A spark to the powder keg: Microneedle-based antitumor nanomedicine targeting reactive oxygen species accumulation for chemodynamic/photothermal/chemotherapy.

HYPOTHESIS: Chemodynamic therapy (CDT) can efficiently kill cancer cells by producing hydroxyl radical (•OH), a kind of high-toxic reactive oxygen species (ROS), via Fenton or Fenton-like reactions. This study involved a versatile nanomedicine, MSN@DOX/GA-Fe/PDA (M@DGP), delivered via microneedles, which was expected to combine chemodynamic/photothermal/chemotherapy and efficiently increase ROS accumulation to achieve significant therapeutic efficacy against melanoma. EXPERIMENTS: The composition of the synthesized nanoparticles was confirmed by a series of characterizations including transmission electron microscopy, Fourier transform infrared spectroscopy, and zeta potential. The photothermal properties of the nanomedicine was evaluated via infrared imaging, and •OH-producing ability was evaluated by UV-Vis and electron spin resonance. The mechanisms of ROS accumulation were studied in B16 cells by detecting intracellular •OH, glutathione, and ROS levels. The drug-loaded microneedles (M@DGP-MNs) were prepared, and their morphology and mechanical strength were characterized. The in vivo antimelanoma effect and biosafety evaluation of the nanomedicine were investigated in tumor-bearing C57 mice. FINDINGS: M@DGP was successfully prepared and could achieve ROS accumulation through a photothermal-enhanced Fenton reaction, polydopamine-induced glutathione consumption, and doxorubicin-mediated mitochondrial dysfunction which induced oxidative stress and apoptosis of tumor cells. M@DGP-MNs showed superior antitumor efficacy and good biosafety, providing a promising strategy for melanoma treatment.

"Pincer movement": Reversing cisplatin resistance based on simultaneous glutathione depletion and glutathione S-transferases inhibition by redox-responsive degradable organosilica hybrid nanoparticles.

The therapeutic efficacy of cisplatin has been restricted by drug resistance of cancers. Intracellular glutathione (GSH) detoxification of cisplatin under the catalysis of glutathione S-transferases (GST) plays important roles in the development of cisplatin resistance. Herein, a strategy of "pincer movement" based on simultaneous GSH depletion and GST inhibition is proposed to enhance cisplatin-based chemotherapy. Specifically, a redox-responsive nanomedicine based on disulfide-bridged degradable organosilica hybrid nanoparticles is developed and loaded with cisplatin and ethacrynic acid (EA), a GST inhibitor. Responding to high level of intracellular GSH, the hybrid nanoparticles can be gradually degraded due to the break of disulfide bonds, which further promotes drug release. Meanwhile, the disulfide-mediated GSH depletion and EA-induced GST inhibition cooperatively prevent cellular detoxification of cisplatin and reverse drug resistance. Moreover, the nanomedicine is integrated into microneedles for intralesional drug delivery against cisplatin-resistant melanoma. The in vivo results show that the nanomedicine-loaded microneedles can achieve significant GSH depletion, GST inhibition, and consequent tumor growth suppression. Overall, this research provides a promising strategy for the construction of new-type nanomedicines to overcome cisplatin resistance, which extends the biomedical application of organosilica hybrid nanomaterials and enables more efficient chemotherapy against drug-resistant cancers.

Cellular defense system-destroying nanoparticles as a platform for enhanced chemotherapy against drug-resistant cancer.

Cellular defense system represented by glutathione (GSH) greatly weakens the outcomes of cancer therapy by antioxidation and detoxification. GSH depletion has been proved to be an effective way to enhance the efficacy of reactive oxygen species (ROS)-based therapies and chemotherapy. However, the existing strategies of GSH depletion still face the problems of unclear biosafety and high complexity of multicomponent co-delivery. In this study, we developed a GSH-depleting carrier platform based on disulfide-bridged mesoporous organosilica nanoparticles (MONs) to destroy the cellular defense system for cancer therapy. Responding to the high level of GSH in cancer cells, the disulfide bonds in the framework of MONs could be broken and consumed substantial GSH at the same time. Moreover, this process also promoted the degradation of MONs. In order to evaluate the effect of this platform in cancer therapy, chemotherapeutic drug cisplatin was loaded into MONs (Pt@MONs) to treat drug-resistant non-small cell lung cancer. In vitro and in vivo results indicated that Pt@MONs efficiently triggered GSH depletion, promoted platinum-DNA adduct formation, and induced cell apoptosis, resulting in significant tumor growth inhibition without marked toxicity. Taken together, the cellular defense system-destroying nanoparticles provide a promising platform for enhanced cancer therapy.

