Efficient Drug Delivery System Research Articles

The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application.

Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies.

PH-sensitive oleuropein-loaded niosome: Efficient treatment for metastatic brain tumors in initial steps in-vivo

Brain tumors remain life-threatening cancer cases in humans. The short survival rates are almost related to therapeutic restrictions, insufficiency in accurate diagnosis, and the inability of the available therapeutics to reach the brain tissue with the efficient doses required for treatment. The present study aims to present oleuropein-loaded niosome (Oleu-Nio) as an efficient drug delivery system to the brain parenchyma of female rats bearing 4T1 metastatic breast cancer (MBC) cells. The Nio formulation, as Tween 60/ cholesterol 1:1 M ratio, was selected regarding the small size of 79.37 ± 0.12 nm, polydispersity index (Pdi) 0.230 ± 0.043, Zeta-potential 1.38 ± 0.074 mv, high stability for more than 50 days, and high entrapment efficiency 96.89 ± 0.241. Furthermore, it has described sensitivity to acidic pH = 5.3, resulting in a controlled release behavior in-vitro vs. neutral pH = 7.4. In-vitro, the viability of 4T1 cancer cells has decreased significantly in the presence of Oleu-Nio (IC50 = 92.679 µg/ml) compared to free Oleu, where IC50 was none detected. Fluorescent microscopy figures have uncovered the role of Nio in increasing the uptake via 4T1 cancer cells. Moreover, treating female rats presenting brain metastasis (BM) with 10 doses of Oleu-Nio (25 mg/kg body weight) via intravenous route has improved the survival rate for more than 45 days vs. 34.5 days in those treated with Oleu and 16.5 days in the control group. These findings remain promising in drug delivery, especially for brain-related diseases like brain tumors. Additionally, Oleu could be presented as a suitable and safe treatment against primary and metastatic breast cancers.

Solvatochromic Shift Enables Intracellular Fate Determination of Curcumin Nanocrystals

AbstractDrug nanocrystals represent an effective way of delivering poorly water‐soluble substances to target tissues and cells. Due to the large specific surface area, nanocrystals promote dissolution; therefore, the drug usually co‐exists in both crystalline and dissolved forms. Commonly used analytical methods do not make it possible to easily distinguish between these forms within live cells. The present study reports a novel fluorescence microscopy method that makes it possible to distinguish intracellular forms of curcumin based on differences in fluorescence emission spectra. Due to solvatochromism, crystalline curcumin can be distinguished from curcumin dissolved in the lipidic components of cells. The methodology utilization is demonstrated by investigating the effect of surface stabilization of curcumin nanocrystals on cell uptake by different cell lines: macrophages and epithelial cells. The understanding of factors that control drug nanocrystal phagocytosis makes it possible to better interpret the observed anticancer effects of curcumin nanocrystals and design efficient drug delivery systems.

Hydrocortisone을 담지한 Chitosan silver nanoparticles의 약물흡수 및 방출

The final goal of this research was to improve a treatment for allergy rhinitis using chitosan-hydrocortisone silver nanoparticles based on hydrocortisone-deposited chitosan. The nanoparticles were produced by depositing hydrocortisone in chitosan, generating a reaction with highly reactive silver, and placing the nanoparticles into the nasal mucosa. Silver nanoparticles were manufactured after chitosan deposition and the optimal hydrocortisone concentration supporting the highest drug delivery efficiency was identified. For efficient DDS(Drug Delivery Systems applications, an adsorption experiment was performed before silver nanoparticle production according to the hydrocortisone concentration. In addition, a release experiment with different amounts of silver salt was performed to determine the optimal hydrocortisone and silver salt concentrations for producing chitosan-hydrocortisone silver nanoparticles. The amount released was investigated as a parameter of time. When the hydrocortisone concentration was 0.05g, the chitosan adsorption rate was highest at 48%. A release experiment was conducted at 36℃ in PBS, which is similar to the human body condition, while changing the silver salt amount. At approximately 60 hours, the absorbance was constant, indicating that hydrocortisone was emitted from the chitosan particles. In the cases of the 50㎕ reaction and 100㎕ reaction, the release rate was 14.17% and 12.92%, respectively. Otherwise, in the case of using 10㎕ silver salt solution for the reaction, 99.6% of the amount absorbed was released, showing the highest efficiency as a drug delivery agent.

