Drug Delivery Ability Research Articles

Enhancing the preservation of liposomes: The role of cryoprotectants, lipid formulations and freezing approaches

In the last decades, liposomes acquired a striking success in the biomedical field thanks to their biocompatibility and drug delivery ability. Many liposomal drug formulations have been already approved by the Food and Drug Administration (FDA) and used for the treatment of a wide range of pathologies with or without further engineering. Their clinical application requires strict compliance with high standard quality rules, and it is crucial to employ storage methods that do not affect the integrity of the vesicles and preventing the leakage of their cargo.In this work, the design of a suitable formulation for freeze-drying had been investigated for two different liposomes, DOPC-DOTAP and the PEGylated counterpart, DOPC-DOTAP-DSPE-PEG. The role of various cryoprotectants was evaluated paying attention to their ability to preserve the structural integrity of liposomes. At first, the study was focused on freezing and two methodologies were investigated, quenching in liquid nitrogen and shelf-ramped freezing. This analysis showed that the disaccharides (cellobiose, glucose, lactose, sucrose, and trehalose) and the polyol (mannitol) protected successfully the integrity of liposomes, while during the process, in the presence of a surfactant, liposomes were strongly damaged and fragmented by the ice crystals. Furthermore, the choice of the rate of freezing depended on the different compositions of the lipid bilayer. Finally, the effects of lyophilization on liposomes with and without additives were studied; cellobiose, lactose and trehalose showed encouraging results for the maintenance of the morpho-functional parameters of liposomes during the entire freeze-drying process.

Mesoporous calcium silicate nanoparticles for superficial dental tissue reconstruction, in vitro and in vivo.

The underlying dentin could be exposed to a humid atmosphere filled with bacteria if the covering enamel layer is broken because of external chemical and physical conditions. Accordingly, some diseases like bacterial invasion and dentin hypersensitivity often occur, which impact the daily life of patients. The study is aimed at evaluating the occluding effects of mesoporous calcium silicate nanoparticles (MCSNs) on the dentinal tubules in vitro and in vivo, as well as the antibacterial property and drug delivery ability when loaded with chlorhexidine (CHX) in vitro. MCSNs were synthesized according to the standard protocol. After a series of complimentary evaluations in vitro and in vivo, it was found that MCSNs and CHX–MCSNs could continually form apatite-like enamel layers on the exposed dentinal tubules and significantly reduced dentin permeability both in vitro and in vivo. Besides, MCSN and CHX–MCSN possessed low cytotoxicity in vitro, and only mild pulp inflammation was observed in two MCSNs containing groups in vivo. In addition, MCSN loaded with CHX released CHX sustainably and revealed a significant antibacterial effect against E. faecalis in vitro. Therefore, the results suggest that MCSN could be used as a promising biomaterial to occlude the dentinal tubules and carry antibiotics for avoiding further pulp infection.

Chitosan Hydrogel Doped with PEG-PLA Nanoparticles for the Local Delivery of miRNA-146a to Treat Allergic Rhinitis.

To prepare a binary formulation delivering miRNA-146 and evaluate a nucleic acid nasal delivery system by investigating its pharmacodynamic effects in allergic rhinitis. The gel/NPs/miR-146a thermosensitive in situ chitosan hydrogel carrying a nucleic acid was prepared and evaluated for its characteristics, including temperature sensitivity, gel strength, mucosal adhesion and drug release profile. After nasal administration of the formulation to ovalbumin-sensitized rats, the treatment of allergic rhinitis was verified by assessing nasal symptoms, hematology, hematoxylin-eosin (HE) staining and immunohistochemistry. Western Blot(WB) was used to analyze nasal inflammatory factors as well as miRNA-146-related factors, and the miR146 expression level was measured by PCR. Subsequently, the effects of the gel/NPs/miR-146a binary formulation were evaluated for the nasal delivery of nucleic acids in rhinitis therapy. The prepared binary formulation quickly formed a gel in the nasal cavity at a temperature of 34 °C with good mucosal adhesion, which delivered nucleic acids into the nasal mucosa stably and continuously. Gel/NPs/miR-146a was able to sustain the delivery of miRNA into the mucosa after nasal administration. When compared with the monolithic formulations, the gel/NPs/miR-146a binary formulation performed better regarding its nucleic acid delivery ability and pharmacodynamic effects. The gel/NPs/miR-146a binary preparation has a suitable nasal mucosal drug delivery ability and has a positive pharmacodynamic effect for the treatment of ovalbumin-induced rhinitis in rats. It can serve as a potential nucleic acid delivery platform for the treatment of allergic rhinitis.

