Impact of Dexmedetomidine Dosing and Timing on Acute Kidney Injury and Renal Outcomes After Cardiac Surgery: A Meta-Analytic Approach.

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication following cardiac surgery. Dexmedetomidine, a highly selective α2-adrenergic agonist, has shown potential renoprotective effects, but previous studies have yielded conflicting results. OBJECTIVE: This meta-analysis aimed to evaluate the efficacy and safety of dexmedetomidine in preventing AKI and reducing postoperative serum creatinine levels in adult patients undergoing cardiac surgery. METHODS: We comprehensively searched 5 databases for randomized controlled trials comparing dexmedetomidine with control groups in adult cardiac surgery patients. The main outcomes were the incidence of AKI and change in postoperative serum creatinine levels. Meta-analyses were conducted using RevMan 5.4 models, and subgroup analyses were performed based on dexmedetomidine dosing and timing of administration. Continuous outcomes were combined and analyzed using either mean difference (M.D.), while dichotomous outcomes were analyzed using risk ratio (RR) with 95% confidence intervals (CI). RESULTS: Our study included a total of 14 trials involving 2744 patients. Dexmedetomidine administration significantly reduced the incidence of AKI compared to control groups (RR = 0.54, 95% CI: 0.41-0.70, P < 0.00001). Postoperative serum creatinine levels were also lower with dexmedetomidine (MD = -0.14 mg/dL, 95% CI: -0.28 to -0.001, P =0.04). Subgroup analyses revealed that higher initial doses (>0.5 µg/kg) and administration during intraoperative and postoperative periods were associated with more pronounced renoprotective effects. Dexmedetomidine did not significantly affect mortality but reduced the duration of the length of hospital stay and mechanical ventilation. CONCLUSIONS AND RELEVANCE: This meta-analysis demonstrates that dexmedetomidine administration, particularly at higher doses and during both intraoperative and postoperative periods, reduces the risk of AKI in adults undergoing cardiac surgery. These findings support the use of dexmedetomidine as a preventive strategy to enhance renal outcomes in this population.

Key processes in tumor metastasis and therapeutic strategies with nanocarriers: a review.

Cancer metastasis is the leading cause of cancer-related death. Metastasis occurs at all stages of tumor development, with unexplored changes occurring at the primary site and distant colonization sites. The growing understanding of the metastatic process of tumor cells has contributed to the emergence of better treatment options and strategies. This review summarizes a range of features related to tumor cell metastasis and nanobased drug delivery systems for inhibiting tumor metastasis. The mechanisms of tumor metastasis in the ideal order of metastatic progression were summarized. We focus on the prominent role of nanocarriers in the treatment of tumor metastasis, summarizing the latest applications of nanocarriers in combination with drugs to target important components and processes of tumor metastasis and providing ideas for more effective nanodrug delivery systems.

(Pro)Renin Receptor Decoy Peptide PRO20 Protects against Oxidative Renal Damage Induced by Advanced Oxidation Protein Products.

Chronic kidney disease (CKD) is associated with advanced oxidation protein products (AOPPs). A recent study has shown that AOPP-induced renal tubular injury is mediated by the (pro)renin receptor (PRR). However, it is unclear whether the PRR decoy inhibitor PRO20 can protect against renal damage related to AOPPs in vivo. In this study, we examined the role of the PRR in rats with AOPP-induced renal oxidative damage. Male SD rats were subjected to unilateral nephrectomy, and after a four-day recuperation period, they were randomly divided into four groups (n = 6/group) for four weeks: control (CTR), unmodified rat serum albumin (RSA, 50 mg/kg/day via tail-vein injection), AOPPs-RSA (50 mg/kg/day via tail-vein injection), and AOPPs-RSA + PRO20 (50 mg/kg/day via tail-vein injection + 500 µg/kg/day via subcutaneous injection) groups. PRO20 was administered 3 days before AOPPs-RSA injection. Renal histopathology evaluation was performed by periodic acid-Schiff (PAS) staining, and biochemical parameters related to renal injury and oxidative stress biomarkers were evaluated. The expression of related indicators was quantified by RT-qPCR and immunoblotting analysis. In the results, rats in the AOPPs-RSA group exhibited higher levels of albuminuria, inflammatory cell infiltration, and tubular dilation, along with upregulation of oxidative stress, profibrotic and proinflammatory factors, and elevation of AOPP levels. Meanwhile, in the PRO20 group, these were significantly reduced. Moreover, the levels of almost all components of the renin-angiotensin system (RAS) and Nox4-dependent H2O2 production in urine and the kidneys were elevated by AOPPs-RSA, while they were suppressed by PRO20. Furthermore, AOPPs-RSA rats showed elevated kidney expression of the PRR and soluble PRR (sPRR) and increased renal excretion of sPRR. In summary, these findings suggest that PRR inhibition may serve as a protective mechanism against AOPP-induced nephropathy by inhibiting the intrarenal RAS and Nox4-derived H2O2 mechanisms.

