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Abstract: Synthetic chemotherapeutics have played a crucial role in minimizing mostly palliative symptoms associated with cancer; however, they have also created other problems such as system toxicity due to a lack of specificity. This has led to the development of polymer-drug conjugates amongst other novel drug delivery systems. Most of the formulations designed using delivery systems consist of synthetic drugs and face issues such as drug resistance, which has already rendered drugs such as antibiotics ineffective. This is further exacerbated by toxicity due to the long-term use. Given these problems and the fact that conjugation of synthetic compounds to polymers has been relatively slow with no formulation on the market after a decade of extensive studies, the focus has shifted to using this platform with medicinal plant extracts to improve solubility, specificity and increase drug release of medicinal and herbal bioactives. In recent years, various plant extracts such as flavonoids, tannins and terpenoids have been studied extensively using this approach. The success of formulations developed using novel drug-delivery systems is highly dependent on the tumour microenvironment especially on the enhanced permeability and retention effect. As a result, the compromised lymphatic network and ‘leaky’ vasculature exhibited by tumour cells act as a guiding principle in the delivery of these formulations. This review focuses on the state of the polymer-drug conjugates and their exploration with natural compounds, the progress and difficulties thus far, and future directions concerning cancer treatment.

Due to the special physiological and pathological characteristics of gliomas, most therapeutic drugs are prevented from entering the brain. To improve the poor prognosis of existing therapies, researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy. Although these strategies can be used clinically to overcome the blood‒brain barrier (BBB), the accurate delivery of drugs to the glioma lesions cannot be ensured. Nano-drug delivery systems (NDDS) have been widely used for precise drug delivery. In recent years, researchers have gathered their wisdom to overcome barriers, so many well-designed NDDS have performed prominently in preclinical studies. These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions, drug release in response to the glioma microenvironment, biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein, and carriers created according to the active ingredients of traditional Chinese medicines. We reviewed these well-designed NDDS in detail. Furthermore, we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy, and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.

Thanks to their biocompatibility, biodegradability, injectability and self-setting properties, calcium phosphate cements (CPCs) have been the most economical and effective biomaterials of choice for use as bone void fillers. They have also been extensively used as drug delivery carriers owing to their ability to provide for a steady release of various organic molecules aiding the regeneration of defective bone, including primarily antibiotics and growth factors. This review provides a systematic compilation of studies that reported on the controlled release of drugs from CPCs in the last 25 years. The chemical, compositional and microstructural characteristics of these systems through which the control of the release rates and mechanisms could be achieved have been discussed. In doing so, the effects of (i) the chemistry of the matrix, (ii) porosity, (iii) additives, (iv) drug types, (v) drug concentrations, (vi) drug loading methods and (vii) release media have been distinguished and discussed individually. Kinetic specificities of in vivo release of drugs from CPCs have been reviewed, too. Understanding the kinetic and mechanistic correlations between the CPC properties and the drug release is a prerequisite for the design of bone void fillers with drug release profiles precisely tailored to the application area and the clinical picture. The goal of this review has been to shed light on these fundamental correlations., Graphical abstract Image 1, Highlights • Drug release from calcium phosphate cements (CPCs) for bone healing and regeneration. • Release of antibiotics, anti-inflammatories, chemotherapeutics, growth factors, and metallic ions. • Influence of different CPC formulations, matrix porosity, structure, and crystallinity. • Influence of matrix additives and the release medium. • Influence of the drug type, concentration and loading method.

Background: Metal-organic frameworks (MOFs), as attractive hybrid crystalline porous materials, are being increasingly investigated in biomedical applications owing to their exceptional properties, including high porosity, ultrahigh surface areas, tailorable composition and structure, and tunability and surface functionality. Of interest, in this review, is the design and development of MOF-based drug delivery systems (DDSs) that have excellent biocompatibility, good stability under physiological conditions, high drug loading capacity, and controlled/targeted drug release. Objective: This review highlights the latest advances in MOFs as anticancer drug delivery systems (DDSs) along with insights on their design, fabrication, and performance under different stimuli that are either internal or external. The synthesis methods of MOFs, along with their advantages and disadvantages, are briefly discussed. The emergence of multifunctional MOF-based theranostic platforms is also discussed. Finally, the future challenges facing the developments of MOFs in the field of drug delivery are discussed. Methods: The review was prepared by carrying out a comprehensive literature survey using relevant work published in various scientific databases. Results: Novel MOFs in biomedical applications, especially in drug delivery, have shown great potential. MOF-based DDSs can be classified into normal (non-controllable) DDSs, stimuli-responsive DDSs, and theranostic platforms. The normal DDSs are pristine MOFs loaded with therapeutic agents and offer little to no control over drug release. Stimuli-responsive DDSs offer better spatiotemporal control over drug release by responding to either endogenous (pH, redox, ions, ATP) or exogenous stimuli (light, magnetism, US, pressure, temperature). The theranostic platforms combine stimuli-responsive drug delivery with diagnostic imaging functionality, paving the road for imaging-guided drug delivery. Conclusion: This review presented a summary of the various methods utilized in MOF's synthesis along with the advantages and disadvantages of each method. Furthermore, the review highlighted and discussed the latest developments in the field of MOF-based DDSs and theranostic platforms. The review is focused on the characteristics of MOF-based DDSs, the encapsulation of different anticancer drugs as well as their stimuli-responsive release.

Targeted drug delivery has been extensively studied in the last decade, whereas both passive and active targeting strategies still face many challenges, such as off-target drug release. Light-responsive drug delivery systems have been developed with high controllability and spatio-temporal resolution to improve drug efficacy and reduce off-target drug release. Photoremovable protecting groups are light-responsive moieties that undergo irreversible photocleavage reactions upon light irradiation. They can be covalently linked to the molecule of interest to control its structure and function with light. In this review, we will summarize recent applications of photocleavage technologies in nanoparticle-based drug delivery for precise targeting and controlled drug release, with a highlight of strategies to achieve long-wavelength light excitation. A greater understanding of these mechanisms and emerging studies will help design more efficient photocleavage-based nanosystems to advance photoresponsive drug delivery.