Phosphorene and Na-, Ca-, and Fe-doped phosphorene as candidates for delivery of mercaptopurine and fluorouracil anticancer drugs.

Phosphorene ability for delivery of mercaptopurine and fluorouracil was investigated by the density functional theory (DFT) method. However, the effects of Na, Ca, and Fe as dopants on phosphorene electronic properties such as HOMO and LUMO energies, density of states, chemical potential, electrophilicity index, softness, hardness, and its ability for drug delivery were studied. Natural bond orbital (NBO) analysis was performed. Our findings indicate that metallic dopants can improve the ability of phosphorene. Calcium-doped phosphorene has the greatest adsorption energy.

Self-assembled peptide nanoparticles with endosome escaping permits for co-drug delivery

The diagnosis and treatment of major diseases, especially tumors, was the key to improving the cure rate and survival rate of patients. Therefore, one of the main goals of modern medicine was to develop effective, non-toxic treatments. This paper successfully established dipeptide nanoparticles/clofarabine/aptamer AS1411/influenza hemagglutinin peptide/siRNA/doxorubicin (DNPs/Clolar/AS1411/HA/RNA/DOX) multi-functional nanoparticles for specific delivery, cancer treatment and bioimaging. It was an ideal choice for multi-drug synergy treatment. First, non-toxic DNPs formed by self-assembly of dipeptides with safe and biocompatible effect. Second, from the perspective of the multi-functional nanoparticles for nano-drug tumors imaging monitoring, AS1411 and HA were used as cell permits for enhancing the specificity of cell drug delivery ability and improving the endosomal escape, respectively. Third, the multi-functional nanoparticles with Clolar, siRNA and DOX, three drug synergistic treatments were used to improve the therapeutic effect of tumors. Both cell experiments and vivo experiments demonstrated that the synergistic treatment of the multi-drugs was superior to the effect of single-drug therapy. Thus, the proposed multi-functional nanoparticles have initiated new ideas for these hybrid anticancer drugs based on peptide self-assembled nanocarriers and its widely applications in biomedicine.

In Silico Molecular Interaction Studies of Chitosan Polymer with Aromatase Inhibitor: Leads to Letrozole Nanoparticles for the Treatment of Breast Cancer

It takes a lot more studies to evaluate the molecular interaction of nanoparticles with the drug, their drug delivery potential and release kinetics. Thus, we have taken in silico and in vitro approaches into account for the evaluation of the drug delivery ability of the chitosan nanoparticles. The present work was aimed to study the interaction of chitosan nanoparticles with appropriate aromatase inhibitors using in silico tools. Further, synthesis and characterization of chitosan nanoparticles having optimal binding energy and affinity between drug and polymer in terms of size, encapsulation efficiency were carried out. In the current study, molecular docking was used to map the molecular interactions and estimation of binding energy involved between the nanoparticles and the drug molecules in silico. Letrozole is used as a model cytotoxic agent currently being used clinically; hence Letrozole loaded chitosan nanoparticles were formulated and characterized using photomicroscope, particle size analyzer, scanning electron microscope and fourier transform infra-red spectroscopy. Letrozole had the second-highest binding affinity within the core of chitosan with MolDock (-102.470) and Re-rank (-81.084) scores. Further, it was investigated that formulated nanoparticles were having superior drug loading capacity and high encapsulation efficiency. In vitro drug release study exhibited prolonged release of the drug from chitosan nanoparticles. Results obtained from the in silico and in vitro studies suggest that Letrozole loaded nanoparticles are ideal for breast cancer treatment.

Multilayer Alginate-Polycaprolactone Electrospun Membranes as Skin Wound Patches with Drug Delivery Abilities.