Label-free fluorescence DNA walker for protein analysis based on terminal protection and dual enzyme assisted cleavage induced G-quadruplex/berberine conformation.

Development of a simple, fast, cost-efficient and sensitive approach for accurate protein analysis is of high significance due to its potential application in disease diagnosis and biomedicine research. Thus, we established a label-free fluorescence DNA walker for streptavidin detection based on terminal protection and dual enzyme assisted cleavage induced G-quadruplex/berberine conformation. In this paper, the swing arm probe and report probe were pre-assembled on gold nanoparticles. With the addition of a target, through the high-efficiency affinity between streptavidin and biotin in order to prevent the hydrolysis of exonuclease I, the swing arm probe which contains 8-17 DNAzyme cannot be destroyed and plays a role in the catalytic cleavage of the report probe, and the liberating fragment of the report probe which contains a specific sequence (5'-(TTAGGG)4) of G-quadruplex units can combine with berberine and shows an evident fluorescence signal enhancement. Our method, a sensitive and selective method of protein detection, achieves a 20 pM detection limit toward streptavidin. This developed DNA walker, which combines terminal protection and a dual enzyme assisted strategy, provides a prospective channel for streptavidin detection and should also be used for the design of biosensors in bio-detection and disease diagnosis.

Bridging host-guest chemistry with molecule chemistry-covalent organic polyrotaxanes (COPRs): from synthesis to inactivation of bacterial pathogens.

As a thriving artificial material, covalent organic frameworks (COFs), boasting inherent structural designability and functional adaptability, and with compositions akin to biological macromolecules, have emerged as a rising star in the field of material science. However, the progression of COFs is significantly impeded by the arduous and intricate preparation procedures of novel building blocks, as well as the inefficient development process of new reactions. An efficient, uncomplicated, and versatile functionalization approach, which has the potential to not only facilitate customized preparation of COFs based on application demands but also enable precise performance control, has become a focal point of research. The formulation of multi-functional COFs through efficient and cost-effective methods poses a critical challenge for the practical application of COFs. This review aims to present the preparation of COFs by amalgamating rigid molecular chemistry with flexible supramolecular host-guest chemistry, adopting a "couple hardness with softness" strategy to meticulously construct intelligent covalent organic polyrotaxanes (COPRs) using conventional reactions. Herein, novel building blocks can be acquired by amalgamating existing macrocycle complexes with framework blocks. The amalgamation of supramolecular chemistry bolsters the capabilities to generate, sense, respond, and amplify distinctive signals, thereby expediting the advancement of multifaceted materials with sophisticated structures. Concurrently, the infusion of supramolecular force endows COPRs with exceptional performance, facilitating multi-mode collaborative antibacterial therapy. This comprehensive review not only promotes the efficient utilization of resources but also stimulates the rapid advancement of framework materials.

Protective Effect of Black Rice Cyanidin-3-Glucoside on Testicular Damage in STZ-Induced Type 1 Diabetic Rats.

Diabetic testicular damage is quite a common and significant complication in diabetic men, which could result in infertility. The natural fertility rate of type 1 diabetes men is only 50% because of testicular damage. This research first aimed to explore the intervention effect of C3G on testicular tissue damage induced by diabetes. Here, a streptozotocin-induced type 1 diabetic rat model was established, and then C3G was administered. After 8 weeks of C3G supplementation, the symptoms of diabetes (e.g., high blood glucose, lower body weight, polydipsia, polyphagia) were relieved, and at the same time that sperm motility and viability increased, sperm abnormality decreased in C3G-treated diabetic rats. Furthermore, the pathological structure of testis was restored; the fibrosis of the testicular interstitial tissue was inhibited; and the LH, FSH, and testosterone levels were all increased in the C3G-treated groups. Testicular oxidative stress was relieved; serum and testicular inflammatory cytokines levels were significantly decreased in C3G-treated groups; levels of Bax, Caspase-3, TGF-ß1 and Smad2/3 protein in testis decreased; and the level of Bcl-2 was up-regulated in the C3G-treated groups. A possible mechanism might be that C3G improved antioxidant capacity, relieved oxidative stress, increased anti-inflammatory cytokine expression, and inhibited the apoptosis of spermatogenic cells and testicular fibrosis, thus promoting the production of testosterone and repair of testicular function. In conclusion, this study is the first to reveal that testicular damage could be mitigated by C3G in type 1 diabetic rats. Our results provide a theoretical basis for the application of C3G in male reproductive injury caused by diabetes.