Microneedle (MN)-based technologies have been proposed as a means to facilitate minimally invasive sustained delivery of long-acting hormonal contraceptives into the skin. Intradermal administration is a new route of delivery for these contraceptives and therefore no established laboratory methods or experimental models are available to predict dermal drug release and pharmacokinetics from candidate MN formulations. This study evaluates an in vitro release (IVR) medium and a medium supplemented with ex vivo human skin homogenate (SH) as potential laboratory models to investigate the dermal release characteristics of one such hormonal contraceptive that is being tested for MN delivery, levonorgestrel (LNG), and provides details of an accompanying novel two-step liquid–liquid drug extraction procedure and sensitive reversed-phase HPLC–UV assay. The extraction efficiency of LNG was 91.7 ± 3.06% from IVR medium and 84.6 ± 1.6% from the medium supplemented with SH. The HPLC–UV methodology had a limit of quantification of 0.005 µg/mL and linearity between 0.005 and 25 µg/mL. Extraction and detection methods for LNG were exemplified in both models using the well-characterised, commercially available sustained-release implant (Jadelle®). Sustained LNG release from the implant was detected in both media over 28 days. This study reports for the first time the use of biologically relevant release models and a rapid, reliable and sensitive methodology to determine release characteristics of LNG from intradermally administered long-acting drug delivery systems. Graphical abstract Supplementary information The online version contains supplementary material available at 10.1007/s13346-021-01091-5.

Solid lipid nanoparticles (SLN) have been widely used in a variety of drug delivery routes, which have the outstanding advantage of controlled drug release. The release of SLN is dominated by many factors, among which the particle size of SLN is a critical one. The aim of this project was to explore the relationship between drug release profile and particle size of SLN. SLN were synthesized via the hot high-pressure homogenization (HPH) method, budesonide (BUD) was used as the model drug, and BUD-SLN1-BUD-SLN4 with increasing particle size was obtained, i.e. 120, 240, 360, and 480 nm. The prepared SLN has good encapsulation efficiency, drug loading capacity, and stability. In vitro release behavior studies showed that the cumulative release of BUD-SLN in Tris-Maleate (Tris-M) media was negligible, while that in Tris-M plus pancreatin media or Tris-M-ethanol media obeyed Ritger-Peppas model or first-order kinetic model, respectively. Noticeably, the release behavior of SLN was to some extent related to the average particle size of SLN, but the correlation was insignificant when the intersection degree of particle size distribution was great. This study provides a new idea for the understanding of in vitro release of SLN and has a certain referencing value for the research and development of novel nanomedicines.

Self-assembly in nature creates matter with complex structures and unpredictable designs; disordered building blocks spontaneously organize into ordered structures to achieve specific functions. Self-assembly begins to play an important role in the design of advanced drug delivery as well. Though, the behavior of ‘dynamic nanoassembly-based drug delivery systems’ (DNDDS) in biological media and cells remains poorly understood, while this is highly critical for controlling spatiotemporal drug release from DNDDS in vivo. To deepen the understanding of tailor-made DNDDS, this contribution in the Oration - New Horizons section of the Journal of controlled Release aims to highlight nature-inspired designs, construction principles, and controllable functionalities of DNDDS and how they are triggered by endogenous and exogenous stimuli. Furthermore, biomedical applications of tailor-made DNDDS for accurate diagnosis and precise treatment of diseases, including tumors, neurological diseases, injuries and infections are discussed. Finally, current challenges and future perspectives of DNDDS are briefly outlined.

Organogels are excellent drug carrier for controlled release. Organogels based on amino acid derivatives has been widely used in the area of drug delivery. In this study, a series of the organogel system based on amino acid derivatives gelators was designed and prepared to investigate the structure-property correlation in organogels. To investigate the factors that influence the property of drug release, we varied the formulation in the organogels: gelator structure, gelator concentration, volume of antigelation solvent, and drug loading. Through the Box–Behnken tests, the optimum organogel formulation in vitro was obtained. The self-healing properties of the organogel have been utilised for injection of a model lipophilic risperidone in situ, and sustained release of the drug has been studied over about one week in vivo. In conclusion, the gelation ability of gelators could be adjusted by the gelator structure. Gel property is related with the whole composition of the formulation. As drug carrier, the drug release property of organogels is affected by multiple factors. Our investigation of the gel release property will play a theoretical guiding role in the application in the in situ drug delivery system.

Vitamin D3 is available in oral and injectable dosage forms. Interest in the transdermal route as an alternative to the oral and parenteral routes has grown recently. In this study, several film-forming solutions for the transdermal delivery of vitamin D3 were prepared. They contained 6000 IU/mL of vitamin D3 that formed a dry and acceptable film in less than 5 min after application. The formulations consisted of ethanol and acetone 80:20, and one or more of the following ingredients: Eudragit L100-55, PVP, PG, limonene, oleic acid, camphor, and menthol. Vitamin D3 release was studied from both the film-forming solution and pre-dried films using a Franz diffusion cell. The film-forming solution released a significant amount of vitamin D3 compared to the dry film, which is attributed mostly to the saturation driving force due to the evaporation of volatile solvents. In vitro permeation studies through artificial skin Strat M® membrane revealed that the cumulative amount of vitamin D3 permeated after 24 h under the experimental conditions was around 800 IU across 3.14 cm2. The cumulative permeation curve showed faster permeation in earlier stages. Young’s modulus, viscosity, and pH of the formulations were determined. Most of the formulations were stable for 3 weeks.

