The intragastrointestinal fate of paclitaxel-loaded micelles: Implications on oral drug delivery

The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel (PTX). Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact, except in fed-state simulated intestinal fluid and fasted-state pig intestinal fluid, thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) micelles showing higher stability than other micelles. All groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other micelles. The transport of the micelles across Caco-2/Raji (1.6%–3.5%), Caco-2 (0.8%–1%), and Caco-2/HT29-MTX (0.58%–1%) cell monolayers further verified the absorption of micelles and their subsequent transport; however, more TPGS micelles transported across cell monolayers than other groups. Moreover, the histological examination also confirmed that micelles entered the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other groups. Thus, these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug, uptake by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other groups. In conclusion, these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.     

Self-assembled fluorescent tripeptide nanoparticles for bioimaging and drug delivery applications

Peptide self-assembled nanomaterials have attracted more and more attention due to their wide applications such as drug delivery, cell imaging, and real-time drug monitoring. However, the application of the peptide is still limited by its inherent optical properties. Here we proposed and prepared a series of fluorescent tripeptide nanoparticles (TPNPs) through π-π stacking and zinc coordination. The experimental results show that the nanoparticles (TPNPs1) formed by the self-assembly of the tripeptide tryptophan-tryptophan-tryptophan have the highest fluorescence intensity, uniform and appropriate size, and low cytotoxicity. Furthermore, there was fluorescence resonance between TPNPs1 and doxorubicin, which has been successfully applied for real-time cell imaging and drug release monitoring.     

Self-assembled fluorescent tripeptide nanoparticles for bioimaging and drug delivery applications

Peptide self-assembled nanomaterials have attracted more and more attention due to their wide applications such as drug delivery, cell imaging, and real-time drug monitoring. However, the application of the peptide is still limited by its inherent optical properties. Here we proposed and prepared a series of fluorescent tripeptide nanoparticles (TPNPs) through π-π stacking and zinc coordination. The experimental results show that the nanoparticles (TPNPs1) formed by the self-assembly of the tripeptide tryptophan-tryptophan-tryptophan have the highest fluorescence intensity, uniform and appropriate size, and low cytotoxicity. Furthermore, there was fluorescence resonance between TPNPs1 and doxorubicin, which has been successfully applied for real-time cell imaging and drug release monitoring.     

Synthesis,characterization and effects of arm number on properties of amphiphilic polyurethanes as drug delivery carriers

Amphiphilic polyurethanes based on methoxy poly(ethylene glycol) (mPEG) and poly(?-caprolactone) diol (PCL) with different arm numbers such as two, three and four were successfully synthesized. Their structures were confirmed by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance spectroscopy (¹H NMR) and gel permeation chromatography (GPC). The effects of arm number on properties of amphiphilic polyurethanes were studied. Pyrene fluorescence probe technique and dynamic light scattering (DLS) analyses showed that the CMC value and the micellar size of the resultant amphiphilic polyurethanes decreased and the micellar stability against dilution enhanced with increasing the arm number of polyurethane. Using indometacin (IMC) as a model drug, the results indicated that the drug loading capacity and in vitro drug sustained release effect of polyurethane with four arms were better than those of polyurethanes with two and three arms.     

Comparison of drug delivery properties of PEG-<Emphasis Type="Italic">b</Emphasis>-pdhpc micelles with different compositions

An anti-tumor drug doxorubicin was encapsulated in micelles of poly（ethylene glycol）-b-poly（2,2-dihydroxyl-methyl propylene carbonate）（PEG-b-PDHPC） diblock copolymers.The morphology of both blank micelles and drug loaded micelles was characterized by TEM.The in vitro drug release profiles of micelles were investigated.The cytotoxicity of the micelles was evaluated by incubating with Hela tumor cells and 3T3 fibroblasts.The drug loaded micelles were co-cultured with HepG2 cells to evaluate the in vitro anti-tumor efficacies.The results showed that the mean sizes of both micelles with different copolymer compositions increased after being loaded with drugs.The drug release rate of PEG₄₅-b-PDHPC₃₄ micelles was faster than that of mPEG₁₁₄-b-PDHPC₂₆,micelles.Both of the two block copolymers were non-toxic.The confocal laser scanning microscopy and flow cytometry results showed that both the drug loaded micelles could be internalized efficiently in HepG2 cells.The PEG₄₅-b-PDHPC₃₄ micelles exhibited higher anti-tumor activity comparing to mPEG₁₁₄-b-PDHPC₂₆ micelles.     