Covalent organic polyrotaxanes based on ß-cyclodextrin for iodine capture.

Herein, covalent organic polyrotaxanes (COPRs) were integrated with supermolecule self-assembly and dynamic imine bond formation to act as absorbents that captured radioactive iodine from water. The aromatic building blocks were initially complexed with ß-cyclodextrin (ß-CD) to form pseudorotaxanes, which were then condensed with aromatic tri-aldehyde via mechanical grinding and solvothermal synthesis in sequence. The threading of ß-CD throughout the polymer skeleton effectively reduced the usage of expensive building blocks and significantly lowered the cost, while also remarkably enhancing the skeleton polarity, which is closely related to many special applications. Impressively, the threading of CD improved the water dispersibility of COPRs, which displayed an abnormally high iodine adsorption capacity. This novel synthetic strategy allows the incorporation of mechanically interlocked CDs into porous polymeric materials, which provides access to low-cost preparations of COPRs with a brand new structure for specific applications.

Crown-ether threaded covalent organic polyrotaxane framework (COPF) towards synergistic crown/Zn2+/photothermal/photodynamic antibacterial and infected wound healing therapy.

Controllable preparation of materials with new structure has always been the top priority of polymer materials science research. Here, the supramolecular binding strategy is adopted to develop covalent organic frameworks (COFs) with novel structures and functions. Based on this, a two-dimensional crown-ether ring threaded covalent organic framework (COF), denoted as Crown-COPF with intrinsic photothermal (PTT) and photodynamic (PDT) therapeutic capacity, was facilely developed using crown-ether threaded rotaxane and porphyrin as building blocks. Crown-COPF with discrete mechanically interlocked blocks in the open pore could be used as a molecular machine, in which crown-ether served as the wheel sliding along the axle under the laser stimulation. As a result, Crown-COPF combining with the bactericidal power of crown ether displayed a significant photothermal and photodynamic antibacterial activity towards both the Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus), far exceeding the traditional Crown-free COF. Noteworthily, the bactericidal performance could be further enhanced via impregnation of Zn2+ ions (Crown-COPF-Zn) flexible coordinated with the multiple coordination sites (crown-ether, bipyridine, and porphyrin), which not only endow the positive charge with the skeleton, enhancing its ability to bind to the bacterial membrane, but also introduce the bactericidal ability of zinc ions. Notably, in vivo experiments on mice with back infections indicates Crown-COPF-Zn with self-adaptive multinuclear zinc center, could effectively promote the repairing of wounds. This study paves a new avenue for the effectively preparation of porous polymers with brand new structure, which provides opportunities for COF and mechanically interlocked polymers (MIPs) research and applications.

Co-Delivery of VEGF siRNA and THPP via Metal-Organic Framework Reverses Cisplatin-Resistant Non-Small Cell Lung Cancer and Inhibits Metastasis through a MUC4 Regulating Mechanism.

Cisplatin resistance significantly impacts the antitumor efficacy of cisplatin chemotherapy and contributes to poor prognosis, including metastasis. In this study, we present the utilization of metal-organic framework (MOF) nanoparticles as the therapeutic component and drug loading scaffold for implementing a ternary combination therapeutic strategy to combat cisplatin-resistant lung cancer and metastasis. Specifically, by engineering MOFs (Cis@MOF-siVEGF) through the self-assembly of THPP as photosensitizer for photodynamic therapy (PDT), along with the incorporation of cisplatin (DDP) and VEGF siRNA (siVEGF), we propose the leverage of photodynamic-induced oxidative damage and gene silencing of the angiogenic factor to reverse cisplatin resistance and sensitize therapeutic potency. Our findings demonstrated that the chemo/photodynamic/antiangiogenic triple combination therapy via Cis@MOF-siVEGF under irradiation effectively inhibits cisplatin-resistant tumor growth and induces abscopal effects. Importantly, molecular mechanistic exploration suggested that MUC4 exerted regulatory effects on governing cancer metastasis, thus representing a potential immunotherapeutic target for cancer intervention. Overall, our study creates a MOFs-based multicomponent delivery platform for complementary therapeutic modules with synergistically enhanced antitumor efficacy and sheds light on potential regulatory mechanisms on cisplatin-resistance cancers.