Interest in nanomedicines has grown rapidly over the past two decades, owing to the promising therapeutic applications they may provide, particularly for the treatment of cancer. Personalised medicine and ‘smart’ actively targeted nanoparticles represent an opportunity to deliver therapies directly to cancer cells and provide sustained drug release, in turn providing overall lower off-target toxicity and increased therapeutic efficacy. However, the successful translation of nanomedicines from encouraging pre-clinical findings to the clinic has, to date, proven arduous. In this review, we will discuss the use of nanomedicines for the treatment of cancer, with a specific focus on the use of polymeric and lipid nanoparticle delivery systems. In particular, we examine approaches exploring the surface functionalisation of nanomedicines to elicit active targeting and therapeutic effects as well as challenges and future directions for nanoparticles in cancer treatment.

Exploration of effective approaches that allow for the synthesis of smart block copolymers and their nanoassemblies exhibiting enhanced drug release upon stimuli-responsive degradation is in huge d...

Ionic liquids (ILs) have been widely used in biomedical and pharmaceutical fields as solvents or permeation enhancers. Recently, more and more researchers focused on optimizing the physicochemical properties of active pharmaceutical ingredient (API) by ILs technology. Converting APIs into ILs (API-ILs) has shown great potential for drug delivery by eliminating polymorphism, tailoring solubility, improving thermal stability, increasing dissolution, controlling drug release, modulating the surfactant properties, enhancing permeability of APIs and modulating cytotoxicity on tumor cells. In addition, API-ILs are also used in various formulations as active ingredients, such as solutions, emulsions, even tablets or nanoparticles. This paper aims to review current status of API-ILs, including the rational and design, preparation and characterization, the improvement on the physicochemical characteristics of APIs, the compatibility of API-ILs with various formulations, and the future prospects of API-ILs in biomedical and pharmaceutical fields.

Herein, we report a nanocellulose hydrogel that has a packaging structure for on-demand drug release. Zeolitic imidazolate frameworks-8 (ZIF-8) were grown on the surface of polydopamine (PDA) to produce PDA@ZIF-8 nanoparticles. The obtained PDA@ZIF-8 nanoparticles were then incorporated into a network of cellulose nanofibrils (CNFs) to fabricate a PDA@ZIF-8/CNFs composite hydrogel. The loading ratio of the drug tetracycline hydrochloride (TH) was 58%. A slight burst release behavior was observed at the beginning, and the composite hydrogel presented a significant pH-dependent release behavior. The drug delivery time of the PDA@ZIF-8/CNFs composite hydrogel was 3.5 times longer than that of the PDA/CNFs composite hydrogel. Furthermore, NIR light radiation accelerated the drug delivery rate. The drug release mechanism was mainly driven by anomalous transport. Importantly, the novel PDA@ZIF-8/CNFs composite hydrogel was found to be biocompatible according to in vitro cytotoxicity test. Because of its unique multiple drug release responses, the PDA@ZIF-8/CNFs composite hydrogel may be used in future clinical applications as a promising drug delivery carrier.

Nanocarriers, such as liposomes and micelles, were developed to enhance the delivery of therapeutic drugs to malignant tissues. Internal or external stimuli can be applied to achieve spatiotemporal controlled release from these carriers. This will result in enhancing their therapeutic efficacy while reducing toxicity. Mathematical modeling is used to simulate drug release from nanocarriers; this will facilitate and optimize the development and design of desirable nanocarriers in a systematic manner, rather than a trial-and-error approach. This review summarizes nine mathematical models often used to simulate drug release from nanocarriers and reviews studies which employed these models to simulate drug release from conventional as well as temperature-, pH-, and ultrasound-triggered micelles and liposomes.

Background:: pH sensitive dendrimers attached to nanocarriers, as one of the drug release systems, have become quite popular due to their ease of manufacture in experimental conditions and the ability to generate fast drug release in the targeted area. This kind of fast release behavior cannot be represented properly in most of the existing kinetic mathematical models. Besides, these models have either no pH dependence or pH dependence added separately. Therefore, they remained one dimensional. Objective:: The aim of this study was to establish the proper analytic equation to describe the fast release of drugs from pH sensitive nanocarrier systems. Then, to combine it with the pH dependent equation for establishing a two-dimensional model for whole system. Methods:: We used four common kinetic models for the comparison and we fitted them to the release data. As a result, only Higuchi and Korsmeyer-Peppas models show acceptable suitable results. None of these models have pH dependence. To get a better description for pH triggered fast release, we observed the behavior of the slope angle of the release curve. Then we proposed a new analytic equation by using relation between the slope angle and time. Result:: By adding a pH dependent equation, we assumed the drug release is “on” or “off” above/below specific pH value and we modified a step function to get a desired behavior. Conclusion:: Our new analytic model shows good fitting, not only one-dimensional time dependent release, but also two-dimensional pH dependent release, that provides a useful analytic model to represent release profiles of pH sensitive fast drug release systems.

Introduction Rapamycin (Rapa) is an immunosuppressive macrolide that inhibits the mechanistic target of rapamycin (mTOR) activity. Thanks to its anti-proliferative effects towards different cell types, including keratinocytes and T cells, Rapa shows promise in the treatment of skin diseases characterized by cell hyperproliferation. However, Rapa skin penetration is limited due to its lipophilic nature (log P = 4.3) and high molecular weight (MW = 914 g/mol). In previous studies, new microenvironment-sensitive core multishell (CMS) nanocarriers capable of sensing the redox state of inflamed skin were developed as more efficient and selective vehicles for macrolide delivery to inflamed skin. Methods In this study, we tested such redox-sensitive CMS nanocarriers using an inflammatory skin model based on human skin explants co-cultured with Jurkat T cells. Serine protease (SP) was applied on skin surface to induce skin barrier impairment and oxidative stress, whereas phytohaemagglutinin (PHA), IL-17A, and IL-22 were used to activate Jurkat cells. Activation markers, such as CD45 and CD69, phosphorylated ribosomal protein S6 (pRP-S6), and IL-2 release were monitored in activated T cells, whereas pro-inflammatory cytokines were measured in skin extracts and culture medium. Results We found that alteration of skin barrier proteins corneodesmosin (CDSN), occludin (Occl), and zonula occludens-1 (ZO-1) as well as oxidation-induced decrease of free thiol groups occurred upon SP-treatment. All Rapa formulations exerted inhibitory effects on T cells after penetration across ex vivo skin. No effects on skin inflammatory markers were detected. The superiority of the oxidative-sensitive CMS nanocarriers over the other formulations was observed with regard to drug delivery as well as downregulation of IL-2 release. Conclusion Overall, our results demonstrate that nanocarriers addressing features of diseased skin are promising approaches to improve the topical delivery of macrolide drugs., Graphical Abstract

