A Self-Disguised Nanospy for Improving Drug Delivery Efficiency via Decreasing Drug Protonation

Nanoscale drug carriers play a crucial role in reducing side effects of chemotherapy drugs. However, the mononuclear phagocyte system (MPS) and the drug protonation after nanoparticles (NPs) burst release still limit the drug delivery efficiency. In this work, a self-disguised Nanospy is designed to overcome this problem. The Nanospy is composed of: i) poly (lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) loading doxorubicin is the core structure of the Nanospy. ii) CD47 mimic peptides (CD47p) is linked to NPs which conveyed the “don't eat me” signal. iii) 4-(2-aminoethyl) benzenesulfonamide (AEBS) as the inhibitor of Carbonic anhydrase IX (CAIX) linked to NPs. Briefly, when the Nanospy circulates in the bloodstream, CD47p binds to the regulatory protein α (SIRPα) on the surface of macrophages, which causes the Nanospy escapes from phagocytosis. Subsequently, the Nanospy enriches in tumor and the AEBS reverses the acidic microenvironment of tumor. Due to above characteristics, the Nanospy reduces liver macrophage phagocytosis by 25% and increases tumor in situ DOX concentration by 56% compared to PLGA@DOX treatment. In addition, the Nanospy effectively inhibits tumor growth with a 63% volume reduction. This work presents a unique design to evade the capture of MPS and overcomes the influence of acidic tumor microenvironment (TME) on weakly alkaline drugs.     

多孔碳纳米材料构建抗肿瘤药物靶向传递系统的研究进展

抗肿瘤药物靶向传递系统是提高传统化疗药物疗效, 并降低其毒副作用的重要手段。以多孔碳纳米材料为药物载体, 根据肿瘤组织微环境特点, 构建抗肿瘤药物靶向传递系统是实现靶向治疗方案的有效方式。本文围绕基于多孔碳纳米材料的抗肿瘤药物靶向传递系统的构建及应用进行综述, 描述了多孔碳纳米材料适宜载药的设计、合成及功能化修饰; 通过理论与实例相结合的方式, 介绍了提高多孔碳纳米材料载药量和实现联合给药的有效策略; 从内源和外源性敏感刺激的角度, 重点分析了多孔碳纳米材料基于肿瘤微环境构建的靶向传递系统的机制和应用; 阐述了多孔碳纳米材料作为抗肿瘤药物载体面临的生物相容性和生物降解性的问题, 并分析了可能的解决途径; 展望了多孔碳纳米材料在构建肿瘤药物靶向传递系统应用中的前景及发展方向, 为研发靶向、可控的抗肿瘤药物传递系统提供了理论依据和例证支持。     

Dual‐Functional Alginic Acid Hybrid Nanospheres for Cell Imaging and Drug Delivery

An effective and facile approach to prepare gold‐nanoparticle‐encapsulated alginic acid‐poly[2‐(diethylamino)ethyl methacrylate] monodisperse hybrid nanospheres (ALG–PDEA–Au) is developed by using monodisperse ALG–PDEA nanospheres as a precursor nanoparticulate reaction system. This approach utilizes particle‐interior chemistry, which avoids additional reductant or laborious separation process and, moreover, elegantly ensures that all the gold nanoparticles are located inside the hybrid nanospheres and every nanosphere is loaded with gold nanoparticles. These obtained ALG–PDEA–Au hybrid nanospheres have not only uniform size, similar surface properties, and good biocompatibility but also unique optical properties provided by the embedded gold nanoparticles. It is demonstrated that negatively charged ALG–PDEA–Au hybrid nanospheres can be internalized by human colorectal LoVo cancer cells and hence act as novel optical‐contrast reagents in tumor‐cell imaging by optical microscopy. Moreover, these hybrid nanospheres can also serve as biocompatible carriers for the loading and delivery of an anti‐cancer drug doxorubicin. In vitro cell viability tests reveal that drug‐loaded ALG–PDEA–Au hybrid nanospheres exhibit similar tumor cell inhibition to the free drug doxorubicin. Therefore, the obtained hybrid nanospheres successfully combine two functions, that is, cell imaging and drug delivery, into one single system, and may be of great application potential in other biomedical‐related areas.     