Bioresponsive Nanoarchitectonics-Integrated Microneedles for Amplified Chemo-Photodynamic Therapy against Acne Vulgaris.

The excessive colonization of Propionibacterium acnes (P. acnes) is responsible for the genesis of acne vulgaris, a common inflammatory disease of skin. However, the conventional anti-acne therapies are always limited by various side effects, drug resistance, and poor skin permeability. Microneedles (MNs) are emerging topical drug delivery systems capable of noninvasively breaking through the skin stratum corneum barrier to efficiently enhance the transdermal drug penetration. Herein, MNs loaded with intelligent pH-sensitive nanoplatforms were constructed for amplified chemo-photodynamic therapy against acne vulgaris, jointly exerting antimicrobial and anti-inflammatory effects. The photosensitizer indocyanine green (ICG) was loaded into the zeolitic imidazolate framework-8 (ZIF-8) to improve its photostability, which would be triggered by 808 nm laser irradiation to generate cytotoxic reactive oxygen species (ROS) to result in oxidative damage and disturbed metabolic activities of P. acnes. In addition to the efficient drug delivery, the ZIF-8 carrier could selectively degrade in response to the acidic microenvironment of acne lesions, and the released Zn2+ also exhibited a potent antimicrobial activity. The fabricated ZIF-8-ICG@MNs presented an outstanding synergistic anti-acne efficiency both in vitro and in vivo. This bioresponsive microneedle patch is expected to be readily adapted as a generalized, modular strategy for noninvasive therapeutics delivery against superficial skin diseases.

Multifunctional nanoreactors-integrated microneedles for cascade reaction-enhanced cancer therapy.

Starvation therapy based on glucose oxidase (GOx) has attracted considerable attention in tumor treatment. However, several shortcomings severely hinder its further applications, including limited therapeutic efficacy, poor enzyme stability, and potential side effects. Herein, a strategy of cascade reaction-enhanced combined therapy based on the oxygen-evolving multifunctional nanoreactors is proposed for tumor therapy. The GOx and catalase (CAT) are immobilized in metal-organic frameworks by biomimetic mineralization to improve their stability via spatial confinement. The GOx can consume glucose, reduce ATP levels, and down-regulate the expression of heat shock proteins, which consequently sensitize tumor cells to indocyanine green-based photothermal therapy. Furthermore, the hydrogen peroxide generated by GOx as well as overexpressed in tumor can be decomposed by CAT and continuously generate oxygen, which further enhance the efficacy of oxygen-dependent starvation therapy and photodynamic therapy. The nanoreactors are directly delivered to the superficial tumor by microneedles, achieving efficient tumor accumulation and dramatically strengthened antitumor efficacy without obvious side effects, which provides a valuable paradigm for the application of cascade reaction-based combined therapy.

Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy.

Glutathione (GSH) is an important member of cellular antioxidative system. In cancer cells, a high level of GSH is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. Plenty of studies have shown that loss of intracellular GSH makes cancer cells more susceptible to oxidative stress and chemotherapeutic agents. GSH depletion has been proved to improve the therapeutic efficacy of ROS-based therapy (photodynamic therapy, sonodynamic therapy, and chemodynamic therapy), ferroptosis, and chemotherapy. In this review, various strategies for GSH depletion used in cancer therapy are comprehensively summarized and discussed. First, the functions of GSH in cancer cells are analyzed to elucidate the necessity of GSH depletion in cancer therapy. Then, the synthesis and metabolism of GSH are briefly introduced to bring up some crucial targets for GSH modulation. Finally, different approaches to GSH depletion in the literature are classified and discussed in detail according to their mechanisms. Particularly, functional materials with GSH-consuming ability based on nanotechnology are elaborated due to their unique advantages and potentials. This review presents the ingenious application of GSH-depleting strategy in cancer therapy for improving the outcomes of various therapeutic regimens, which may provide useful guidance for designing intelligent drug delivery system.

Versatile Nanoscale Metal-Organic Frameworks (nMOFs): An Emerging 3D Nanoplatform for Drug Delivery and Therapeutic Applications.