In this study, sustained and pH-responsive delivery of drugs were conducted using sealed microcontainers (MCs). The MCs were fabricated using a polydimethylsiloxane (PDMS) stencil. The polymer solution was filled into holes of the stencil space; then, the organic solvent was evaporated to obtain MCs. Poly(lactic-co-glycolic acid) (PLGA) was used as the material for the MCs. The MCs were sealed by covering them with a lid layer after filling the model drug—metronidazole—into the MCs. The diameter and height of the fabricated MCs were 500 and 350 µm, respectively. The drug delivery of sealed MCs was analyzed using the absorbance of the released drug while varying the pH and observing the FE-SEM image, before and after drug release. MCs are expected to be useful in various biomedical applications of drug delivery and microfluidic systems by supporting various functional materials in pH-responsive MCs.

Organic nanotubes (ONTs) have attracted growing attention in biomedical applications because of their unique inner and outer nanospaces. Here, ONTs were functionalized and hybridized with poly(ethylene glycol) (PEG) to construct nanocomposite hydrogels, with the aim of enhancing their mechanical strength and controlling their release properties. These nanoengineered hydrogels have 4-fold greater mechanical stiffness than unreinforced hydrogels and show a more stable network. The effects of ONT concentration and crosslinkable site density on the hydrogel mechanical properties were systematically assessed. Moreover, the incorporation of ONTs enabled simple and effective post-loading of the model drug, as well as a sustained drug release profile from the hydrogels. These results provide a novel method to generate mechanically enhanced nanocomposite hydrogels with improved drug delivery in an easy, efficient and tunable manner, and the obtained nanocomposite hydrogels may have potential applications in drug delivery and other related bioapplications. Organic nanotubes (ONTs) were functionalized and hybridized with poly(ethylene glycol) (PEG) to generate mechanically enhanced nanocomposite hydrogels with improved drug delivery in an easy, efficient and tunable manner. These nanoengineered hydrogels have 4-fold greater mechanical stiffness than unreinforced hydrogels and show a more stable network. The incorporation of ONTs enabled simple and effective post-loading of the model drug, as well as a sustained drug release profile from the hydrogels.

The design and development of multifunctional nano-drug delivery systems (NDDSs) is a solution that is expected to solve some intractable problems in traditional cancer treatment. In particular, metal-organic frameworks (MOFs) are novel hybrid porous nanomaterials which are constructed by the coordination of metal cations or clusters and organic bridging ligands. Benefiting from their intrinsic superior properties, MOFs have captivated intensive attentions in drug release and cancer theranostic. Based on what has been achieved about MOF-based DDSs in recent years, this review introduces different stimuli-responsive mechanisms of them and their applications in cancer diagnosis and treatment systematically. Moreover, the existing challenges and future opportunities in this field are summarized. By realizing industrial production and paying attention to biosafety, their clinical applications will be enriched.

Background Intranasal corticosteroid sprays (INCSs) used to treat chronic rhinosinusitis are suboptimal due to limited penetration into the middle meatus, rapid clearance, and poor patient compliance. A bioresorbable drug matrix, developed with the XTreoTM drug delivery platform, may overcome the limitations of INCS by providing continuous dosing over several months. Objective To evaluate the in vitro drug release and in vivo pharmacokinetics of novel mometasone furoate (MF) matrices in a rabbit dorsal maxillary osteotomy model. Methods XTreoTM matrices were formulated to consistently elute MF for up to 6 months. Matrices were surgically placed bilaterally into the maxillary sinuses of New Zealand White (NZW) rabbits. Tissue and plasma MF concentrations were measured to assess the in vivo drug delivery. The in vivo and in vitro drug release kinetics of the matrices were quantified and compared to those of rabbits receiving daily Nasonex® MF nasal sprays. Results XTreoTM matrices self-expanded upon deployment to conform to the irregular geometry of the maxillary sinus cavities in the NZW rabbits. Sustained release of MF was demonstrated in vitro and in vivo for 2 MF matrices of distinct release durations and an in vitro–in vivo correlation was established. Therapeutic levels of MF in local tissues were measured throughout the intended dosing durations. In contrast to the variable peaks and troughs of daily nasal sprays, sustained dosing via a single administration of MF matrices was confirmed by quantifiable plasma MF concentrations over the intended dosing duration. Conclusion The XTreoTM MF matrices provided targeted and efficient dosing to local sinus tissues that was superior to INCS. Sustained drug release was confirmed both in vitro and in vivo. The novel XTreoTM technology may provide precisely tuned, long-lasting drug delivery to sinus tissues with a single treatment.

The delivery of drugs to the posterior segment of the eye remains a tremendously difficult task. Prolonged treatment in conventional intravitreal therapy requires injections that are administered frequently due to the rapid clearance of the drug molecules. As an alternative, intraocular implants can offer drug release for long-term therapy. However, one of the several challenges in developing intraocular implants is selecting an appropriate in vitro dissolution testing model. In order to determine the efficacy of ocular implants in drug release, multiple in vitro test models were emerging. While these in vitro models may be used to analyse drug release profiles, the findings may not predict in vivo retinal drug exposure as this is influenced by metabolic and physiological factors. This review considers various types of in vitro test methods used to test drug release of ocular implants. Importantly, it discusses the challenges and factors that must be considered in the development and testing of the implants in an in vitro setup. Graphical abstract

In the present paper, we propose a mechanistic mathematical model describing the process of drug release from a drug delivery system. This model takes various aspects of drug release into account, namely gradual penetration of the surrounding solution into the system, dissolution of solid drug particles embedded within, diffusion of the dissolved drug, dissolution of the carrier and its collapse. Modeling the various processes in a holistic physics-based approach allows us to describe, first, the phenomenon of a sudden “burst” of drug release after a few weeks and, second, the premature termination of the release, which can be observed on drug release curves, for example, these described in Macha et al. (Front Bioeng Biotechnol 7(37):1–14, 2019), Trang et al. (Mater Today Proc 17:836–845, 2019) or Tang et al. (Dalton Trans 39(18):4435–4439, 2010).