Engineering Macrophages for Cancer Immunotherapy and Drug Delivery

Macrophages play an important role in cancer development and metastasis. Proinflammatory M1 macrophages can phagocytose tumor cells, while anti-inflammatory M2 macrophages such as tumor-associated macrophages (TAMs) promote tumor growth and invasion. Modulating the tumor immune microenvironment through engineering macrophages is efficacious in tumor therapy. M1 macrophages target cancerous cells and, therefore, can be used as drug carriers for tumor therapy. Herein, the strategies to engineer macrophages for cancer immunotherapy, such as inhibition of macrophage recruitment, depletion of TAMs, reprograming of TAMs, and blocking of the CD47-SIRPα pathway, are discussed. Further, the recent advances in drug delivery using M1 macrophages, macrophage-derived exosomes, and macrophage-membrane-coated nanoparticles are elaborated. Overall, there is still significant room for development in macrophage-mediated immune modulation and macrophage-mediated drug delivery, which will further enhance current tumor therapies against various malignant solid tumors, including drug-resistant tumors and metastatic tumors.     

Advances in Natural Polymer-Based Transdermal Drug Delivery Systems for Tumor Therapy

As an alternative to traditional oral and intravenous injections with limited efficacy, transdermal drug delivery (TDD) has shown great promise in tumor treatment. Over the past decade, natural polymers have been designed into various nanocarriers due to their excellent biocompatibility, biodegradability, and easy availability, providing more options for TDD. In addition, surface functionalization modification of the rich functional groups of natural polymers, which in turn are developed into targeted and stimulus-responsive functional materials, allows precise delivery of drugs to tumor sites and release of drugs in response to specific stimuli. It not only improves the treatment efficiency of tumor but also reduces the toxic and side effects to normal tissues. Therefore, the development of natural polymer-based TDD (NPTDD) systems has great potential in tumor therapy. In this review, the mechanism of NPTDD systems such as penetration enhancers, nanoparticles, microneedles, hydrogels and nanofibers prepared from hyaluronic acid, chitosan, sodium alginate, cellulose, heparin and protein, and their applications in tumor therapy are overviewed. This review also outlines the future prospects and current challenges of NPTDD systems for local treatment tumors.     

Engineering Biomimetic Platesomes for pH‐Responsive Drug Delivery and Enhanced Antitumor Activity

Biomimetic camouflage, i.e., using natural cell membranes for drug delivery, has demonstrated advantages over synthetic materials in both pharmacokinetics and biocompatibility, and so represents a promising solution for the development of safe nanomedicine. However, only limited efforts have been dedicated to engineering such camouflage to endow it with optimized or additional properties, in particular properties critical to a “smart” drug delivery system, such as stimuli‐responsive drug release. A pH‐responsive biomimetic “platesome” for specific drug delivery to tumors and tumor‐triggered drug release is described. This platesome nanovehicle is constructed by merging platelet membranes with functionalized synthetic liposomes and exhibits enhanced tumor affinity, due to its platelet membrane–based camouflage, and selectively releases its cargo in response to the acidic microenvironment of lysosomal compartments. In mouse cancer models, it shows significantly better antitumor efficacy than nanoformulations based on a platesome without pH responsiveness or those based on traditional pH‐sensitive liposomes. A convenient way to incorporate stimuli‐responsive features into biomimetic nanoparticles is described, demonstrating the potential of engineered cell membranes as biomimetic camouflages for a new generation of biocompatible and efficient nanocarriers.     

Immune Cell‐Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery

Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.     