Fine-tuning the encapsulation of a photosensitizer in nanoparticles reveals the relationship between internal structure and phototherapeutic effects.

Photodynamic therapy (PDT) is a cancer therapy that uses a photosensitizer (PS) in the presence of oxygen molecules. Since singlet oxygen is highly reactive, it is important to deliver it to the target site. Thus, an efficient drug delivery system (DDS) is essential for enhancing the efficacy of such a treatment and protecting against the side effects of PDT. Here, we report on attempts to increase the therapeutic effect of PDT by using a DDS, a lipid nanoparticle (LNP). We prepared a porphyrin analog, rTPA (PS) that was encapsulated in LNPs using a microfluidic device. The findings indicated that the internal structure of the prepared particles changed depending on the amount of rTPA in LNPs. The photoactivity and cell-killing effect of PS in LNPs also changed when the amount of the cargo increased. These results suggest that the internal structure of LNPs is important factors that affect drug efficacy.

Compatibility of selected active pharmaceutical ingredients with poly(D, L-lactide-co-glycolide): Computational and experimental study

Biodegradable polyesters have emerged as a promising class of polymers for the development of efficient drug delivery systems for various treatments (including cancer treatment) due to their biocompatibility, low toxicity, and controlled drug release. This study presents a computational and experimental evaluation of the compatibility of selected model active pharmaceutical ingredients (APIs) with poly(D, L-lactide-co-glycolide) (PLGA), which is a key parameter to designing drug delivery systems based on amorphous solid dispersions (ASDs) and polymeric micro- or nanoparticles. PLGA with different molar ratios of the monomer units, i.e., lactide to glycolide ratio of 50:50 (PLGA50) or 75:25 (PLGA75), were investigated as polymeric carriers for the following model APIs: ibuprofen (IBU), paracetamol (PARA), naproxen (NAP), and indomethacin (IND). The phase diagrams obtained by a combination of calorimetric measurements and modeling using the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS) demonstrated low solubility of the model APIs in the studied copolymers at storage temperature (25 °C). The amorphous-amorphous phase separation was predicted by the PC-SAFT EOS for all API–PLGA systems and experimentally detected for the IBU–PLGA50, IBU–PLGA75, and NAP–PLGA75 systems. To investigate the physical stability of the API–PLGA systems and their link to the constructed phase diagrams, API–PLGA75 formulations were prepared using a melting process, and their solid-state properties were monitored over time. Of the analyzed API–PLGA75 formulations, only IND–PLGA75 remained in the amorphous state after 20 weeks of storage under dry conditions at 25 °C, while the other formulations recrystallized rapidly after preparation (IBU–PLGA75 and NAP–PLGA75) or after a limited storage period (PARA–PLGA75), reflecting poor compatibility of the investigated APIs with the PLGA copolymers and limited kinetic stabilization, as predicted from the constructed phase diagrams. Another important output of this work is the evaluation of the pure predictions of phase diagrams using the PC-SAFT EOS and its performance in ranking API–polymer compatibility.

Utilizing TPGS for Optimizing Quercetin Nanoemulsion for Colon Cancer Cells Inhibition

Background: Colorectal cancer is one of the most challenging cancers to treat. Exploring novel therapeutic strategies is necessary to overcome drug resistance and improve patient outcomes. Quercetin (QR) is a polyphenolic lipophilic compound that was chosen due to its colorectal anticancer activity. Nanoparticles could improve cancer therapy via tumor targeting by utilizing D-tocopheryl polyethylene glycol succinate (vitamin-E TPGS) as a surfactant in a nanoemulsion preparation, which is considered an efficient drug delivery system for enhancing lipophilic antineoplastic agents. Thus, this study aims to develop and optimize QR-loaded nanoemulsions (NE) using TPGS as a surfactant to enhance the QR antitumor activity. Method: The NE was prepared using a self-assembly technique using the chosen oils according to QR maximum solubility and TPGS as a surfactant. The prepared QR-NE was evaluated according to its particle morphology and pH. QR entrapment efficiency and QR in vitro drug release rate were determined from the selected QR-NE then we measured the QR-NE stability. The anticancer activity of the best-selected formula was studied on HT-29 and HCT-116 cell lines. Results: Oleic acid was chosen to prepare QR-NE as it has the best QR solubility. The prepared NE, which had particles size < 200 nm, maximum entrapment efficiency > 80%, and pH 3.688 + 0.102 was selected as the optimal formula. It was a physically stable formula. The prepared QR-NE enhanced the QR release rate (84.52 ± 0.71%) compared to the free drug. QR-NPs significantly improved the cellular killing efficiency in HCT-116 and HT-29 colon cancer cell lines (lower IC50, two folds more than free drug). Conclusion: The prepared QR-NE could be a promising stable formula for improving QR release rate and anticancer activity.