A multilayer nanofibrous membrane consisting of a layer of polycaprolactone and one of physically cross-linked alginate-embedding ZnO nanoparticles is prepared via electrospinning technique as potential wound healing patches with drug delivery capabilities. A washing–cross-linking protocol is developed to obtain stable materials at the same time removing poly(ethylene oxide), which was used here as a cospinning agent for alginate, without interfering with the membrane’s peculiar nanofibrous structure. The mechanical behavior of the samples is assessed via a uniaxial tensile test showing appropriate resistance and manageability together with a good thermal stability as proved via thermogravimetric analysis. The polycaprolactone external layer enriches the samples with good liquid-repellent properties, whereas the alginate layer is able to promote tissue regeneration owing to its capability to promote cell viability and allow exudate removal and gas exchanges. Moreover, using methylene blue and methyl orange as model molecules, promising drug delivery abilities are observed for the mats. Indeed, depending on the nature and on the dye-loading concentration, the release kinetic can be easily tuned to obtain a slow controlled or a fast burst release. Consequently, the proposed alginate–polycaprolactone membrane represents a promising class of innovative, simple, and cost-effective wound healing patches appropriate for large-scale production.

Facile preparation of pH-sensitive chitosan microspheres for delivery of curcumin; characterization, drug release kinetics and evaluation of anticancer activity

Curcumin (CUR) is a lowly water-soluble natural polyphenol with chemopreventive and chemotherapeutic activities. Hence, to achieve the system with good CUR loading ability, porous MIL-88 (Fe) was prepared in the presence of the presynthesized graphene quantum dots (GQDs) (GQDs@MIL-88 (Fe)). In the following, CUR loaded in the fabricated GQDs@MIL-88 (Fe) nanohybrid. The characterization techniques; Fourier transform infrared (FT-IR), X-ray powder diffraction (XRD), scanning electron microscope (SEM), photoluminescence (PL), and Brunauer–Emmett–Teller (BET) analysis showed success in the synthesis of GQDs@MIL-88 (Fe). Moreover, the FT-IR analysis displayed the loading of CUR and the formation of CUR@GQDs@MIL-88(Fe). Chitosan (CS) was used as a green coating to enhance the biocompatibility of the prepared system (CS/CUR@GQDs@MIL-88(Fe). The fabricated microspheres showed pH-sensitive swelling behavior and released 38.3% of CUR in pH 5.0 which is better fitted with the First-order kinetic model (R2 = 0.9726). In comparison with CUR@GQDs@MIL-88(Fe), the MTT and DAPI assay exhibited less toxic effect for CS/CUR@GQDs@MIL-88(Fe) against MDA-MB 231 cells. Moreover, the safety of the CS/CUR@GQDs@MIL-88(Fe) confirmed after incubation against MCF 10A as a model of the normal cell line. The results conveyed a new concept that the CS/CUR@GQDs@MIL-88(Fe) is a potential candidate for using as a biocompatible carrier with controlled drug delivery ability.

Bilayer Hydrogel Sheet-Type Intraocular Microrobot for Drug Delivery and Magnetic Nanoparticles Retrieval.

By virtue of minimum invasiveness and driving ability using a magnetic field, drug delivery with the aid of a microrobot has an inherent potential for targeted treatment for the eye. The use of microrobots, however, has the limitation of leaving magnetic nanoparticles (MNPs) in the eye that can cause side effects. In this study, a bilayer hydrogel microrobot capable of retrieving MNPs after drug delivery is proposed that overcomes the limitations of existing microrobots. The bilayer hydrogel microrobot is composed of an MNPs layer and a therapeutic layer. Upon applying an alternating magnetic field (AMF) at the target point, the therapeutic layer is dissolved to deliver drug particles, and then the MNPs layer can be retrieved using a magnetic field. The targeting and MNPs retrieval tests validate the drug delivery and MNPs retrieval ability of the microrobot. The ex vivo bovine vitreous and in vitro cell tests demonstrate the potential for the vitreous migration of the microrobot and the therapeutic effect against retinoblastoma Y79 cancer cells. This bilayer hydrogel sheet-type intraocular microrobot provides a new drug delivery paradigm that overcomes the limitations of microrobot by maintaining the advantages of conventional microrobots in delivering drugs to the eye and retrieving MNPs after drug delivery.