Bioinspired self-assembly supramolecular hydrogel for ocular drug delivery

Based on a recent report concerning endogenous agents (i.e., pyridoxal phosphate, adenosine triphosphate, adenosine monophosphate, folinic acid) that modulate the oligomerization of apoptosis-associated speck-like protein (ASC) via the peptide epitope of KKFKLKL, we rationally designed and synthesized a nonapeptide (NapFFKKFKLKL), which can co-assemble with dexamethasone sodium phosphate (Dexp) to generate a NapFFKKFKLKL/Dexp supramolecular hydrogel for ocular drug delivery. The NapFFKKFKLKL/Dexp hydrogel formed instantly after the complexation of NapFFKKFKLKL with Dexp in aqueous solution. The formed supramolecular hydrogels were thoroughly characterized by transmission electron microscopy (TEM), fluorescent spectrum, circular dichroism (CD) spectra and rheology. The peptide concentration significantly affected the in vitro release behavior of Dexp from the supramolecular hydrogel, and the higher peptide concentration resulted in the slower drug release. Following a single intravitreal injection, the proposed NapFFKKFKLKL/Dexp hydrogel displayed good intraocular biocompatibility without having an adverse impact on the retinal architecture and eyesight functions during one month of follow-up. Using an experimental autoimmune uveitis (EAU) rat model, we demonstrated that the resulting NapFFKKFKLKL/Dexp hydrogel had potent capacity to alleviate the intraocular inflammation and retain the morphology of retinal architecture. Overall, the resulting NapFFKKFKLKL/Dexp hydrogel may be a promising drug carrier system to treat various posterior disorders (i.e., uveitis).     

Recent advances in surface-active ionic liquid-assisted self-assembly systems for drug delivery

Surface-active ionic liquids (SAILs) are receiving growing interest as environmentally friendly designer surfactants for various applications, including drug formulation and delivery. The use of SAILs in the pharmaceutical industry has the potential to address the challenges associated with conventional surfactants. The tunable formation of complementary ion pairs from a diverse range of ions enables the task-specific optimization of SAILs. SAILs comprising second and third-generation cations and anions have been used to design biocompatible self-assembled systems including micelles, microemulsions, vesicles, liposomes, and nanoparticles for drug delivery carriers. Compared with conventional surfactant-based carriers, SAIL-based systems offer better pharmacokinetic and pharmacodynamic properties. This mini-review highlights recent findings on the formation of ionic liquid-based self-assembled systems and their potential applications in drug delivery.     

Supramolecular hydrogels for enzymatically triggered self-immolative drug delivery

For the first time the combination of self-immolative spacers and supramolecular hydrogels has been tested in enzyme triggered drug release. Low-molecular weight drug-gelator conjugates have been prepared, which contain a gel forming lysine moiety linked to model drugs (benzylamine and phenethylamine) through a self-immolating spacer (p-aminobenzyloxycarbonyl). In the presence of trypsin the amide linkage between the gelator moiety and the spacer is hydrolyzed leading to the release of the model drug. This approach provides with distinct advantages, such as sustained release or versatility associated to the use of supramolecular hydrogels and self-immolative spacers, respectively.     

两亲聚合物胶束自组装包药研究进展

两亲聚合物胶束具有突出的理化性能和独特功能,能够在溶液中自组形成具有核壳结构的聚合物胶束,同时实现药物的负载。自组装包药技术能够缓解我国药物辅料缺乏的现状,符合目前药物辅料发展的新趋势。通过自组装形成的聚合物胶束在药物控释、药物靶向载体、药物制剂开发、新型药物辅料等方面具有广阔的应用前景。本文综述了两亲聚合物胶束自组装包载药物的原理以及方法,重点介绍了三类两亲聚合物在自组装包药方面的最新研究成果和发展趋势。本文还对载药胶束在药物释放方面的应用进行了概述。     

Functional and site-specific macromolecular micelles as high potential drug carriers