Cardiovascular Diseases (CVD) remain the leading cause of mortality and morbidity worldwide. To date, significant progress has been made in developing stimuli-responsive nanosystems that can intrinsically interact with pathological microenvironment to achieve site-specific delivery along with on-demand drug release for precise CVD treatment. Herein, this review summarizes recent advances on smart nanosystems in response to a wide range of biological cues, including pH, enzymes, ROS, shear force, ATP, etc., which can boost drug delivery performance or monitor disease progression in a non-invasive manner. The designs, compositions and main outcomes of the single and multi-responsive nanosystems for drug delivery and/or detection purposes are provided and discussed.

Regardless of progress in therapy management which are developed for colon cancer (CC), it remains the third most common cause of mortality due to cancers around the world. Conventional medicines pose side effects due to untoward action on non-target cells. Their inability to deliver drugs to the affected regions of the colon locally, in a reproducible manner raises a concern towards the efficacy of therapy. In this regard, nanoparticles emerged as a promising drug delivery system due to their flexibility in designing, drug release modulation and cancer cell targeting. Not only are nanoparticles making their way into colon cancer research in the revolution of conventional onco-therapeutics, but they also offer promising scope in the development of colon cancer vaccines and theranostic tools. However, there are challenges with respect to drug delivery using nanoparticles, which may hamper the delivery of these novel carriers to the colon. The present review addresses recent advents in nanotechnology for colon-specific drug delivery (CDDS) which may help to overcome the existing challenges and intends to recognize futuristic potentials in the treatment of CC with CDDS.

Multifunctional drug delivery systems enabling effective drug delivery and comprehensive treatment are critical to successful cancer treatment. Overcoming nonspecific release and off-target effects remains challenging in precise drug delivery. Here, we design triple-interlocked drug delivery systems to perform specific cancer cell recognition, controlled drug release and effective comprehensive therapy. Gold nanocages (AuNCs) comprise a novel class of nanostructures possessing hollow interiors and porous walls. AuNCs are employed as a drug carrier and photothermal transducer due to their unique structure and photothermal properties. A smart triple-interlocked I-type DNA nanostructure is modified on the surface of the AuNCs, and molecules of the anticancer drug doxorubicin (DOX) are loaded as molecular cargo and blocked. The triple-interlocked nanostructure can be unlocked by binding with three types of tumor-related mRNAs, which act as “keys” to the triple locks, sequentially, which leads to precise drug release. Additionally, fluorescence-imaging-oriented chemical–photothermal synergistic treatment is achieved under illumination with infrared light. This drug delivery system, which combines the advantages of AuNCs and interlocked I-type DNA, successfully demonstrates effective and precise imaging, drug release and photothermal therapy. This multifunctional triple-interlocked drug delivery system could be used as a potential carrier for effective cancer-targeting comprehensive chemotherapy and photothermal therapy treatments., Schematic illustration of the multiple-mRNA-controlled and heat-driven drug release from gold nanocages.

Currently, molecular dynamics simulation is being widely applied to predict drug–polymer interaction, and to optimize drug delivery systems. Our study describes a combination of in silico and in vitro approaches aimed at improvement in polymer-based nanoparticle design for cancer treatment. We applied the PASS service to predict the biological activity of novel carboplatin derivatives. Subsequent molecular dynamics simulations revealed the dependence between the drug–polymer binding energy along with encapsulation efficacy, drug release profile, and the derivatives’ chemical structure. We applied ICP-MS analysis, the MTT test, and hemolytic activity assay to evaluate drug loading, antitumor activity, and hemocompatibility of the formulated nanoparticles. The drug encapsulation efficacy varied from 0.2% to 1% and correlated with in silico modelling results. The PLGA nanoparticles revealed higher antitumor activity against A549 human non-small-cell lung carcinoma cells compared to non-encapsulated carboplatin derivatives with IC50 values of 1.40–23.20 µM and 7.32–79.30 µM, respectively; the similar cytotoxicity profiles were observed against H69 and MCF-7 cells. The nanoparticles efficiently induced apoptosis in A549 cells. Thus, nanoparticles loaded with novel carboplatin derivatives demonstrated high application potential for anticancer therapy due to their efficacy and high hemocompatibility. Our results demonstrated the combination of in silico and in vitro methods applicability for the optimization of encapsulation and antitumor efficacy in novel drug delivery systems design.

In the present work, Risperidone microparticles from poly(lactic acid)/poly(hexylene succinate) (PLA-b-PHSu) block copolymers in different ratios, 95/05, 90/10 and 80/20 w/w, were examined as long-acting injectable formulations. Nuclear magnetic resonance (NMR) was used to verify the successful synthesis of copolymers. Enzymatic hydrolysis showed an increase in weight loss as the content of PHSu increased, while the cytotoxicity studies confirmed the biocompatibility of the copolymers. The polyesters were further used to encapsulate Risperidone by spray drying. The drug-loaded microparticles were studied by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and X-ray diffraction (XRD). SEM microphotographs confirmed that spherically shaped microparticles were prepared with sizes about 5–12 μm, while XRD and differential scanning calorimetry (DSC) studies evidenced that Risperidone was encapsulated in amorphous form. The drug loading and the entrapment efficiency of Risperidone were studied as well as the in vitro release from the prepared microparticles. As the content of PHSu increased, a higher release of Risperidone was observed, with PLA-b-PHSu 80/20 w/w succeeding to release 100% of RIS within 12 days. According to theoretical modeling, the kinetics of RIS release from PLA-b-PHSu microparticles is complex, governed by both diffusion and polymer erosion.