Antibacterial, drug delivery, and osteoinduction abilities of bioglass/chitosan scaffolds for dental applications

Treating dental infections requires removing the damaged tissue and inserting a filling material. Scaffolds are very successful in numerous biomedical applications, especially dental/bone substitution. Here, hematite-doped bioglass/chitosan scaffolds are investigated as an alternative implant system for delivering 2% chlorhexidine gluconate (CHX) to repair infected root canals as well as for evaluating their osteoinduction ability. The antibacterial activity of the fabricated scaffolds was assessed using the agar diffusion method. Furthermore, ex vivo antibacterial tests were performed in infected teeth using Enterococcus faecalis. CHX's in vitro release was determined in PBS after 1, 7, and 14 days. Their osteoinductive ability was determined using white male Wistar-Furth rats. The antibacterial results show an obvious behavioral difference between the pure CHX and the CHX-loaded scaffolds against E. faecalis. Moreover, the CHX release behavior from the CHX-loaded scaffolds depended on its concentration within the scaffolds. The presence of hematite (Fe2O3) enhanced drug release and completely eliminated bacterial growth after 14 days, as revealed by the in vitro drug release and antibacterial tests. Scaffold implantation resulted in remarkable osteoinduction for both scaffolds. This study illustrates that the prepared scaffolds show antibacterial, drug delivery, and osteoinduction abilities that could potentially be used in endodontic therapy.

Bioactive Glass as a Nanoporous Drug Delivery System for Teicoplanin

Bioactive glass (BG) was made by the sol–gel method and doped with boron (B) to increase its bioactivity. Microstructures of BG and B-doped BG were observed by scanning electron microscopy, and phase identification was performed using an X-ray diffraction diffractometer. The ion concentrations released after soaking in simulated body fluid (SBF) for 1, 4, and 7 days were measured by inductively coupled plasma mass spectrometry, and the pH value of the SBF was measured after soaking samples to determine the variation in the environment. Brunauer–Emmett–Teller (BET) analysis was performed to further verify the characteristics of mesoporous structures. High performance liquid chromatography was used to evaluate the drug delivery ability of teicoplanin. Results demonstrated that B-doped BG performed significantly better than BG in parameters assessed by the BET analysis. B-doped BG has nanopores and more rough structures, which is advantageous for drug delivery as there are more porous structures available for drug adsorption. Moreover, B-doped BG was shown to be effective for keeping pH values stable and releasing B ions during soaking in SBF. The cumulative release of teicoplanin from BG and B-doped BG reached 20.09% and 3.17% on the first day, respectively. The drug release gradually slowed, reaching 29.43% and 4.83% after 7 days, respectively. The results demonstrate that the proposed bioactive glass has potential as a drug delivery system.

Synthesis and characterization of binary selenides of transition metals to investigate its photocatalytic, antimicrobial and anticancer efficacy

Development of resilient and efficient composite materials that exhibit substantial antimicrobial activity, ample photocatalytic ability and considerable capacity for drug delivery is highly desirable. The present study demonstrates the incorporation of selenium (Se) in transition metals (vanadium-V, niobium-Nb, and tantalum-Ta) via standard solid-state hydrothermal reaction method. Generated nanostructures (V:Se, Nb:Se, Ta:Se) were characterized using various techniques. XRD analysis confirmed the presence of monoclinic phase compounds while crystallite size (~ 13.5–26.2 nm) was calculated using Debye–Scherrer equation. FESEM was used to examine surface morphologies of V:Se (rod-like and disc-shaped) and of Nb and Ta selenides (irregular agglomerated nanospheres). Compositional and functional group analysis was undertaken through FTIR spectroscopy and EDS coupled with SEM, respectively. Raman spectroscopy was carried out to ascertain the bending and stretching vibrational modes in samples. Optical properties were investigated through UV–Vis spectroscopy and the PL emission spectra were acquired to evaluate the charge separation and recombination behavior of compounds. Thermal stability of designed composites was measured using TGA/DSC. Potential uses of the prepared nanoparticles were explored in multiple fields including photocatalysis, antimicrobial and drug delivery systems. Methylene blue dye was degraded under 400–700 nm wavelength in the presence of synthesized wide band gap composites as photocatalysts. The selenium–metal particles were subjected as antimicrobial agents against gram (−ve) and gram (+ve) bacteria and experimental results suggested this material to be an effective antibiotic. Furthermore, synthesized nanocomposites were examined as carrier of anticancer drug (DOX) and their drug delivery profile was also investigated.

Functional Bioglass-Biopolymer Double Nanostructure for Natural Antimicrobial Drug Extracts Delivery.

