Haonan Xing

Dissolution enhancement of tadalafil by liquisolid technique.

Abstract This study aimed to enhance the dissolution of tadalafil, a poorly water-soluble drug by applying liquisolid technique. The effects of two critical formulation variables, namely drug concentration (17.5% and 35%, w/w) and excipients ratio (10, 15 and 20) on dissolution rates were investigated. Pre-compression tests, including particle size distribution, flowability determination, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and scanning electron microscopy (SEM), were carried out to investigate the mechanism of dissolution enhancement. Tadalafil liquisolid tablets were prepared and their quality control tests, dissolution study, contact angle measurement, Raman mapping, and storage stability test were performed. The results suggested that all the liquisolid tablets exhibited significantly higher dissolution rates than the conventional tablets and pure tadalafil. FT-IR spectrum reflected no drug-excipient interactions. DSC and XRD studies indicated reduction in crystallinity of tadalafil, which was further confirmed by SEM and Raman mapping outcomes. The contact angle measurement demonstrated obvious increase in wetting property. Taken together, the reduction of particle size and crystallinity, and the improvement of wettability were the main mechanisms for the enhanced dissolution rate. No significant changes were observed in drug crystallinity and dissolution behavior after storage based on XRD, SEM and dissolution results.

Guanidinylated bioresponsive poly(amido amine)s designed for intranuclear gene delivery

Guanidinylated poly(amido amine)s with multiple disulfide linkages (Gua-SS-PAAs) were designed and constructed as nonviral gene carriers. The main chains of these novel carriers were synthesized based on monomers containing guanidino groups (guanidine hydrochloride and chlorhexidine), which could avoid complicated side-chain-modification reactions while introducing the guanidino groups. The synthesized Gua-SS-PAAs polymers were characterized by 1H nuclear magnetic resonance, molecular weight, and polydispersity. Furthermore, Gua-SS-PAAs polymers were complexed with pDNA, and the properties of the complexes were determined, including entrapment efficiency, particle size, ζ-potential, atomic force microscopy images, stability, DNA complexation ability, reduction sensitivity, cytotoxicity, and transfection efficiency. The new Gua-SS-PAAs carriers exhibited higher transfection efficiency and lower cytotoxicity compared with two widely used gene delivery carriers, polyethylenimine and lipofectamine 2000. Furthermore, the relationship between the side-chain structure and morphological/biological properties was extrapolated, and the results showed that guanidine in the side chain aids in the improvement of transfection efficiency. In addition, the introduction of guanidino group might confer the new carriers with nuclear localization function compared to carriers without it.

Recent advances on extracellular vesicles in therapeutic delivery: Challenges, solutions, and opportunities

Graphical abstract Figure. No Caption available. Abstract Extracellular vesicles (EVs) are intrinsic mediators of intercellular communication in our body, allowing functional transfer of biomolecules (lipids, proteins, and nucleic acid) between diverse locations. Such an instrumental role evokes a surge of interest within the drug delivery community in tailoring EVs for therapeutic delivery. These vesicles represent a novel generation of drug delivery systems, providing high delivery efficiency, intrinsic targeting properties, and low immunogenicity. In the recent years, considerable research efforts have been directed toward developing safe and efficient EV‐based delivery vehicles. Although EVs are shown to harbor great promise in therapeutic delivery, substantial improvements in exploring standardized isolation techniques with high efficiency and robust yield, scalable production, standard procedures for EV storage, efficient loading methods without damaging EV integrity, understanding their in vivo trafficking, and developing novel EV‐based nanocarriers are still required before their clinical transformation. In this review, we seek to summarize the recent advance on harnessing EVs for drug delivery with focus on state‐of‐the‐art solutions for overcoming major challenges.

A method for the preparation of sustained release-coated Metoprolol Succinate pellet-containing tablets

Abstract The purpose of this study was to develop a method to prepare Metoprolol Succinate (MS) sustained release pellets and compress them into pellet-containing tablets without losing sustained release property. The drug layered pellets were coated with Eudragit NE 30D to obtain a sustained release (SR) property. The mechanical properties and permeability of the coating film were tailored by adjusting the proportion of talc in the coating dispersion and the weight gain of the coating film. Pellets with different MS release rates were tested and then mixed together by different ratios to optimize drug release rate. The mixed pellets were compressed into tablets with cushioning excipients. The results showed that when the ratio of talc and coating material was 1:4, the coating operation could be conducted successfully without pellet conglutination and the mechanical property of the coating film was enhanced to withstand the compress force during tableting. Blending SR-coated pellets of 20% weight gain with SR-coated pellets of 40% weight gain at the ratio of 1:5 could produce a constant and desired drug release rate. The formulation and the procedure developed in the study were suitable to prepare MS pellet-containing tablets with selected SR properties.