Aptamer-functionalized quercetin thermosensitive liposomes for targeting drug delivery and antitumor therapy

Chemo-thermotherapy, as a promising cancer combination therapy strategy, has attracted widespread attention. In this study, a novel aptamer functionalized thermosensitive liposome encapsulating hydrophobic drug quercetin was fabricated as an efficient drug delivery system. This aptamer-functionalized quercetin thermosensitive liposomes (AQTSL) combined the merits of high-loading yield, sustained drug release, long-term circulation in the body of PEGylated liposomes, passive targeting provided by 100–200 nm nanoparticles, active targeting and improved internalization effects offered by AS1411 aptamer, and temperature-responsive of quercetin release. In addition, AQTSL tail vein injection combined with 42 °C water bath heating on tumor site (AQTSL + 42 °C)treatment inhibited the tumor growth significantly compared with the normal saline administration (p < 0.01), and the inhibition rate reached 75%. Furthermore, AQTSL + 42 °C treatment also slowed down the tumor growth significantly compared with QTSL combined with 42 °C administration (p < 0.05), confirming that AS1411 decoration on QTSL increased the active targeting and internalization effects of the drug delivery system, and AS1411 aptamer itself might also contribute to the tumor inhibition. These data indicate that AQTSL is a potential carrier candidate for different hydrophobic drugs and tumor targeting delivery, and this kind of targeted drug delivery system combined with temperature responsive drug release mode is expected to achieve an ideal tumor therapy effect.

Tumor cell-derived microparticles packaging monocarboxylate transporter4 inhibitor fluvastatin suppress lung adenocarcinoma via tumor microenvironment remodeling and improve chemotherapy

Monocarboxylate transporter4 (MCT4) is responsible for the efflux of lactate and high expression of MCT4 is related to poor prognosis in multiple cancers. Herein, Fluvastatin, regarded as a lipid-metabolic regulator, has been screened out as an inhibitor of MCT4 for lung adenocarcinoma (LUAD) treatment. As tumor cell-derived microparticles (TMPs) have advantages in low toxicity, biocompatibility and biological targeting, TMPs serve as a highly efficient drug-delivery system to transport Fluvastatin in a relatively low dosage. TMPs encapsulating Fluvastatin (TMP-F), consistent with antitumor function of Fluvastatin, can impede lactate efflux by inhibiting MCT4 expression, resulting in attenuated LUAD progression. TMP-F provokes reversion of immunosuppressive tumor microenvironment (TME) by appealing to infiltration of NK and CD8+ T cells, polarizing M2-type to M1-type macrophages, and decreasing Treg and myeloid-derived suppressor cells (MDSC). In addition, co-administration of TMP-F and chemotherapy Cisplatin still reinforces the antitumor immune response. Meanwhile, TMP-F improves antitumor efficiency of Cisplatin and curbs lung metastasis. Overall, TMP-F or therapeutic alliance with Cisplatin represents a promising strategy for enhancing therapeutic effect on LUAD.