Multifunctional Hybrid Nanoparticles for Traceable Drug Delivery and Intracellular Microenvironment‐Controlled Multistage Drug‐Release in Neurons

Innovative nanoparticles hold promising potential for disease therapy as drug delivery systems. For brain‐disease therapy, a drug delivery system that can sustainably control drug‐release and monitor fluorescence of the drug cargos is highly desirable. In this study, a light‐traceable and intracellular microenvironment‐responsive drug delivery system was developed based on the combination of glutathione‐responsive autoflurescent nanogel, dendrimer‐like mesoporous silica nanoparticles, and gold nanoparticles. The resulting hybrid nanoparticles represent a new class of delivery system that can efficiently load, transport, and control multistage‐release of sulfydryl‐containing drugs into neurons, with light‐traceable monitoring for future brain‐disease therapy.     

Drug delivery to the brain--realization by novel drug carriers

Delivery of drugs to the brain is still a major challenge. Successful delivery across the bloodbrain barrier has only been achieved in some cases, e.g., using pro-drugs. The review describes the delivery to the brain using nanoparticulate drug carriers in combination with the novel targeting principle of "differential protein adsorption" (PathFinder technology). The PathFinder technology exploits proteins in the blood which adsorb onto the surface of intravenously injected carriers for targeting. Apolipoprotein E is the targeting moiety for the delivery of particles to the endothelials of the blood-brain barrier. To reach therapeutic drug level in the brain, nanoparticulate drug carriers with sufficiently high loading capacity are reviewed, including drug nanocrystals (nanosuspensions), lipid drug conjugate (LDC) nanoparticles and lipid nanoparticles (solid lipid nanoparticles-SLN, nanostructured lipid carriers-NLC). The features are described, including regulatory aspects and large scale production.     

High drug loading polymer micelle@ZIF-8 hybrid core–shell nanoparticles through donor–receptor coordination interaction for pH/H2O2-responsive drug release

Smart drug delivery nanocarriers with high drug loading capacity are of great importance in the treatment of diseases, and can improve therapeutic effectiveness as well as alleviate side effects in patients. In this work, a pH and H₂O₂-responsive drug delivery platform with high doxorubicin (DOX) loading capacity has been established through coordination interaction between DOX and phenylboronic acid containing block polymer. A composited drug nanocarrier is further fabricated by growing a zeolitic imidazolate framework 8 (ZIF-8) on the surface of drug-loaded polymer micelles. The study verifies that ZIF-8 shell can act as intelligent “switch” to prevent DOX leaking from core–shell nanoparticles upon H₂O₂ stimulus. However, a burst drug release is detected upon pH and H₂O₂ stimuli due to the further disassociation of ZIF-8 in acid solution. Moreover, the in vitro anti-cancer experiments demonstrate that the DOX-loaded core–shell nanoparticles provide effective treatment towards cancer cells but have negligible effect on normal cells, which results from the high concentration of H₂O₂ and low pH in the microenvironment of tumor cells.     

Microfluidic Synthesis of pH‐Sensitive Multicompartmental Microparticles for Multimodulated Drug Release

Stimuli‐responsive carriers releasing multiple drugs have been researched for synergistic combinatorial cancer treatment with reduced side‐effects. However, previously used drug carriers have limitations in encapsulating multiple drug components in a single carrier and releasing each drug independently. In this work, pH‐sensitive, multimodulated, anisotropic drug carrier particles are synthesized using an acid‐cleavable polymer and stop‐flow lithography. The particles exhibit a faster drug release rate at the acidic pH of tumors than at physiological pH, demonstrating their potential for tumor‐selective drug release. The drug release rate of the particles can be adjusted by controlling the monomer composition. To accomplish multimodulated drug release, multicompartmental particles are synthesized. The drug release profile of each compartment is programmed by tailoring the monomer composition. These pH‐sensitive, multicompartmental particles are promising drug carriers enabling tumor‐selective and multimodulated release of multiple drugs for synergistic combination cancer therapy.     

酶响应型捏合淀粉药物载体的制备和性能

采用机械捏合的方法制备了不同抗消化性能的捏合淀粉基载体材料。利用扫描电子显微技术(SEM)、X射线衍射技术(XRD)和体外模拟人体消化试验(In-Vitro)对捏合淀粉的颗粒形貌、结晶结构和在人体上消化道中的消化性能进行了考察。发现随着抗消化性能的降低,淀粉颗粒的破损程度越大,淀粉结晶结构结晶形态由B型向V型转变,消化速度增大。同时以胰酶为模型药物,考察了捏合淀粉对药物的体外释放性能。结果显示,不同抗消化性能的捏合淀粉可望作为不同消化道靶向要求的药物载体材料。     

Has nanotechnology led to improved therapeutic outcomes?