For decades, nanoscale metal-organic frameworks (nMOFs) have attracted extensive interest in biomedicine due to their distinct characteristics, including facile synthesis, porous interior, and tunable biocompatibility. With high porosity, versatile nMOFs allow for the facile encapsulation of various therapeutic agents with exceptionally high payloads. Constructed from metal ions and organic linkers through coordination bonds, nMOFs with plentiful functional groups enable the surface modification for active targeting and enhanced biocompatibility. This review outlines the up-to-date progresses on the exploration of nMOFs in the field of biomedicine. First, the classification and synthesis of nMOFs are discussed, followed by the concrete introduction of drug loading strategies of nMOFs and mechanisms of stimulation-responsive drug release. Second, the smart designs of the nMOFs-based platforms for anticancer and antibacterial treatment are summarized. Finally, the basic challenges faced by nMOFs research and the great potential of biomimetic nMOFs are presented. This review article affords an inspiring insight into the interdisciplinary research of nMOFs and their biomedical applications, which holds great expectation for their further clinical translation.

A homogenous nanoporous pulmonary drug delivery system based on metal-organic frameworks with fine aerosolization performance and good compatibility.

Pulmonary drug delivery has attracted increasing attention in biomedicine, and porous particles can effectively enhance the aerosolization performance and bioavailability of drugs. However, the existing methods for preparing porous particles using porogens have several drawbacks, such as the inhomogeneous and uncontrollable pores, drug leakage, and high risk of fragmentation. In this study, a series of cyclodextrin-based metal-organic framework (CD-MOF) particles containing homogenous nanopores were delicately engineered without porogens. Compared with commercial inhalation carrier, CD-MOF showed excellent aerosolization performance because of the homogenous nanoporous structure. The great biocompatibility of CD-MOF in pulmonary delivery was also confirmed by a series of experiments, including cytotoxicity assay, hemolysis ratio test, lung function evaluation, in vivo lung injury markers measurement, and histological analysis. The results of ex vivo fluorescence imaging showed the high deposition rate of CD-MOF in lungs. Therefore, all results demonstrated that CD-MOF was a promising carrier for pulmonary drug delivery. This study may throw light on the nanoporous particles for effective pulmonary administration.

Cyclodextrin-based metal-organic frameworks for pulmonary delivery of curcumin with improved solubility and fine aerodynamic performance.

Pulmonary drug delivery has attracted considerable attention in recent years. However, it is still a major challenge to deliver poorly water-soluble drugs to lungs with good solubility and fine aerodynamic performance. In this study, curcumin was loaded into cyclodextrin-based metal-organic frameworks (CD-MOFs) for pulmonary delivery. Compared with micronized curcumin prepared by jet milling, curcumin-loaded CD-MOFs (Cur-CD-MOFs) exhibited excellent aerodynamic performance, which was attributed to the unique porous structure and lower density of CD-MOFs. The dissolution test showed that the drug release rate of Cur-CD-MOFs was much faster than that of micronized curcumin. The all-atom molecular dynamic simulation showed that curcumin molecules were loaded into the hydrophobic cavities of CD-MOFs or entered into the large hydrophilic cavities to form nanoclusters. The elevated wettability of Cur-CD-MOFs and the unique spatial distribution feature of curcumin in porous interior of CD-MOFs might be favorable for the improved dissolution rate. The DPPH radical scavenging test showed that Cur-CD-MOFs had prominent antioxidant activities. Therefore, CD-MOFs were expected to be promising carriers for pulmonary delivery of poorly water-soluble drugs.

Smart phase transformation system based on lyotropic liquid crystalline@hard capsules for sustained release of hydrophilic and hydrophobic drugs.

Smart phase transformation systems@hard capsule (SPTS@hard capsule) based on lyotropic liquid crystalline (LLC) were developed for oral sustained release in this study. Doxycycline hydrochloride (DOXY) and meloxicam (MLX) were used as hydrophilic and hydrophobic model drug, respectively. Two systems were added with different additives, that is, gelucire 39/01, PEG 1000 and Tween 80 to adjust their melting point and release profiles. The phase transformation of these systems could be triggered by water as well as temperature. They could spontaneously transform into cubic phase or hexagonal phase when coming across with water, to achieve the 24 h sustained release profile. In addition, the obtained systems could switch between semisolid state and liquid state when temperature changed within room temperature and body temperature, which facilitated the phase transformation in gastrointestinal tract and during their encapsulation into hard capsules. LLC-based SPTS@hard capsule revealed potential for the industrialization of its oral administration on account of its drugs accommodation with different solubility, controllable release profile and simple preparation process.