Hybrid metal–polymer-coordinated complex, as a class of supramolecular coordinated complex, represents a great opportunity for the development of the multipurpose intelligent system of nanomedicine in drug delivery. These structures and their interesting functions are created after the self-assembly process and coordination bond formation between different metal ions and polymers. There is an important difference between metal–organic framework (MOF) and metal–polymer-coordinated complex (MPC). MPCs are convergent structures made of metal and polymeric linkers’ combination in 1D, 2D and 3D architectures while MOFs are divergent 3D network structures with metal cores and organic ligands linkers. Until now, many reviews have been published about MOF-based systems while there is no comprehensive review on MPCs. Moreover, the MPCs have exhibited potential nano-chemistry properties to be utilized in nanomedicine applications as smart and multifunction nanovesicles for drug delivery. In this review, the MPC architectures, their synthesis process and their applications in drug delivery are described. The advantages and disadvantages of MPC are summarized. We also categorized smart MPCs for on-demand drug release and intelligent delivery.

This practical is aimed at students who have been introduced to the tableting process, drug delivery systems, and dissolution. The student can design and manufacture a tablet investigating the effect of excipients and their role in tablet design and then generate a release profile of the tablet by using a dissolution apparatus, flow-through cell, and UV–vis kinetics. Economical alternatives to the otherwise expensive dies, presses, and dissolution apparatus required to conduct the practical are included so that this can be applied across a range of budgets. With the assumption that most undergraduate laboratories possess a 13 mm KBr die and hydraulic press, a 10 mm die and 6 mm die can cost in excess of €850, while homemade versions can be manufactured for less than €5.

NDDS is advanced drug delivery system which improves drug potency, control drug release to give a sustained therapeutic effect, provide greater safety, finally it is to target a drug specifically to a desired tissue. Novel drug delivery system have been developed to overcome the limitation of conventional drug delivery systems, such as of gastric retention by decreasing fluctuations in the concentration of the drug in blood,resulting in the reduction in unwanted toxicity and poor efficiency. As compared to traditional dosage forms bilayer tablets are more efficient for sequential release of two drugs that can be different or identical. Bilayer tablet is also capable of separating two incompatible substances and also for sustained release. Gastro retentive drug delivery system retains the period of dosage forms in the stomach or upper gastro intes-tinal tract ,as to improve bioavailability and the therapeutic efficacy of the drugs. Mainly the bilayer drug delivery system is suitable for drugs whose therapethic windows are narrow in the gastrointestinal tract (GIT) and also they have low elimination half life: 3-4 h. The purpose of this review is to disclose the challenges faced during the formulation of bilayer tablets. Finally, the whole article is firmly analyzed in a concluding paragraph. KEYWORDS: Conventional drug delivery systems, Bilayer tablet, Gastro retentive, Bioavailability

A MoS2 nanosheets drug delivery system with photothermal conversion ability was synthesized. The drug loading content of the synthesized was as high as 24.5%. The drug HCPT was modified by lipoic a...

Microneedle (MN) patches consisting of miniature needles have emerged as a promising tool to perforate the stratum corneum and translocate biomolecules into the dermis in a minimally invasive manner. Stimuli-responsive MN patches represent emerging drug delivery systems that release cargos on-demand as a response to internal or external triggers. In this review, a variety of stimuli-responsive MN patches for controlled drug release are introduced, covering the mechanisms of action toward different indications. Future opportunities and challenges with respect to clinical translation are also discussed.

Hollow structures have demonstrated great potential in drug delivery owing to their privileged structure, such as high surface-to-volume ratio, low density, large cavities, and hierarchical pores. In this review, we provide a comprehensive overview of hollow structured materials applied in targeting recognition, smart response, and drug release, and we have addressed the possible chemical factors and reactions in these three processes. The advantages of hollow nanostructures are summarized as follows: hollow cavity contributes to large loading capacity; a tailored structure helps controllable drug release; variable compounds adapt to flexible application; surface modification facilitates smart responsive release. Especially, because the multiple physical barriers and chemical interactions can be induced by multishells, hollow multishelled structure is considered as a promising material with unique loading and releasing properties. Finally, we conclude this review with some perspectives on the future research and development of the hollow structures as drug carriers.

Pain remains a global health challenge affecting approximately 1.5 billion people worldwide. Pain has been an implicit variable in the equation of human life for many centuries considering different types and the magnitude of pain. Therefore, developing an efficacious drug delivery system for pain management remains an open challenge for researchers in the field of medicine. Lack of therapeutic efficacy still persists, despite high throughput studies in the field of pain management. Research scientists have been exploiting different alternatives to curb the adverse side effects of pain medications or attempting a more substantial approach to minimize the prevalence of pain. Various drug delivery systems have been developed such as nanoparticles, microparticles to curb adverse side effects of pain medications or minimize the prevalence of pain. This literature review firstly provides a brief introduction of pain as a sensation and its pharmacological interventions. Second, it highlights the most recent studies in the pharmaceutical field for pain management and serves as a strong base for future developments. Herein, we have classified drug delivery systems based on their sizes such as nano, micro, and macro systems, and for each of the reviewed systems, design, formulation strategies, and drug release performance has been discussed.

Magnetic nanoparticles are one of the most important and widely used types of nanomaterials, whose unique properties make them special compared to other nanostructures. These particles can be used in various fields. But their role in biomedicine, especially in the field of drug delivery, is significant because their inherent magnetism facilitates many tasks, including targeting, which is very important and necessary in drug delivery. In the present article, an attempt has been made to give general information about magnetic nanoparticles and the properties of particles in biomedical applications. In the following, special attention has been paid to the properties of these particles in drug delivery and their various applications have been studied. The importance of coating magnetic nanoparticles has also been mentioned as a basic requirement for medical applications. In the following, the method of drug loading in magnetic nanoparticles, the entry of particles into the body, targeting, and drug release are discussed, and finally, a brief discussion is presented regarding the pharmacokinetics of drugs and their toxicity in the body.