Near-infrared active ferrocenyl porous organic polymer with photothermal enhanced enzymatic activity for combination antibacterial application.

As a severe ongoing global problem, bacterial contamination exists in every aspect of human life and the search for new antibacterial agents is urgently needed. Herein, a ferrocenyl porous organic polymer (FMC-POP) broad-spectrum antibacterial agent based on synergistic photothermal and peroxidase-like activity was prepared in a facile manner via the copolymerization of ferrocene diformaldehyde and cinnamaldehyde with mannitol through the acid-responsive acetal bond. The photoactive FMC-POP, with high photothermal conversion efficiency (41.45%), could convert not only the near-infrared laser irradiation into local heat to eradicate bacteria, but also low-concentration H2O2 into radical oxygen species (˙OH) that are effective against bacteria. Compared with single-mode photothermal (PTT) and enzymatic therapies, this combination therapy could significantly improve the bactericidal effect, exhibiting a germicidal efficiency of up to 99% (vs. 80.42% for PTT and 70% for enzyme). Thus, our work paves the way for a synergistic non-invasive antimicrobial therapy, which could expand the applications of POP-based artificial enzymes in biomedicine.

Composite porphyrin-based conjugated microporous polymer/graphene oxide capable of photo-triggered combinational antibacterial therapy and wound healing.

Developing antibiotic-free treatment strategies to cope with the crisis on drug-resistant bacteria, are urgently needed. Antibiotics-independent physical approaches, especially the non-invasive phototherapies, worked through the assistance of photosensitizer (PS), have geared intensive attention and interests. Here, composite porphyrin-based conjugated microporous polymer/graphene oxide, denoted as GO-TAPP, combining the advantages of each component perfectly, was developed as broad-spectrum antibacterial agent. GO-TAPP, prepared via the self-oxidation coupling of tetraethynyl porphyrin on the surface of graphene oxide, could exert synergistic photothermal (PTT, ascribed to the graphene) and photodynamic (PDT, derived from the Porphyrin polymer) antimicrobial effectiveness. Both the in vivo and in vitro experiments have confirmed GO-TAPP are extremely potent against the Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) pathogens, which presents a remarkably enhanced sterilizing effect in comparison with its counterparts (the bare GO, and TAPP). Meanwhile, the synergistic effect of GO-TAPP could significantly accelerate the healing of open wound infected by bacterial. Altogether, this work proposed a new approach for the rational preparation of highly biocompatible graphene-based composite materials as antibiotic-free agents with synergistic antibacterial effect to combat bacterial infections.

Recent progress in nanocarrier-based drug delivery systems for antitumour metastasis.

Tumour metastasis is one of the major factors leading to poor prognosis as well as lower survival among cancer patients. A number of studies investigating the inhibition of tumour metastasis have been conducted. It is difficult to achieve satisfactory results with surgery alone for distant metastatic tumours, and chemotherapy can boost the healing rate and prognosis of patients. However, the poor therapeutic efficacy of chemotherapy drugs due to their low solubility, lack of tumour targeting, instability in vivo, high toxicity and multidrug resistance hinder their application. Immunotherapy is beneficial to the treatment of metastatic cancers, but it also has disadvantages such as adverse reactions and acquired resistance. Fortunately, delivery of chemotherapeutic drugs with nanocarriers can reduce systemic reactions caused by chemotherapeutic agents and inhibit metastasis. This review discusses the underlying mechanisms of metastasis, therapeutic approaches for antitumour metastasis, the advantages of nanodrug delivery systems and their application in reducing metastasis.

A dual drug-loaded peptide system with morphological transformation prolongs drug retention and inhibits breast cancer growth.

