological environment. After the nanoparticles were internalized by the tumor cells, the nanoparticles could transport to the entire tumor cells and showed a pH-responsive drug release behavior. In vivo experiments confirmed excellent biological safety of the two nanoparticles. These results demonstrated that nanocarrier-based chemical bonding strategy provided advantages for the development pH-responsive nanomedicine for cancer therapy.

Nano-in-micro electronspun membrane: merging nanocarriers and microfibrous scaffold for long-term scar inhibition

The development of general strategies for efficiently loading drugs with distinct physicochemical properties, for example, hydrophilicity, lipophilicity and hydrophobicity, is currently a great challenge in the field of drug delivery. In this work, a poly (N-isopropyl acrylamide) (PNIPAAm) nanoparticle with reversible hydrophilic-to-hydrophobic property was first prepared. Owing to the switchable property of the PNIPAAm particles, all the water-soluble, lipo-soluble and poorly soluble drugs could be successfully loaded in the PNIPAAm particles. Then, these drug-loaded PNIPAAm nanoparticles could be introduced into electronspun fibrous as a medical scaffold. Another advantage of such two-stage drug loading strategy is that an extended release of the loaded drug would be achieved. We also found that the preparation of this nano-in-micro system also showed negligible effects on the drug loading ratio and drug activity, probably due to the mid and efficient nature of this approach. Moreover, the nano-in-micro scaffold exhibits excellent drug release characteristics such as a slow and persistent drug delivery for up to 4 months. A preclinical application of this 20S-Ginsenoside Rg3-loaded nano-in-micro scaffold showed a pronounced hypertrophic scar (HS) inhibitory effect in both early-stage and later-stage of HS formation. In short, the nano-in-micro scaffold with reversible hydrophilic-to-hydrophobic property in the drug-loaded nanoparticles would provide a facile, effective and general strategy to fabricate diverse drug delivery system with long-term release.

Melt Amorphisation of Orlistat with Mesoporous Silica Using a Supercritical Carbon Dioxide: Effects of Pressure, Temperature, and Drug Loading Ratio and Comparison with Other Conventional Amorphisation Methods.

The aim of this work was to develop an amorphous orlistat-loaded mesoporus silica formulation using the melt-amorphisation by supercritical fluid (MA-SCF) and to investigate the effects of pressure and temperature on the pharmaceutical properties of the developed formulation. In addition, the effect of orlistat mass ratio to the mesoporus silica was also evaluated. The carbon dioxide was used as a supercritical fluid, and Neusilin®UFL2 was selected as the mesoporous silica. For comparison with conventional amorphisation methods, orlistat formulations were also prepared by solvent evaporation and hot melt methods. Various pharmaceutical evaluations including differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, specific surface area, total pore volume, and content uniformity were performed to characterise the prepared orlistat formulation. The melting point depression and the solubility of orlistat in supercritical carbon dioxide (SC-CO2) were selected for the interpretation of evaluated results in relation to temperature and pressure. The total pore volume of the prepared orlistat-loaded mesoporus silica decreased with an increasing density of SC-CO2 to about 500 g/L at a constant temperature or pressure. From these results, it was suggested that increasing the density of SC-CO2 to about 500 g/L could result in the easier penetration of CO2 into molten orlistat and lower viscosity, hence facilitating the introduction and loading of orlistat into the pores of Neusilin®UFL2. However, when the density of SC-CO2 increased to more than 500 g/L, the total pore volume increased, and this may be due to the release out of orlistat from the pores of Neusilin®UFL2 by the increased orlistat solubility in SC-CO2. Interestingly, as the total pore volume decreased by the filling of the drug, the drug crystallinity decreased; hence, the dissolution rate increased. Furthermore, it was shown that the most desirable mass ratio of Neusilin®UFL2:orlistat for the amorphisation was 1:0.8 at an optimised supercritical condition of 318 K and 10 MPa. Compared with other amorphisation methods, only the sample prepared by the MA-SCF method was in pure amorphous state with the fastest dissolution rate. Therefore, it was concluded that the amorphous orlistat-loaded mesoporus silica prepared using MA-SCF under optimised conditions was more advantageous for enhancing the dissolution rate of orlistat than other conventional amorphisation methods.

High internal phase emulsions stabilized with carboxymethylated lignin for encapsulation and protection of environmental sensitive natural extract

Oil-in-water (O/W) high internal phase emulsions (HIPEs) are widely used in foods, pharmaceuticals and cosmetics due to the high drug loading ratio, specific rheological behaviors and long shelf life. However, protective performance of active components within HIPEs maintains a low level. Herein, a series of carboxymethylated enzymatic hydrolysis lignin (EHL-CM-x) were synthesized by nucleophilic substitution and applied as macromolecular surfactant to stabilize the O/W HIPEs. It was found that EHL-CM-x combined with a small dosage of alkyl polyglycoside (APG) are able to stabilize HIPEs with 87 vol% soybean oil under neutral condition, which could be recognized as the highest internal phase reported in foods and pharmaceuticals. As a bioactive compound carrier, such EHL-CM-x stabilized HIPEs enable to provide outstanding UV, thermal and oxidation protection for sensitive natural extracts. The residual drug level obtained in this work is more than two times other gliadin/chitosan hybrid particles and sulfomethylated lignin stabilized HIPEs after UV irradiation. In vitro experiments showed that the minimum inhibitory concentration of curcumin within HIPEs against S. aureus and E. coli was 3.13 mg/mL and 12.5 mg/mL, respectively. Such lignin stabilized HIPEs could be potentially used in various areas, especially those with high stability and biosafety requirements.

Focused ultrasound-triggered chemo-gene therapy with multifunctional nanocomplex for enhancing therapeutic efficacy

Nanotechnology-based combination therapies, especially chemo-gene therapy, have been spotlighted as promising alternatives for cancer therapy. However, only a small amount of systemically administered nanomedicines reach the tumor site by the enhanced permeability and retention (EPR) effect, resulting in the limited therapeutic efficacy. Furthermore, the design of ideal drug delivery system for chemo-gene therapy has been impeded by the chemical and physical differences between nucleic acids and chemotherapeutics. Herein, we report a precisely designed nanocomplex which exhibits a focused ultrasound (FU)-responsive release and enhanced accumulation of released therapeutics to tumor site. After the nanocomplex composed of siRNA nanoparticles (siRNA-NP) and chemotherapeutics-loaded microbubbles was systemically injected, the nanocomplex was collapsed around the tumor tissue by FU exposure, and both siRNA-NP and chemotherapeutics were penetrated the dense extracellular matrix (ECM) of tumor site, leading to the enhanced chemo-gene therapeutic efficacy. The two-in-one nanocomplex is expected as a promising platform for combination therapy that can enhance the therapeutic efficiency of combination drugs at the cell and/or tissue levels with high drug loading ratio.