Fenofibrate Solid Dispersion Processed by Hot-Melt Extrusion: Elevated Bioavailability and Its Cell Transport Mechanism.

BACKGROUND: Fenofibrate (FNB) is an effective drug for the treatment of hypertriglyceridemia, hypercholesterolemia as well as mixed hyperlipidemia. However, due to its poor aqueous solubility, FNB has the problem of poor oral absorption followed by low bioavailability. OBJECTIVE: The aim of this research was to construct FNB amorphous solid dispersion employing PVP VA64 as the carrier by hot-melt extrusion method, in order to improve the oral bioavailability. Additionally, the cell transport experiment was conducted to further investigate the mechanism of promoted osmotic absorption. METHODS: The physical state of the obtained solid dispersion was characterized using SEM, DSC and XRD. Besides, in vitro Caco-2 cells were used to evaluate the cytotoxicity of the carrier and mimic gastrointestinal drug permeation. At last, in vitro dissolution test and in vivo bioavailability study were also carried out. RESULTS: The prepared FNB solid dispersion was found to be an amorphous state after hot-melt extrusion process. In vitro cytotoxicity test on Caco-2 cells confirmed the excellent biocompatibility of the carrier PVP VA64. Besides, transwell cell transport assay and in vitro dissolution test revealed that FNB released from amorphous solid dispersion was equipped with an improved transmembrane transport and dissolution rate. Moreover, pharmacokinetic study in beagle dogs showed that comparing with commercial micronized product Lipanthyl®, the oral bioavailability of FNB solid dispersion was significantly enhanced (2.45 fold). CONCLUSION: In conclusion, PVP VA64 can be regarded as a promising polymer to enhance the bioavailability of poorly water-soluble drugs such as FNB processed by hot-melt extrusion. Besides, investigations on the mechanism of the enhanced penetration are expected to lay a foundation on the subsequent development of effective and practical solid dispersion.

Ultramild One-Step Encapsulating Method as a Modular Strategy for Protecting Humidity-Susceptible Metal-Organic Frameworks Achieving Tunable Drug Release Profiles.

Metal-organic frameworks (MOFs), composed of metal ions or clusters and organic ligands, have emerged as a new class of porous materials. However, water instability of many MOFs has impeded their further applications. Herein, an ultramild one-step encapsulating method has been developed by incorporating γ-cyclodextrin-based MOFs (CD-MOFs) into hydrophobic ethylcellulose to fabricate composite microparticles for ideal hydrolytic stability. The whole process can be completed at ambient temperature by the novel ultrafine particle processing system in several minutes without any purification or drying steps. The composite microparticles well retained their morphology and crystal structure of CD-MOFs even after being exposed to extreme humid environment for 30 d. The composite microparticles were further exploited for drug delivery. The composite microparticles not only exhibited sustained and tunable pH-dependent drug release profiles in simulated physiological conditions but also reduced cell toxicity compared with drug-loaded CD-MOFs, which demonstrated that the composite microparticles were promising as drug carriers. In summary, this study developed a modular strategy for protecting humidity-susceptible MOFs with controlled release profiles, which is expected to open up a new avenue to expand their applications in the biomedical field.

Comparative studies on amphotericin B nanosuspensions prepared by a high pressure homogenization method and an antisolvent precipitation method.

Amphotericin B (AmB) is a widely used polyene antifungal agent; however, its poor solubility limits its clinical application. In this study, AmB nanosuspensions were prepared by a high pressure homogenization method (AmB-HPH) and an antisolvent precipitation method (AmB-AP) to improve the drug solubility. To reveal the distinct influences of these two different preparation methods, systematic comparisons of particle size, crystalline state, wettability, in vitro dissolution and in vivo pharmacokinetics on the properties of AmB-HPH and AmB-AP were performed. The results indicated that AmB-AP was in an amorphous state, exhibiting higher saturation solubility and dissolution rate than those of AmB-HPH in the crystalline state. However, the relative bioavailability of AmB-HPH was higher than that of AmB-AP in vivo, which was likely attributed to its better stability. In conclusion, both AmB-HPH and AmB-AP can enhance the solubility and bioavailability of AmB, but the stability of the nanosuspension prepared by the anti-solvent precipitation method should be carefully considered.