The treatment of breast cancer relies heavily on chemotherapy, but chemotherapy is limited by the disadvantages of poor targeting, susceptibility to extracellular matrix (ECM) interference and a short duration of action in tumor cells. To address these limitations, we developed an amphipathic peptide containing an RGD motif, Pep1, that encapsulated paclitaxel (PTX) and losartan potassium (LP) to form the drug-loaded peptide PL/Pep1. PL/Pep1 self-assembled into spherical nanoparticles (NPs) under normal physiological conditions and transformed into aggregates containing short nanofibers at acidic pH. The RGD peptide facilitated tumor targeting and the aggregates prolonged drug retention in the tumor, which allowed more drug to reach and accumulate in the tumor tissue to promote apoptosis and remodel the tumor microenvironment. The results of in vitro and in vivo experiments confirmed the superiority of PL/Pep1 in terms of targeting, prolonged retention and facilitated penetration for antitumor therapy. In conclusion, amphipathic peptides as coloaded drug carriers are a new platform and strategy for breast cancer chemotherapy.

Biodegradable porous polymeric drug as a drug delivery system: alleviation of doxorubicin-induced cardiotoxicity via passive targeted release.

Doxorubicin (DOX) is an effective chemotherapeutic drug developed against a broad range of cancers, and its clinical applications are greatly restricted by the side effects of severe cardiotoxicity during tumour treatment. Herein, the DOX-loaded biodegradable porous polymeric drug, namely, Fc-Ma-DOX, which was stable in the circulation, but easy to compose in the acidic medium, was used as the drug delivery system avoiding the indiscriminate release of DOX. Fc-Ma was constructed via the copolymerization of 1,1'-ferrocenecarbaldehyde with d-mannitol (Ma) through the pH-sensitive acetal bonds. Echocardiography, biochemical parameters, pathological examination, and western blot results showed that DOX treatment caused increased myocardial injury and oxidative stress damage. In contrast, treatment with Fc-Ma-DOX significantly reduced myocardial injury and oxidative stress by DOX treatment. Notably, in the Fc-Ma-DOX treatment group, we observed a significant decrease in the uptake of DOX by H9C2 cells and a significant decrease in reactive oxygen species (ROS) production.

PEG-modified carbon-based nanoparticles as tumor-targeted drug delivery system reducing doxorubicin-induced cardiotoxicity.

Herein, a doxorubicin-loaded carbon-based drug delivery system, denoted as PC-DOX, composed of pH-responsive imine bond was developed for the tumor-targeted treatment. PC-DOX with a uniform particle size around 180 nm was synthesized by coating of as-synthesized hollow carbon-based nanoparticles (NPs) with dialdehyde PEG, which was used as carrier to attach DOX covalently through dynamic covalent bond. The unique structure endowed the advantages of specific tumor targeting and tumor microenvironment (TME) specific drug delivery capacity with PC-DOX. For the one hand, the tumor targeting caused by the enhanced permeability and retention (EPR) effect could significantly improve the tumor cellular uptake. For the other hand, the pH-responsiveness could realize the effective DOX accumulation in tumor tissues, avoiding the unwanted side effect to the normal tissues. As a result, PC-DOX with high DOX loading capacity (70.12%) and excellent biocompatibility, concurrently, presented a significant anti-tumor effect at a low mass concentration (DOX equivalent dose: 20 µg/mL). Another attractive characteristic of PC-DOX was the remarkable protective effect towards DOX-induced cardiotoxicity, which could be clearly observed from in vitro cellular, and animal assays. Compared with free DOX, the cardiomyocyte viability increased by average 30.58%, and the heart function was also significantly improved. This novel drug delivery nanoplatform provides a new method for the future clinical application of DOX in the cancer's therapeutics.

A diselenium-bridged covalent organic framework with pH/GSH/photo-triple-responsiveness for highly controlled drug release toward joint chemo/photothermal/chemodynamic cancer therapy.