Nanoparticulate drug delivery systems provide new opportunities for solving issues associated with problematic drugs or disease states and have, therefore, created great expectations in the field of drug delivery. This review focuses on the potential benefits of nanoparticles compared with other conventional delivery systems. Several nanoparticulate drug delivery systems have already been marketed or are currently under development and are presented in this review. Results from clinical trials demonstrate that nanoparticulate formulations generally enable superior therapeutic outcomes than compared with standard formulations. Therefore, the implementation of nanotechnology in drug delivery represents an important advance with substantial potential to improve therapeutic effectiveness and increase patient’s quality of life.     

Microfluidic Assembly of Monodisperse Multistage pH‐Responsive Polymer/Porous Silicon Composites for Precisely Controlled Multi‐Drug Delivery

We report an advanced drug delivery platform for combination chemotherapy by concurrently incorporating two different drugs into microcompoistes with ratiometric control over the loading degree. Atorvastatin and celecoxib were selected as model drugs due to their different physicochemical properties and synergetic effect on colorectal cancer prevention and inhibition. To be effective in colorectal cancer prevention and inhibition, the produced microcomposite contained hypromellose acetate succinate, which is insoluble in acidic conditions but highly dissolving at neutral or alkaline pH conditions. Taking advantage of the large pore volume of porous silicon (PSi), atorvastatin was firstly loaded into the PSi matrix, and then encapsulated into the pH‐responsive polymer microparticles containing celecoxib by microfluidics in order to obtain multi‐drug loaded polymer/PSi microcomposites. The prepared microcomposites showed monodisperse size distribution, multistage pH‐response, precise ratiometric controlled loading degree towards the simultaneously loaded drug molecules, and tailored release kinetics of the loaded cargos. This attractive microcomposite platform protects the payloads from being released at low pH‐values, and enhances their release at higher pH‐values, which can be further used for colon cancer prevention and treatment. Overall, the pH‐responsive polymer/PSi‐based microcomposite can be used as a universal platform for the delivery of different drug molecules for combination therapy.     

Supramolecular Nanodiscs Self-Assembled from Non-Ionic Heptamethine Cyanine for Imaging-Guided Cancer Photothermal Therapy

Supramolecular nanomedicines, which use supramolecular design to improve the precision and effectiveness of pharmaceutical practice and optimize pharmacokinetic profiles, have gathered momentum to battle cancer and other incurable diseases, for which traditional small-molecular and macromolecular drugs are less effective. However, the lack of clinical approval of supramolecular assembly-based medicine underscores the challenges facing this field. A 2D nanodisc-based supramolecular structure is formed by a non-ionic heptamethine cyanine (Cy7) dye, which generates fluorescence self-quenching but unique photothermal and photoacoustic properties. These Cy7-based supramolecular nanodiscs exhibit passive tumor-targeting properties to not only visualize the tumor by near-infrared fluorescence imaging and photoacoustic tomography but also induce photothermal tumor ablation under irradiation. Due to the nature of organic small molecule, they induce undetectable acute toxicity in mice and can be eliminated by the liver without extrahepatic metabolism. These findings suggest that the self-assembling cyanine discs represent a new paradigm in drug delivery as single-component supramolecular nanomedicines that are self-delivering and self-formulating, and provide a platform technology for synergistic clinical cancer imaging and therapy.     