PLA‐b‐SMA as an Amphiphilic Diblock Copolymer for Encapsulation of Lipophilic Cargo

AbstractThe encapsulation of active pharmaceutical ingredients (APIs) within drug delivery systems such as polymeric nanoparticles (PNPs) vastly improves the therapeutic efficiency of the incorporated APIs. PNPs synthesized using amphiphilic block copolymers are efficient drug delivery systems as the hydrophobic block facilitates the encapsulation of lipophilic components and the hydrophilic block constitutes the hairy corona of the PNP that stabilizes the nanocarriers against aggregation in solution. Poly(styrene‐alt‐maleic acid) (SMA) is an attractive polymer for the hydrophilic corona of PLA‐based nanoparticles as it allows for post polymerization functionalization and aids in the prevention of NP aggregation. The synthesis of a novel PLA‐b‐SMA block copolymer, via sequential ring opening polymerization (ROP) and reversible addition–fragmentation chain transfer (RAFT) polymerization, is presented. PLA macro‐CTAs, synthesized via ROP, can be chain extended via RAFT copolymerization of styrene and maleic anhydride to yield PLA‐b‐SMAnh and via RAFT polymerization of N‐vinylpyrrolidone to yield PLA‐b‐PVP block copolymers. Controlled hydrolysis of the anhydride moieties converts PLA‐b‐SMAnh into PLA‐b‐SMA. Monodisperse PLA‐b‐SMA and PLA‐b‐PVP nanoparticles (NPs) ranging in diameter between 60 and 220 nm are prepared. The lipophilic fluorescent dye DiI is encapsulated within the NPs successfully and these fluorescent NPs are used in a preliminary cell uptake study.

Targeting necroptosis as an alternative strategy in tumor treatment: From drugs to nanoparticles.

Over last decades, most antitumor therapeutic strategies have focused on apoptosis, however, apoptosis resistance and immunological silence usually led to treatment failure. In this sense, triggering other programmed cell death such as necroptosis may achieve a better therapeutic efficacy and has gained widespread attentions in tumor therapy. Studies in this field have identified several types of necroptosis modulators and highlighted the therapeutic potential of necroptotic cell death in cancer. Nanoparticles further provide possibilities to improve therapeutic outcomes as an efficient drug delivery system, facilitating tumor targeting and controlled cargo release. Furthermore, some nanoparticles themselves can trigger/promote programmed necrosis through hyperthermia, ultrasound and autophagy blockage. These investigations have entered necroptosis for consideration as a promising strategy for tumor therapy, though numerous challenges remain and clinical applications are still distant. In this review, we would briefly introduce molecular mechanism and characteristics of necroptosis, and then summarize recent progress of programmed necrosis and their inducers in tumor therapy. Furthermore, the antitumor strategies that take advantages of nanoparticles to induce necroptosis are also discussed.

Physical-chemical and toxicological properties of osmolyte-based cationic surfactants and spontaneously formed low-toxic catanionic vesicles out of them

• Synthesis and properties of osmolyte based cationic surfactants. • Spontaneous formation of low toxic catanionic vesicles composed of these osmolyte based cationic surfactants and soaps. • Appearance of facetted vesicles. • High biodegradability of these novel cationic surfactants and the corresponding catanionic vesicles. In the context of efficient drug delivery systems, catanionic vesicles offer several advantages, such as spontaneous formation and long-term stability. However, especially the cationic component of such vesicles is often toxic. Thus, the search for less toxic, biocompatible amphiphiles, while maintaining the desirable aggregation properties is crucial. In this work, we present cytotoxicity towards the human cell line Hela as well as biodegradability data of some cationic surfactants based on the natural osmolytes choline and ectoine. The synthesis, aggregation and solubility behaviour as well as the stability in water of these compounds is discussed. In order to induce the spontaneous formation of vesicles, several of these cationic surfactants are combined with choline carboxylates with varying chain length in different mixing ratios and characterised with cryo-TEM. Further, the cytotoxic effect of such novel catanionics is evaluated as a function of the cationic-anionic ratio and compared to that of classical combinations of sodium dodecylsulfate and dodecyltrimethylammonium bromide.