Here, a novel joint chemo/photothermal/chemodynamic therapy was developed using a pH/GSH/photo triple-responsive 2D-covalent organic framework (COF) drug carriers for passive target treatment of tumors with extraordinarily high efficiency. The well-designed COF (DiSe-Por) with simultaneous dynamic diselenium and imine bonds, synthesized by the copolymerization of 4,4'-diselanediyldibenzaldehyde (DiSe) with 5,10,15,20-(tetra-4-aminophenyl)-porphyrin (Por) via Schiff base chemistry, which was applied as the host for effective encapsulation and highly controlled release of anticancer drug (DOX), was stable under normal physiological settings and can effectively accumulate in tumor sites. After being internalized into the tumor cells, the unique microenvironment i.e., acidic pH and overexpressed GSH, triggered substantial degradation of DiSe-Por-DOX, promoting DOX release to kill the cancer cells. Meanwhile, the breaking of Se-Se bonds boosted the generation of intracellular ROS, disturbing the redox balance of tumor cells. The highly extended 2D structure endowed the drug delivery system with significant photothermal performance. The rise of temperature with external laser irradiation (808 nm) further promoted drug release. Additionally, the phototherapy effect was further augmented after the loading of DOX, guaranteeing an almost complete drug release to tumor tissue. As a result, the triple-responsive drug delivery system achieved a synergistic amplified therapeutic efficacy with a growth inhibitory rate of approximately 93.5% for the tumor xenografted in nude mice. Moreover, the body metabolizable and clearable DiSe-Por-DOX presented negligible toxicities toward major organs in vivo. All these characteristics verified the great potential of DiSe-Por-DOX nanosheets for multi-modality tumor treatment, accelerating the application range of COFs in biomedical fields.

Nanosized FeS/ZnS heterojunctions derived using zeolitic imidazolate Framework-8 (ZIF-8) for pH-universal oxygen reduction and High-efficiency Zn-air battery.

Low-cost, stable, and highly active electrocatalysts for oxygen reduction reaction (ORR), especially for pH-universal ORR, are vital for developing numerous renewable energy devices. Herein, a hierarchical N, S-codoped porous carbon-based catalyst (ZFP-800) coupled with abundant FeS/ZnS heterojunctions was facilely prepared via direct pyrolysis of a Ferrocene-crosslinked pyrrole hydrogel composited with zeolitic imidazolate framework-8 (ZIF-8) templates. Compared with the heterojunction-free catalytic activity, the ZFP-800 catalytic activity was significantly higher in pH-universal ranges. Moreover, the ZFP-800 exhibited competitive ORR performance to commercial Pt/C (20%) in various electrolytes, in terms of onset (Eonset), half-wave potentials (E1/2), limiting current density (JL), durability, and methanol immunity. For instance, it exhibited super ORR catalytic activity on Eonset and E1/2, and exceeded that of the benchmark Pt/C in both the alkaline and neutral media. Furthermore, the application of ZFP-800 as a cathode catalyst in a home-made Zn-air battery demonstrated its operation capability in ambient conditions with a competitive performance on the specific energy density (828 mA·h·gZn-1), maximum discharge power density (205.6 mW·cm-2), rate performance, and the long-term stability (188 h at 5 mA·cm-2). This study can facilitate the development of advanced heterojunction-based materials for renewable energy applications.

Retraction of "Porous Organic Polymer-Derived Fe2P@N,P-Codoped Porous Carbon as Efficient Electrocatalysts for pH Universal ORR".

[This retracts the article DOI: 10.1021/acsomega.9b03851.].

Enzyme-Induced Transformable Peptide Nanocarriers with Enhanced Drug Permeability and Retention to Improve Tumor Nanotherapy Efficacy.

Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this "transformer"-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.

Enzyme-induced morphological transformation of drug carriers: Implications for cytotoxicity and the retention time of antitumor agents.

Nanocarriers have been widely employed to deliver chemotherapeutic drugs for cancer treatment. However, the insufficient accumulation of nanoparticles in tumors is an important reason for the poor efficacy of nanodrugs. In this study, a novel drug delivery system with a self-assembled amphiphilic peptide was designed to respond specifically to alkaline phosphatase (ALP), a protease overexpressed in cancer cells. The amphiphilic peptide self-assembled into spherical and fibrous nanostructures, and it easily assembled into spherical drug-loaded peptide nanoparticles after loading of a hydrophobic chemotherapeutic drug. The cytotoxicity of the drug carriers was enhanced against tumor cells over time. These spherical nanoparticles transformed into nanofibers under the induction of ALP, leading to efficient release of the encapsulated drug. This drug delivery strategy relying on responsiveness to an enzyme present in the tumor microenvironment can enhance local drug accumulation at the tumor site. The results of live animal imaging showed that the residence time of the morphologically transformable drug-loaded peptide nanoparticles at the tumor site was prolonged in vivo, confirming their potential use in antitumor therapy. These findings can contribute to a better understanding of the influence of drug carrier morphology on intracellular retention.