Aseptic loosening and periprosthetic infections are the main causes of implant failure. Strategies to mitigate this drawback are therefore mandatory to avoid primary and revision replacement surgeries. A functional bioapatite–biopolymer double nanostructure fabricated by matrix-assisted pulsed laser evaporation to prevent infection of orthopedic and dental implants could promote osseointegration and ensure controlled delivery of natural antimicrobial drugs. The synthesized nanostructure consists of two overlapping layers, the lower from a biocompatible polymer for anticorrosive protection, and the upper of bioactive glass incorporating antimicrobial plant extract, acting as a potential drug delivery system. Morphology, composition, adherence, ability for drug delivery and biological properties (cytotoxicity and antimicrobial effect) were studied. Structures proved compact and stable, conserving a remarkable drug delivery ability for more than 21 days, i.e., enough to ensure long-term microbes’ eradication.

Coating and Functionalization Strategies for Nanogels and Nanoparticles for Selective Drug Delivery.

Drug delivery is a fascinating research field with several development opportunities. Great attention is now focused on colloidal systems, nanoparticles, and nanogels and on the possibility of modifying them in order to obtain precise targeted drug delivery systems. The aim of this review is to give an overview of the main available surface functionalization and coating strategies that can be adopted in order to modify the selectivity of the nanoparticles in the delivery process and obtain a final system with great targeted drug delivery ability. We also highlight the most important fields of application of these kinds of delivery systems and we propose a comparison between the advantages and disadvantages of the described functionalization strategies.

PH- and Ultrasound-Responsive Paclitaxel-Loaded Carboxymethyl Chitosan Nanodroplets for Combined Imaging and Synergistic Chemoradiotherapy.

BackgroundSynergistic chemoradiotherapy (CRT) has become a primary effective curative approach for many solid cancers. However, CRT is still associated with several obstacles, including the increases in side effects and systemic toxicity. Incorporating nanocarriers into CRT is a new and exciting approach to solve these obstacles. The purpose of the present study was to design a unique pH- and ultrasound-responsive perfluoropentane-encapsulated, paclitaxel (PTX)-loaded carboxymethyl chitosan nanodroplets (NDs) for combined imaging and synergistic CRT.Materials and MethodsThe NDs were prepared by a homogenization/emulsion method. Their physicochemical properties, echogenicity and biocompatibility were evaluated. PTX-loaded NDs with a high loading efficiency and encapsulation efficiency were prepared and their pH-responsive drug release profile was determined by dialysis sack method. Then, PC3 cells were exposed to (1) PTX (4 μg/mL), (2) NDs (30 μg/mL), (3) PTX-loaded NDs (34 μg/mL), (4) RT (6 Gy), (5) RT (10 Gy), (6) combination of PTX (4 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6 Gy), (7) combination of NDs (30 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6Gy), (8) combination of PTX-loaded NDs (30 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6 Gy). 24 hrs later, CCK-8 assay, flow cytometry and migration assay were carried out to evaluate their therapeutic effects in CRT.ResultsThe desired NDs were successfully prepared, which were with round, spherical shapes, relatively smooth surfaces, core-shell structures and uniform in sizes (<300 nm with PDI<0.3 when at pH≧6.0). The NDs exhibited good abilities in pH-dependent charge conversion, biocompatibility and ultrasound contrast echogenicity. The in vitro drug release from PTX-loaded NDs (the highest loading efficiency and encapsulation efficiency were 20.35% and 91.58%) was pH dependent and exhibited an initial burst followed by a sustained drug release. The results of the CCK-8 assay, flow cytometry and migration assay all showed PTX-loaded NDs combined ultrasound and RT significantly enhanced cell responses in CRT.ConclusionThe pH- and ultrasound-responsive PTX-loaded NDs, which exhibited a high echogenicity, drug delivery ability and radiosensitization ability, could be a feasible option for combined imaging and novel enhancing approach in synergistic CRT.

Fluorine-Doped Carbon Dots with Intrinsic Nucleus-Targeting Ability for Drug and Dye Delivery.

A new type of fluorine-doped carbon dots (FCDs) with the nucleus-targeting capability was prepared and utilized as a promising candidate for drug and dye delivery. Doxorubicin (DOX) and boron dipyrromethene (BODIPY) was used as a model drug and dye, respectively, to construct FCD-DOX and FCD-BODIPY nanocomposites via coassembly with FCDs. The results demonstrate that FCDs can remarkably increase the cellular uptake and delivery of DOX and BODIPY. This work developed a convenient strategy to construct CDs-based nanohybrids for nucleus-targeted bioimaging and cancer treatment.