Investigation of self-assembled poly(ethylene glycol)-poly(L-lactic acid) micelle as potential drug delivery system for poorly water soluble anticancer drug abemaciclib

Polymer-based drug delivery systems have the ability to organize stable self-assembled nanocarriers containing hydrophobic cores allow to delivery of poorly water-soluble anticancer drugs by drug encapsulation process. Computational investigations can assist in designing of efficient drug-delivery systems. However, the high computational cost of simulation of nanocarrier self-assembly processes due to long-timescale required for equilibration are challenging. In this study we investigated the assembly mechanism of the abemaciclib anticancer drug encapsulated by the PEG-PLA copolymer micelle; molecular dynamics simulations were carried out for analyzing the aggregation of the PEG-PLA copolymer chains. The process of drug encapsulation is mostly operated by the hydrophobic and hydrophilic interactions. The hydrogen bonding and electrostatic interactions also play an important role in aggregation of the PEG-PLA copolymer chains. Analyses of radial distribution function and solvent accessible surface area show that the PEG-PLA copolymer micelles can increase the hydrophobic drugs solubility. The study presents insights into the mechanism of the structure of drug-loaded PEG-PLA copolymer micelles to design the drug delivery systems with helpful properties.

Exploiting PET-RAFT polymerization mediated by cross-linked zinc porphyrins for the thermo-sensitive regulation of poly(N-isopropylacrylamide-b-acrylamide)

A series of thermo-sensitive block copolymers poly(N-isopropylacrylamide-b-acrylamide) (P(NIPAm-b-AM)) are prepared via photoinduced electron/energy transfer-reversible addition-fragmentation chain transfer (PET-RAFT) polymerization mediated by the cross-linked zinc porphyrins (ZnTHP-Me2Si) with superior photo-catalytic properties using one-pot method. The thermal transition temperatures of P(NIPAm-b-AM) samples are analyzed via lower critical solution temperature (LCST) measurements in water/P(NIPAm-b-AM) mixtures, which show that the thermo-sensitive of P(NIPAm-b-AM) could be tuned by regulating the molar ratio of AM/NIPAm. Very interestingly, when the mole fraction of AM increased from 0 to 0.4, the LCST and water contact angle of P(NIPAm-b-AM) aqueous solution increased linearly, which means the thermo-sensitive polymers with target LCST or hydrophilicity could be prepared by increasing or decreasing AM content. In addition, the hardness of P(NIPAm-b-AM) also enhanced as the AM content increased. According to the density functional theory (DFT) calculations and radial distribution function (RDF) analyses, ZnTHP-Me2Si has smaller energy gap, and the H-bonding interaction between P(NIPAm-b-AM) and water molecules could be enhanced with increasing AM content. The outcomes of this work open new approaches to develop thermo-sensitive polymers with biocompatibility for the wide applications in highly efficient and controlled drug delivery system.

Synthesis, characterization, and evaluation of in vitro cytotoxicity and in vivo antitumor activity of asiatic acid-loaded poly lactic-co-glycolic acid nanoparticles: A strategy of treating breast cancer

Asiatic acid (AA), an aglycone of pentacyclic triterpene glycoside, obtained from the leaves of Centella asiatica exerts anticancer effects by inhibiting cellular proliferation and inducing apoptosis in a wide range of carcinogenic distresses. However, its chemotherapeutic efficacy is dampened by its low bioavailability. Polymeric nanoparticles (NPs) exhibit therapeutic efficacy and compliance by improving tissue penetration and lowering toxicity. Thus, to increase the therapeutic effectiveness of AA in the treatment of breast cancer, AA-loaded poly lactic-co-glycolic acid (PLGA) NPs (AA-PLGA NPs) have been formulated. The AA-PLGA NPs were characterized on the basis of their average particle size, zeta potential, electron microscopic imaging, drug loading, and entrapment efficiency. The NPs exhibited sustained drug release profile in vitro. Developed NPs exerted dose-dependent cytotoxicity to MCF-7 and MDA-MB-231 cells without damaging normal cells. The pro-oxidant and pro-apoptotic properties of AA-PLGA NPs were determined by the study of the cellular levels of SOD, CAT, GSH-GSSG, MDA, protein carbonylation, ROS, mitochondrial membrane potential, and FACS analyses on MCF-7 cells. Immunoblotting showed that AA-PLGA NPs elicited an intrinsic pathway of apoptosis in MCF-7 cells. In vivo studies on female BALB/c mice exhibited reduced volume of mammary pad tumor tissues and augmented expression of caspase-3 when administered with AA-PLGA NPs. No systemic adverse effect of AA-PLGA NPs was observed in our studies. Thus, AA-PLGA NPs can act as an efficient drug delivery system against breast cancer.