Influence of Polymers on the Physical and Chemical Stability of Spray-dried Amorphous Solid Dispersion: Dipyridamole Degradation Induced by Enteric Polymers.

Amorphous solid dispersions (ASDs) are inherently unstable because of high internal energy. Evaluating physical and chemical stability during the process and storage is essential. Numerous researches have demonstrated how polymers influence the drug precipitation and physical stability of ASDs, while the influence of polymers on the chemical stability of ASDs is often overlooked. Therefore, this study aimed to investigate the effect of polymers on the physical and chemical stability of spray-dried ASDs using dipyridamole (DP) as a model drug. Proper polymers were selected by assessing their abilities to inhibit drug recrystallization in supersaturated solutions. HPMC E5, Soluplus®, HPMCP-55, and HPMCAS-LP were shown to be effective stabilizers. The optimized formulations were further stored at a high temperature (60 °C) and high humidity (40 °C, 75% RH) for 2 months, and their physical and chemical stability was evaluated using polarizing optical microscopy, FTIR, HPLC, and mass spectrometry (MS). In general, crystallization was observed in all samples, which indicated the physical instability under stressed storage conditions. Also, it was noted that the polymers in ASDs rather than physical mixtures, induced a dramatic drug degradation after being exposed to a high temperature (HPMCP-55 > 80% and HPMCAS-LP > 50%) and high humidity (HPMCP-55 > 40% and HPMCAS-LP > 10%). The MS analysis further confirmed the degradation products, which might be generated from the reaction between dipyridamole and phthalic anhydride decomposed from HPMCP-55 and HPMCAS-LP. Overall, the exposure of ASDs to stressed conditions resulted in recrystallization and even the chemical degradation induced by polymers.

Mesoporous silica nanoparticles for drug and gene delivery.

Mesoporous silica nanoparticles (MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume, selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly, the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted.

Supersaturable solid self-microemulsifying drug delivery system: precipitation inhibition and bioavailability enhancement.

Solid self-emulsifying drug delivery system (SSEDDS), which incorporates liquid SEDDS into a solid dosage form, has been recently introduced to improve the oral bioavail-ability of poorly water-soluble drugs. However, supersaturated drug generated by SSEDDS is thermodynamically unstable and tends to precipitate rapidly prior to absorption, resulting in compromised bioavailability. The aim of this study was to construct a novel supersaturated SSEDDS (super-SSEDDS) by combining SSEDDS with appropriate precipitation inhibitor. Fenofibrate (FNB), a sparingly soluble drug, was selected as a model drug in this study. An optimized SSEDDS was prepared by solvent evaporation by using mesoporous silica Santa Barbara Amorphous-15 as the inert carrier. Supersaturation assay was conducted to evaluate the precipitation inhibition capacity of different polymers, and the results showed that Soluplus® could retard the FNB precipitation more effectively and sustain a higher apparent concentration for ~120 min. This effect was also clearly observed in the dissolution profiles of FNB from SSEDDS under supersaturated condition. The study of the mechanism suggested that the inhibition effect might be achieved both thermodynamically and kinetically. The area under the concentration-time curve of the super-SSEDDS was 1.4-fold greater than that of SSEDDS in the absence of Soluplus, based on an in vivo pharmacokinetic study conducted in beagle dogs. This study has demonstrated that the approach of combining SSEDDS with Soluplus as a supersaturation stabilizer constitutes a potential tool to improve the absorption of poorly water-soluble drugs.

Influence of physical properties of carrier on the performance of dry powder inhalers.

Dry powder inhalers (DPIs) offer distinct advantages as a means of pulmonary drug delivery and have attracted much attention in the field of pharmaceutical science. DPIs commonly contain micronized drug particles which, because of their cohesiveness and strong propensity to aggregate, have poor aerosolization performance. Thus carriers with a larger particle size are added to address this problem. However, the performance of DPIs is profoundly influenced by the physical properties of the carrier, particularly their particle size, morphology/shape and surface roughness. Because these factors are interdependent, it is difficult to completely understand how they individually influence DPI performance. The purpose of this review is to summarize and illuminate how these factors affect drug-carrier interaction and influence the performance of DPIs.