Electrospun nanofibers is a promising and versatile avenue for building controlled drug release system because of the facile fabrication and the broad range of polymer materials. This research systematically studied the morphological effect of thermosensitive electrospun nanofibers, including porous and coaxial structures, on controllable drug release. Three types of drugs, nicotinamide, paracetamol, and ibuprofen, with different hydrophilicity were applied in this study. The data of drug release were all fitted to the first-order kinetic model regardless of the drug properties, and the release rates paralleled with their hydrophilicity. Sol-gel phase transition of the thermosensitive poly(

Maryam Zarghami Dehaghani,1 Farrokh Yousefi,2 Babak Bagheri,3 Farzad Seidi,1 Amin Hamed Mashhadzadeh,4 Navid Rabiee,5 Payam Zarrintaj,6 Ebrahim Mostafavi,7,8 Mohammad Reza Saeb,4 Yeu-Chun Kim3 1Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources and Joint International Research Lab of Lignocellulosic Functional Materials, Nanjing Forestry University, Nanjing, 210037, People’s Republic of China; 2Department of Physics, University of Zanjan, Zanjan, 45195-313, Iran; 3Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Republic of Korea; 4Center of Excellence in Electrochemistry, School of Chemistry, College of Science, University of Tehran, Tehran, Iran; 5Department of Chemistry, Sharif University of Technology, Tehran, 11155-3516, Iran; 6School of Chemical Engineering, Oklahoma State University, Stillwater, OK, 74078, USA; 7Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA; 8Department of Medicine, Stanford University School of Medicine, Stanford, CA, USACorrespondence: Ebrahim MostafaviStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USAEmail ebimsv@stanford.eduAmin Hamed MashhadzadehCenter of Excellence in Electrochemistry, School of Chemistry, College of Science, University of Tehran, Tehran, 14155-6455, IranEmail amin.hamed.m@gmail.comIntroduction: Antimicrobial peptides are potential therapeutics as anti-bacteria, anti-viruses, anti-fungi, or anticancers. However, they suffer from a short half-life and drug resistance which limit their long-term clinical usage.Methods: Herein, we captured the encapsulation of antimicrobial peptide HA-FD-13 into boron nitride nanotube (BNNT) (20,20) and its release due to subsequent insertion of BNNT (14,14) with molecular dynamics simulation.Results: The peptide-BNNT (20,20) van der Waals (vdW) interaction energy decreased to − 270 kcal·mol− 1 at the end of the simulation (15 ns). However, during the period of 0.2– 1.8 ns, when half of the peptide was inside the nanotube, the encapsulation was paused due to an energy barrier in the vicinity of BNNT and subsequently the external intervention, such that the self-adjustment of the peptide allowed full insertion. The free energy of the encapsulation process was − 200.12 kcal·mol− 1, suggesting that the insertion procedure occurred spontaneously.Discussion: Once the BNNT (14,14) entered into the BNNT (20,20), the peptide was completely released after 83.8 ps. This revealed that the vdW interaction between the BNNT (14,14) and BNNT (20,20) was stronger than between BNNT (20,20) and the peptide; therefore, the BNNT (14,14) could act as a piston pushing the peptide outside the BNNT (20,20). Moreover, the sudden drop in the vdW energy between nanotubes to the value of the − 1300 Kcal·mol− 1 confirmed the self-insertion of the BNNT (14,14) into the BNNT (20,20) and correspondingly the release of the peptide.Keywords: drug delivery, boron nitride nanotubes, molecular dynamics simulation, drug release, antimicrobial peptide

Ocular inflammation is one of the common ophthalmic disorders triggered by different underlying causes and affecting both anterior and posterior segments of the eye. The functional barriers within the eye greatly impede the efficient ocular drug delivery, and hence the efficient relief of inflammation. The conventional treatment approaches are often limited to the topical applications of eye solutions, suspensions or ointments, in addition to the intravitreal injections in case of diffuse inflammatory conditions. These strategies suffer from poor patient acceptance and compliance because of their ineffectiveness and lack of safety. During the past few decades, a research attention was focused on the development of innovative ophthalmic dosage forms. Lipid nano-platforms had particular importance in drug delivery in terms of safety, biocompatibility, sustainment of drug release, enhancement of drug bioavailability, and hence patient compliance. This review attempts to highlight the current state of lipid-based nanocarriers as a promising non-invasive approach in the management of superficial and diffuse ocular inflammations with special emphasis on their reported outcomes, and also to focus on future perspectives to fill the gaps in this area.

Nanoemulgel is an emanating drug delivery system particularly being explored in research and development of various topical formulations for both pharmaceutical and cosmeceutical applications. Nanoemulgel consists of emulsion, which can be water in oil or oil in water type, incorporated into gel base. The gel base is prepared using gelling agent which modifies emulsion into non-greasy, more stable, and viscous formulation. Incorporation of hydrophobic drugs in a topical gel formulation along with favorable patient compliance is not feasible, but nanoemulgel form of the same drug does that efficiently. Rationalized formulation development of nanoemulgel for various drugs could solve various problems related to drug solubility, stability and drug release associated with other topical formulations.

Background: Development of controlled drug delivery systems can improve the pharmacokinetic characteristics of drug molecules in the human body, thereby significantly improving the utilization rate of drugs and reducing toxicity and side effects caused by their high concentrations, which can occur when delivery is not controlled. Metal organic frameworks are a new class of very promising crystalline microporous materials, especially when the size is reduced to the nanometer range. Metal-organic frameworks exhibit large specific surface areas, tunable compositions, and easy functionalization. In recent years, an increasing number of studies have reported the remarkable advances in multifunctional nanoscale metal-organic frameworks in drug delivery. Objective: To review the latest research involving advances in stimuli-responsive nanoscale metal organic frameworks as drug delivery systems in controlled-release drugs. Discussion: We first introduce the two main strategies associated with nanoscale metal organic frameworks used in drug loading: direct assembly and post-encapsulation. We next focus on the latest discoveries of nanoscale metal-organic framework-based stimulus response systems for drug delivery, including pH, magnetics, light, ion, temperature, and other stimuli, as well as multiple stimulus- responsive drug delivery systems. Finally, we discuss the challenges and future developmental directions of nanoscale metal-organic framework-based controlled drug release.