A Comprehensive Review of One Decade of Microfluidic Platforms Applications in Synthesis of Enhanced Carriers Utilized in Controlled Drug Delivery

AbstractNovel nanocarriers such as multifunctional nanoparticles (NPs) have recently attracted attention due to their various applications, specifically in medicine and treatment. However, it is vital that these particles be synthesized with meticulous control of different structural, chemical, and physical properties. In response to this demand, microfluidic (MF) technology as a reliable procedure can provide promising results in the development of desired NPs and efficient drug delivery systems. By controlling the flow rates of multiphase fluids and conditions of chemical reactions, MF technology enables the fabrication of uniform and highly stable particles with enhanced surfaces, higher encapsulation efficiency, and controlled release of therapeutic agents compared with conventional bulk methods. This review article investigates the MF‐based methods utilized in the synthesis of NPs and their advantages in developing novel drug delivery systems. It also provides a comprehensive comparison with conventional methods from a different point of view, emphasizing a novel category of nanocarriers’ critical characteristics. In addition, a summary of the most recent representative works on NPs fabrication by MF procedures is presented, and their potential and applications in drug delivery are discussed.

CD33‐targeting extracellular vesicles deliver antisense oligonucleotides against FLT3‐ITD and miR‐125b for specific treatment of acute myeloid leukaemia

IntroductionAcute Myeloid Leukaemia (AML) is the most common blood cancer in adults. Although 2 out of 3 AML patients go into total remission after chemotherapies and targeted therapies, the disease recurs in 60%–65% of younger adult patients within 3 years after diagnosis with a dramatically decreased survival rate. Therapeutic oligonucleotides are promising treatments under development for AML as they can be designed to silence oncogenes with high specificity and flexibility. However, there are not many well validated approaches for safely and efficiently delivering oligonucleotide drugs. This issue could be resolved by utilizing a new generation of delivery vehicles such as extracellular vesicles (EVs).MethodsIn this study, we harness red blood cell‐derived EVs (RBCEVs) and engineer them via exogenous drug loading and surface functionalization to develop an efficient drug delivery system for AML. Particularly, EVs are designed to target CD33, a common surface marker with elevated expression in AML cells via the conjugation of a CD33‐binding monoclonal antibody onto the EV surface.ResultsThe conjugation of RBCEVs with the CD33‐binding antibody significantly increases the uptake of RBCEVs by CD33‐positive AML cells, but not by CD33‐negative cells. We also load CD33‐targeting RBCEVs with antisense oligonucleotides (ASOs) targeting FLT3‐ITD or miR‐125b, 2 common oncogenes in AML, and demonstrate that the engineered EVs improve leukaemia suppression in in vitro and in vivo models of AML.ConclusionTargeted RBCEVs represent an innovative, efficient, and versatile delivery platform for therapeutic ASOs and can expedite the clinical translation of oligonucleotide drugs for AML treatments by overcoming current obstacles in oligonucleotide delivery.

Biomimetic and temporal-controlled nanocarriers with ileum transporter targeting for achieving oral administration of chemotherapeutic drugs

BackgroundOral chemotherapy is preferred for patients with cancer owing to its multiple advantages, including convenience, better patient compliance, and improved safety. Nevertheless, various physical barriers exist in this route that hamper the development of oral chemotherapeutic formulations, including destruction of drugs in the gastrointestinal tract (GIT), low permeability in enterocytes, and short residence time in the intestine. To overcome these limitations, it is necessary to design an efficient oral drug delivery system with high efficacy and improved safety.ResultsHerein, we designed novel glycocholic acid (GCA)-functionalized double layer nanoparticles (GCA-NPs), which can act via an endogenous pathway and in a temporally controlled manner in the intestine, to enhance the oral bioavailability of hydrophobic chemotherapeutic drugs such as paclitaxel (PTX). GCA-NPs were composed of quercetin (Qu)-modified liposomes (QL) coated with GCA-chitosan oligosaccharide conjugate (GCOS). The GCA-NPs thus prepared showed prolonged intestinal retention time and good GIT stability due to the presence of chitosan oligosaccharide (COS) and enhanced active transportation via intestinal apical sodium-dependent bile acid transporter (ASBT) due to the presence of GCA. GCA-NPs also efficiently inhibited intestinal P-gp induced by Qu. PTX-loaded GCA-NPs (PTX@GCA-NPs) had a particle size of 84 nm and an entrapment efficiency of 98% with good stability. As a result, the oral bioavailability of PTX was increased 19-fold compared to that of oral Taxol® at the same dose. Oral PTX@GCA-NPs displayed superior antitumor efficacy and better safety than Taxol® when administered intravenously.ConclusionsOur novel drug delivery system showed remarkable efficacy in overcoming multiple limitations and is a promising carrier for oral delivery of multiple drugs, which addresses several challenges in oral delivery in the clinical context.Graphical