Novel guanidinylated bioresponsive poly(amidoamine)s designed for short hairpin RNA delivery

Two different disulfide (SS)-containing poly(amidoamine) (PAA) polymers were constructed using guanidino (Gua)-containing monomers (ie, arginine [Arg] and agmatine [Agm]) and N,N′-cystamine bisacrylamide (CBA) by Michael-addition polymerization. In order to characterize these two Gua-SS-PAA polymers and investigate their potentials as short hairpin RNA (shRNA)-delivery carriers, pSilencer 4.1-CMV FANCF shRNA was chosen as a model plasmid DNA to form complexes with these two polymers. The Gua-SS-PAAs and plasmid DNA complexes were determined with particle sizes less than 90 nm and positive ζ-potentials under 20 mV at nucleic acid:polymer weight ratios lower than 1:24. Bioresponsive release of plasmid DNA was observed from both newly constructed complexes. Significantly lower cytotoxicity was observed for both polymer complexes compared with polyethylenimine and Lipofectamine 2000, two widely used transfection reagents as reference carriers. Arg-CBA showed higher transfection efficiency and gene-silencing efficiency in MCF7 cells than Agm-CBA and the reference carriers. In addition, the cellular uptake of Arg-CBA in MCF7 cells was found to be higher and faster than Agm-CBA and the reference carriers. Similarly, plasmid DNA transport into the nucleus mediated by Arg-CBA was more than that by Agm-CBA and the reference carriers. The study suggested that guanidine and carboxyl introduced into Gua-SS-PAAs polymers resulted in a better nuclear localization effect, which played a key role in the observed enhancement of transfection efficiency and low cytotoxicity. Overall, two newly synthesized Gua-SS-PAAs polymers demonstrated great potential to be used as shRNA carriers for gene-therapy applications.

Liquisolid technique and its applications in pharmaceutics

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Factors influencing the nuclear targeting ability of nuclear localization signals

Abstract A nuclear localization signal (NLS) is a short amino acid sequence derived from eukaryotic nuclear proteins and viral proteins. Many NLS peptides can efficiently mediate the intranucleus transport of cargo molecules, so they have been widely used for non-viral gene transfer and shown potential ability to improve nuclear delivery of DNA. In order to maximally utilize NLS peptides to enhance gene transfer, several factors such as methods of incorporating NLS peptide, type and property of NLS peptide, number of NLS peptide, and spacer between NLS peptide and DNA should be considered. This review article summarizes how these factors influence the ability of NLS peptides in enhancing non-viral gene delivery and aids in defining the requirements for successful NLS-enhanced transfection.

Comparison of exosome-mimicking liposomes with conventional liposomes for intracellular delivery of siRNA

Graphical abstract Figure. No Caption available. Abstract Exosomes have been extensively explored as delivery vehicles due to low immunogenicity, efficient cargo delivery, and possibly intrinsic homing capacity. However, therapeutic application of exosomes is hampered by structural complexity and lack of efficient techniques for isolation and drug loading. Liposomes represent one of the most successful therapeutic nanocarriers, but are frequently criticized by short blood circulation and inefficient intracellular drug delivery. In this circumstance, a promising strategy is to facilitate a positive feedback between two fields. Herein, exosome‐mimicking liposomes were formulated with DOPC/SM/Chol/DOPS/DOPE (21/17.5/30/14/17.5, mol/mol), and harnessed for delivery of VEGF siRNA to A549 and HUVEC cells. Compared with Lipo 2000 and DOTAP liposomes, exosome‐mimicking liposomes exhibited less than four‐fold cytotoxicity but higher storage stability and anti‐serum aggregation effect. Exosome‐mimicking liposomes appeared to enter A549 cells through membrane fusion, caveolae‐mediated endocytosis, and macropinocytosis, while enter HUVEC through caveolae‐mediated endocytosis, which revealed that the uptake pathway was dependent on cell types. Notably, exosome‐mimicking liposomes exhibited significantly higher cellular uptake and silencing efficiency than PC‐Chol liposomes (>three‐fold), suggesting the unique lipid composition did enhance the intracellular delivery efficiency of exosome‐mimicking liposomes to a significantly greater extent. However, it still remained far from satisfactory delivery as compared to cationic Lipo 2000 and DOTAP liposomes, which warranted further improvement in future research. This study may encourage further pursuit of more exosome‐mimicking delivery vehicles with higher efficiency and biocompatibility.

Functionalized extracellular vesicles as advanced therapeutic nanodelivery systems

&NA; Extracellular vesicles (EVs) are membrane enclosed vesicles that are shed by almost all cell types, and play a fundamental role in cell‐to‐cell communication. The discovery that EVs are capable of functionally transporting nucleic acid‐ and protein‐based cargoes between cells, rapidly promotes the idea of employing them as drug delivery systems. These endogenous vesicles indeed hold tremendous promise for therapeutic delivery. However, issues associated with exogenously administered EVs, including rapid clearance by the immune system, apparent lack of targeting cell specificity, and insufficient cytoplasmic delivery efficiency, may limit their therapeutic applicability. In this review, we discuss recent research avenues in EV‐based therapeutic nanodelivery systems. Furthermore, we narrow our focus on the development of modification strategies to enhance the delivery properties of EVs, and elaborate on how to rationally harness these functionalized vesicles for therapeutic delivery. Graphical abstract Figure. No caption available.

Exosome-based small RNA delivery: Progress and prospects

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