Since several years, macromolecular micelles based on amphiphilic block copolymers have attracted much interest as drug carriers. These micelles show a long term blood circulation time resulting from their small diameter and the steric repulsion created by the poly(ethylene oxide) chains which constitute micelle corona, as well as from their high thermodynamic stability. Besides this long term blood circulation time generating a passive targeting, an active targeting, chemical or physical affinity targeting, might allow the preparation of more efficient drug carriers. In order to obtain such double targeting properties, we have prepared two kinds of macromolecular micelles. The first one is based on amphiphilic poly(ethylene oxide)/poly(β-benzyl -aspartate) ---PEO/PBLA--- block copolymers having hydroxy groups at the free end of PEO chains. As a result of their structure, such micelles have hydroxy groups on their outer-shell which can be further modified in order to introduce a targeting moiety (sugar, etc.). The characteristics (diameter, critical micellar concentration (cmc), drug loading capacity) have been determined. Moreover, doxorubicin loaded -hydroxy PEO/PBLA micelles have been shown to be slightly more cytotoxic than the corresponding -methoxy PEO/PBLA micelles. The second type of micelles is based on thermosensitive amphiphilic poly(N-isopropyl acrylamide)/polystyrene ---PIPAAm/PSt--- block copolymers. Such micelles have a small diameter and a low cmc in addition to thermosensitivity properties which are similar to those of PIPAAm.     

Dendritic polyurethane-based prodrug as unimolecular micelles for precise ultrasound-activated localized drug delivery

Ultrasound has been recognized as an exciting tool to enhance the therapeutic efficacy in tumor chemotherapy owing to the triggered drug release, facilitated intracellular drug delivery, and improved spatial precision. Aiming for a precise localized drug delivery, novel dendritic polyurethane-based prodrug (DOX-DPU-PEG) was fabricated with a drug content of 18.9% here by conjugating DOX onto the end groups of the functionalized dendritic polyurethane via acid-labile imine bonds. It could easily form unimolecular micelles around 38 nm. Compared with the non-covalently drug-loaded unimolecular micelles (DOX@Ph-DPU-PEG), they showed excellent pH/ultrasound dual-triggered drug release performance, with drug leakage of only 4% at pH 7.4, but cumulative release of 14% and 88% at pH 5.0 without and with ultrasound, respectively. The ultrasound responsiveness was attributed to the unique strawberry-shaped topological structure of the DOX-DPU-PEG, in which DOX was embedded in the skin layer of the hydrophobic DPU cores. With ultrasound, the DOX-DPU-PEG unimolecular micelles possessed enhanced tumor growth inhibition than free DOX but showed no obvious cytotoxicity on the tumor cells without ultrasound. Such feature makes them promising potential for precise localized drug delivery.     

Preparation and drug controlled-release of polyion complex micelles as drug delivery systems

Block copolymers, poly(N-vinylprrolidone)-block-poly(styrene-alter-maleic anhydride) (PVP-b-PSMA) and poly(N-vinylprrolidone)-block-poly(N,N-dimethylaminoethyl methacrylate) (PVP-b-PDMAEMA), were synthesized by reversible addition- fragmentation chain transfer (RAFT) polymerization. In aqueous media, this a pair of oppositely-charged diblock copolymers could self-assemble into stable and narrow distribution polyion complex micelles (PICMs). Transmission electron micrographs (TEM) and dynamic light scattering (DLS) analysis showed that the micelles to be spherically shaped with mean hydrodynamic diameter around 70 nm. In addition, the PICMs display ability to response to external stimuli. All of theses features are quite feasible for utilizing it as a novel intelligent drug delivery system. In order to assess its application in biomedical area, release profiles of coenzyme A (Co A) from PICMs were studied under both simulated gastric and intestinal pH conditions. The release was much quicker in pH 7.4 buffer than in pH 2.0 solution. Based on these results, these PICMs could be a potential pH-sensitive carrier for colon-specific drug delivery system.     

Micelle or polymersome formation by PCL-PEG-PCL copolymers as drug delivery systems

Polymeric micelles and polymersomes may have great potential as the drug delivery vehicles for solubilization of hydrophobic drugs.     

Self-assembled thermosensitive luminescent nanoparticles with peptide-Au conjugates for cellular imaging and drug delivery

A facile and efficient strategy has been developed to fabricate a multifunctional,theranostic anticancer drug delivery platform featuring active targeting,controlled drug release and fluorescence imaging for real-time control of delivery.To this end,thermo sensitive poly(N-isopropyl acrylamide)(PNIPAM)nanospheres are decorated with peptide-Au cluster conjugates as a smart nanomedicine platform.A sophisticated trifunctional peptide is designed to release the anticancer drug doxorubicin(DOX),target cells and reduce Au^3+ions to form luminescent Au cluste rs.Importantly,the peptide-Au cluster moieties are attached to the PNIPAM nanospheres via amide bonds rather than noncovalent interactions,significantly improving their stability in biological medium and drug release efficiency.The in vitro experiments showed that DOX was released in an efficient and controlled manner under physiological conditions.     