Retrograde Axonal Transport of Liposomes from Peripheral Tissue to Spinal Cord and DRGs by Optimized Phospholipid and CTB Modification.

Despite recent advancements in therapeutic options for disorders of the central nervous system (CNS), the lack of an efficient drug-delivery system (DDS) hampers their clinical application. We hypothesized that liposomes could be optimized for retrograde transport in axons as a DDS from peripheral tissues to the spinal cord and dorsal root ganglia (DRGs). Three types of liposomes consisting of DSPC, DSPC/POPC, or POPC in combination with cholesterol (Chol) and polyethylene glycol (PEG) lipid were administered to sciatic nerves or the tibialis anterior muscle of mature rats. Liposomes in cell bodies were detected with infrared fluorescence of DiD conjugated to liposomes. Three days later, all nerve-administered liposomes were retrogradely transported to the spinal cord and DRGs, whereas only muscle-administered liposomes consisting of DSPC reached the spinal cord and DRGs. Modification with Cholera toxin B subunit improved the transport efficiency of liposomes to the spinal cord and DRGs from 4.5% to 17.3% and from 3.9% to 14.3% via nerve administration, and from 2.6% to 4.8% and from 2.3% to 4.1% via muscle administration, respectively. Modification with octa-arginine (R8) improved the transport efficiency via nerve administration but abolished the transport capability via muscle administration. These findings provide the initial data for the development of a novel DDS targeting the spinal cord and DRGs via peripheral administration.

Research on the Construction of Bispecific-Targeted Sustained-Release Drug-Delivery Microspheres and Their Function in Treatment of Hepatocellular Carcinoma.

Lenvatinib (LEN) is approved as one of the commonly used drugs in the treatment of hepatocellular carcinoma (HCC). It is recognized to be a novel therapeutic choice for the direct and targeted delivery of effective drugs to HCC tumor sites. The key to the proposed method lies in the requirement for efficient targeted drug delivery carriers with targeting performance to deliver effective drugs directly and safely to tumor lesions. Methods: Here, magnetic liposomes (MLs) were modified by phosphatidylinositol proteoglycan 3 (GPC3) and epithelial cell adhesion molecules (EpCAMs). Subsequently, bispecific-targeted sustained-release drug-loaded microspheres containing LEN (GPC3/EpCAM-LEN-MLs) were constructed. In addition, both cytotoxicity and magnetic resonance imaging (MRI) analyses were performed to establish a mouse model and further perform corresponding performance assessments. Results: The corresponding results showed that GPC3/EpCAM-LEN-MLs were spherical-shaped and evenly dispersed. The encapsulation and drug-loading efficiencies were 91.08% ± 1.83% and 8.22% ± 1.24%, respectively. Meanwhile, GPC3/EpCAM-LEN-MLs showed a high inhibition rate on the proliferation of HCC cells and significantly increased their apoptosis. Furthermore, MRI revealed that the system possessed the function of tracking and localizing tumor cells, and animal experiments verified that it could exert the function of disease diagnosis. Conclusions: Our experiments successfully constructed a safe and efficient bispecific-targeted sustained-release drug delivery system for HCC tumor cells. It provides a useful diagnostic and therapeutic scheme for the clinical diagnosis and targeted therapy of HCC. Moreover, it can be used as a potential tumor-specific MRI contrast agent for the localization and diagnosis of malignant tumors.