Gastro-retentive drug delivery systems (GRDDS) attributes to gastric maintenance time combined with the medication discharge for expanded time has essentially improved patient consistency. Medications for which the chief fundamental site of ingestion is the stomach or the proximal piece of the small digestive tract or have the assimilation issue in the distal piece of the digestive system are reasonable for GRDDS. Orally sustaining or controlling the drug release combined with gastric retention property can avoid recurrent dosing in the case of drugs with short half-lives. GRDDS is also effective in locally treating gastric and duodenal ulcers, including oesophagitis and Helicobacter pylori infections. In this current survey, the physiology of the stomach alongside its motility design, typically called migrating motor complex (MMC), was discussed. Various approaches to GRDDS with a focus on floating drug delivery systems (FDDS) were reviewed. The vacillations in plasma drug focus are limited and portion subordinate unfriendly impacts can be forestalled by FDDS, particularly for the medications with a restricted restorative list. Slow arrival of the medication into the body by means of FDDS limits the counter movement prompting higher medication proficiency. Further, the Advantages, limitations, suitable drug candidates, factors affecting and Future challenges of FDDS were discussed.

The stimulator of interferon genes (STING) shows promising clinical activity in infectious diseases and tumors. However, the lack of targeting capability and intracellular stability of STING agonists severely limits the therapeutic efficacy. Recently, drug delivery systems (DDSs) overcome these delivery barriers of STING agonists via passive or active cell targeting, prolonged blood circulation and drug release, and lysosome escape, etc. In this review, we will describe in detail how existing DDSs are designed to overcome delivery barriers and activate the STING pathway, and the current biomedical applications of STING-activating DDSs in the treatments of infectious diseases and tumors. Finally, the prospects and challenges of DDSs in STING activation are discussed.

Yuanbo Wu,1,* Jiandong Zhang,2,* Jiangwei Ni,2 Zhihao Yang,2 Kun Chen,2 Liangcheng Zheng,2 Zhifeng He2 1Department of Cardiothoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liangcheng Zheng; Zhifeng He Email dr.zlc@163.com zhif_he@126.comBackground: This study aimed to evaluate the properties and functions of polysaccharide-based porous microsphere (PPM) for drug delivery, as well as its inhibitory effect on malignant tumors.Materials and Methods: PPM was prepared using the inverse emulsion polymerization method. FT-IR measurements were conducted to measure the wavenumber of PPM. Particle size distribution was tested with a particle analyzer, and surface morphologies of PPM were observed using a scanning electron microscope (SEM). Dialysis method, Cell Counting Kit-8 (CCK-8), and cell apoptosis analysis were adopted to evaluate the drug release, cytotoxicity and biocompatibility of mitomycin-C (MMC), respectively. Finally, an in vivo study was performed in C57BL/6 mice to confirm the function of MMC-loaded PPM on tumor growth.Results: FT-IR spectra proved the successful preparation of MMC-loaded PPM. PPM had an average size of 25.90 ± 0.34 μm and then increased to 30.10 ± 0.20 μm after drug loading. Under SEM, the surface morphology was lotus seedpod surface-like, with macropits on the surface and micropores in macropits. Compared with the free MMC group, MMC-loaded PPM exhibited a delayed drug release rate in a pH-dependent manner and higher cell viability. Flow cytometry results showed that the cell apoptosis in the PPM/MMC group was lower than that in the free MMC group. In vivo experiment revealed the inhibitory efficacy of MMC-loaded PPM on malignant tumors.Conclusion: In summary, MMC-loaded PPM exhibited favorable surface morphology, sustained drug release ability, nontoxicity and excellent biocompatibility, suggesting that PPM might be a potential drug carrier for tumor treatment.Keywords: polysaccharide-based porous microsphere, tumor treatment, mitomycin-C, drug release, inverse emulsion polymerization

Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment. A variety of versatile nanocarriers with controllable physicochemical properties, tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment. This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance, pro-resolving therapy or regulating the immunometabolism for RA treatments., Graphical abstract This review summarizes the characteristics of physiological microenvironment of the inflamed joint in the development of rheumatoid arthritis (RA) and discusses the current therapeutic strategies for RA.Image 1

Drug releasing particles are valued for their ability to deliver therapeutics to targeted locations and for their controllable release patterns. The development of microfluidic technologies, which are designed specifically to manipulate small amounts of fluids, to manufacture particles for drug delivery applications reflects a recent trend due to the advantages they confer in terms of control over particle size and material composition. This review takes a comprehensive look at the different types of microfluidic devices used to fabricate such particles from different types of biomaterials, and at how the on-chip features enable the production of particles with different types of properties. The review concludes by suggesting avenues for future work that will enable these technologies to fulfill their potential and be used in industrial settings for the manufacture of drug releasing particles with unique capabilities.

The present review article relates to some theoretical aspects of liquid crystals, particularly types and phases of liquid crystals. In recent years mesophase has gained a great deal of attention and is yet another exciting lipid-based system for drugs, Proteins, and vaccine delivery. On the whole, the existing research advancement of different phases of liquid crystals as a drug delivery system has been discussed and explored in detail. It is concluded that different phases of liquid crystals are promising to sustain the drug release from the internal nanostructure. Peptide-based therapeutics and enzymes can also be delivered through liquid crystals. Liquid crystals may be the drug carriers of choice soon.

To avoid excessive usage of antibiotics and antimicrobial agents, smart wound dressings permitting controlled drug release for treatment of bacterial infections are highly desired. In search of a sensitive stimulus to activate drug release under physiological conditions, we found that the glass transition temperature (