Advanced drug delivery systems: Nanotechnology of health design A review

Nanotechnology has finally and firmly entered the realm of drug delivery. Performances of intelligent drug delivery systems are continuously improved with the purpose to maximize therapeutic activity and to minimize undesirable side-effects. This review describes the advanced drug delivery systems based on micelles, polymeric nanoparticles, and dendrimers. Polymeric carbon nanotubes and many others demonstrate a broad variety of useful properties. This review emphasizes the main requirements for developing new nanotech-nology-based drug delivery systems.     

Controlled drug delivery systems based on calixarenes

Recent advances on calixarene-based drug delivery systems in the form of inclusion complexes, amphiphilic self-assembly nanocarriers including micelles, hydrogels, vesicles and liposomes, and supramolecular nanovalves on mesoporous silicas, were reviewed and discussed.     

Cellulose esters in drug delivery

Cellulose esters have played a vital role in the development of modern drug delivery technology. They possess properties that are not only well-suited to the needs of pharmaceutical applications, but that enable construction of drug delivery systems that address critical patient needs. These properties include very low toxicity, endogenous and/or dietary decomposition products, stability, high water permeability, high T _g, film strength, compatibility with a wide range of actives, and ability to form micro- and nanoparticles. This suite of properties has enabled the creation of a wide range of drug delivery systems employing cellulose esters as key ingredients. The following is a review of the most important types of these systems, and of the critical roles played by cellulose esters in making them work, focusing on more recent developments.     

Self-assembled small molecular weight hydrogels of prodrugs

Prodrugs as building unit for construction of various hydrogelator in response to different stimulus (e.g., temperature, enzyme, pH value, ion).     

Stabilization and activation of Pluronic micelles for tumor-targeted drug delivery

In order to be used as drug carriers, Pluronic micelles require stabilization to prevent degradation caused by significant dilution accompanying IV injection. This article studies three routes of Pluronic micelle stabilization. The first route was direct radical crosslinking of micelles cores which resulted in micelle stabilization. However, this compromised the drug loading capacity of Pluronic micelles. In the second route, a small concentration of vegetable oil was introduced into diluted Pluronic solutions. This decreased micelle degradation upon dilution while not compromising the drug loading capacity of oil-stabilized micelles. The third route was a novel technique based on polymerization of the temperature-responsive LCST hydrogel in the core of Pluronic micelles. The hydrogel phase was in a swollen state at room temperature, which provided a high drug loading capacity of the system. The hydrogel collapsed at physiological temperatures which locked the core of micelles thus preventing them from fast degradation upon dilution. This new drug delivery system was called Plurogel®. Phase transitions in Plurogel® caused by variations in temperature or concentration were studied by the EPR. The effect of Pluronic concentration in the incubation medium on the intracellular uptake of two anti-cancer drugs was studied. At low Pluronic concentrations, when the drugs were located in the hydrophilic environment, drug uptake was increased, presumably due to the effect of a polymeric surfactant on the permeability of cell membranes. In contrast, when the drugs were encapsulated in the hydrophobic cores of Pluronic micelles, drug uptake by the cells was substantially decreased. This may be advantageous in the prevention of undesired drug interactions with normal cells. Ultrasonication enhanced intracellular drug uptake from dense Pluronic micelles. These findings permitted the formulation of a new concept of a localized drug delivery.     

Structural dynamics,phase behavior,and applications of polyelectrolyte complex micelles

Self-assembly between oppositely charged polyelectrolytes conjugated to neutral polymeric blocks form polyelectrolyte complex (PEC) micelles. These nanostructures have gained significant interest in the field of nucleic acid and protein delivery, along with emerging applications in biosensing and catalysis. These carriers are highly modular systems, with the ability to engineer stimuli-responsive and targeting properties, making them smart platforms for biomedical applications. In this review, we discuss the current understanding of mechanisms involved in the assembly and disassembly of these nanoparticles, and the structural and functional changes as a response to solution conditions. We also discuss the latest and most impactful applications of PEC micellar systems in the biomedical field, with far-reaching influence on the treatment of various human diseases.