Benzoic acid derivative-modified chitosan-g-poly(N-isopropylacrylamide): Methoxylation effects and pharmacological treatments of Glaucoma-related neurodegeneration

Long-acting drug delivery systems with advanced functionalities are critically important to pharmacologically treat glaucomatous optic neuropathy, a chronic and multifactorial neurodegenerative disease. Here, a novel strategy based on the methoxylation effects of benzoic acid derivatives was exploited to rationally design a biodegradable and injectable thermogel, which possesses potent antioxidant activities and sustained drug delivery abilities for treating glaucomatous nerve damage. In particular, 4-hydroxy-3,5-dimethoxybenzoic acid, consisting of two methoxyl groups and one hydroxyl group at the position para to the carboxylic group, was demonstrated to contribute to the strong antioxidant activities of a chitosan-g-poly(N-isopropylacrylamide) biomaterial while maintaining the drug encapsulation/release efficiencies of the thermogel. The pharmacological treatment relies on the intracameral injection of the thermogel coloaded with pilocarpine and RGFP966 and exhibits significant improvement in the attenuation of neurodegeneration via suppressing oxidative stress, lowering ocular hypertension, reducing retinal ganglion cell loss and enhancing myelin growth and neuron regeneration. These findings on the development of long-acting drug delivery systems with extended functions show great promise for the management of glaucoma-related neurodegeneration.

Functional targeting nanomicelles with ph-triggered peptide activation for improved drug delivery in lung cancer

Mild acidic environment and tumor angiogenesis are two typical features. The specific response toward lower pH may increase the targeting ability both for drug delivery. Herein, we present a responding self-assembled nanoparticle that is tumor angiogenesis targeting and pH triggered based on a novel recognition peptide DP. DP is pH-responsive as well as the affinity ligand of tumor marker EGFR. Efficient drug delivery and in vitro therapy in cell level could be accelerated in the conditions of EGFR overexpression and a mild acidic environment. We believed that such responsive materials will open a new way to turn on target imaging diagnostics and specific cancer therapies.

Preparation and performance of thermosensitive poly(N‐isopropylacrylamide) hydrogels by frontal photopolymerization

AbstractIn this study, frontal photopolymerization was applied to the fabrication of thermosensitive poly(N‐isopropylacrylamide) (PNIPAm) hydrogels. The influence of experimental conditions and reactant components on the feature of the polymerization front was investigated. The morphology of the samples indicated the successful preparation of PNIPAm hydrogels. The mechanical properties and thermal stability of the obtained hydrogels are discussed. The results indicated that the performance of the hydrogels is related to their microstructure and the type of crosslinkers. The swelling behavior and drug delivery ability were determined under different temperature conditions. The hydrogels exhibit a classical thermoresponsive behavior, which was also demonstrated by the DSC results. Therefore, frontal photopolymerization can be an alternative method for the preparation of PNIPAm hydrogels under mild conditions. © 2019 Society of Chemical Industry

Recent Progress of Crosslinking Strategies for Polymeric Micelles with Enhanced Drug Delivery in Cancer Therapy.

The drug delivery by versatile types of self-assembled micelles for tumor treatment, which improved the diagnostic and therapeutic effectiveness, is advocated. However, despite the numerous advantages, applications of most micelle system have been retarded by low in vivo bio-stability which led to premature drug release and nonspecific tissue accumulation. To date, a range of chemistries has been introduced in intermolecular non-covalent/covalent crosslinking strategies for these dynamic nanostructures to produce robust functional nanoparticles with enhanced circulation stability and lower non-targeted organ toxicity. We focused on recent developments in crosslinking polymeric nanoparticles in cancer therapy. Types of chemistries used in the crosslinking strategies of the micelles are outlined and their enhanced drug delivery abilities are discussed. We reviewed one hundred and nineteen papers and discussed in six aspect. More than 30 examples have been carefully discussed. Over the last decade, numerous of strategies for micelles crosslinking, such as disulfide coupling, free radical polymerization, physical interactions, chelation, and formation of microenvironment- responsive bonds, have been developed for enhancing micelles circulation stability, minimizing organ toxicity and achieving higher tumor targeting specificity. The application of these chemistries for micelle stabilizing might bring a new generation of versatile crosslinked micelles with enhanced therapeutic index and facilitate their further clinical translations.