Subcellular‐Scale Drug Transport via Ultrasound‐Degradable Mesoporous Nanosilicon to Bypass Cancer Drug Resistance

Delivering and releasing anticancer agents directly to their subcellular targets of action in a controlled manner are almost the ultimate goal of pharmacology, but it is challenging. In recent decades, plenty of efforts have been made to send drugs to tumor tissue or even specifically to cancer cells; however, at the subcellular scale, cancer cells have multiple cunning ways to hinder drugs from reaching their final action targets. Here, we demonstrate a strategy to bypass the last defense of cancer drug resistance by contolling the drug transportation and release at subcellular scale. We developed a platform based on ultrasound‐degradable mesoporous nanosilicon, which allows drug delivery towards, ultrasound controlled drug release into the cell nucleus. This strategy altered the drug distribution within cells and remarkably enhanced the drug accumulation ratio at the action target, i.e. nucleus. In vitro and in vivo studies proved that this strategy reduced the drug dosage by an order of magnitude, prolonged drug retention and amplified therapeutic efficacy in tumor‐bearing mice. These results offer new insights into bypassing cancer drug resistance through transport and release drugs directly to their action targets in a controlled manner.     

Bioinspired Nano‐Prodrug with Enhanced Tumor Targeting and Increased Therapeutic Efficiency

Nanotechnology‐based drug delivery has a great potential to revolutionize cancer treatment by enhancing anticancer drug efficacy and reducing drug toxicity. Here, a bioinspired nano‐prodrug (BiNp) assembled by an antineoplastic peptidic derivative (FA‐KLA‐Hy‐DOX), a folate acid (FA)‐incorporated proapoptotic peptide (KLAKLAK)₂ (KLA) to doxorubicin (DOX) via an acid‐labile hydrozone bond (Hy) is constructed. The hydrophobic antineoplastic agent DOX is efficiently shielded in the core of nano‐prodrug. With FA targeting moieties on the surface, the obtained BiNp shows significant tumor‐targeting ability and enhances the specific uptake of cancer cells. Upon the trigger by the intracellular acidic microenvironment of endosomes, the antineoplastic agent DOX is released on‐demand and promotes the apoptosis of cancer cells. Simultaneously, the liberated FA‐KLA can induce the dysfunction of mitochondria and evoke mitochondria‐dependent apoptosis. In vitro and in vivo results show that the nano‐prodrug BiNp with integrated programmed functions exhibits remarkable inhibition of tumor and achieves a maximized therapeutic efficiency with a minimized side effect.     

Redox and pH Dual Responsive Polymer Based Nanoparticles for In Vivo Drug Delivery

Responsive nanomaterials have emerged as promising candidates as drug delivery vehicles in order to address biomedical diseases such as cancer. In this work, polymer‐based responsive nanoparticles prepared by a supramolecular approach are loaded with doxorubicin (DOX) for the cancer therapy. The nanoparticles contain disulfide bonds within the polymer network, allowing the release of the DOX payload in a reducing environment within the endoplasm of cancer cells. In addition, the loaded drug can also be released under acidic environment. In vitro anticancer studies using redox and pH dual responsive nanoparticles show excellent performance in inducing cell death and apoptosis. Zebrafish larvae treated with DOX‐loaded nanoparticles exhibit an improved viability as compared with the cases treated with free DOX by the end of a 3 d treatment. Confocal imaging is utilized to provide the daily assessment of tumor size on zebrafish larva models treated with DOX‐loaded nanoparticles, presenting sustainable reduction of tumor. This work demonstrates the development of functional nanoparticles with dual responsive properties for both in vitro and in vivo drug delivery in the cancer therapy.     

pH‐ and NIR Light‐Responsive Polymeric Prodrug Micelles for Hyperthermia‐Assisted Site‐Specific Chemotherapy to Reverse Drug Resistance in Cancer Treatment

Despite the exciting advances in cancer chemotherapy over past decades, drug resistance in cancer treatment remains one of the primary reasons for therapeutic failure. IR‐780 loaded pH‐responsive polymeric prodrug micelles with near infrared (NIR) photothermal effect are developed to circumvent the drug resistance in cancer treatment. The polymeric prodrug micelles are stable in physiological environment, while exhibit fast doxorubicin (DOX) release in acidic condition and significant temperature elevation under NIR laser irradiation. Phosphorylcholine‐based biomimetic micellar shell and acid‐sensitive drug conjugation endow them with prolonged circulation time and reduced premature drug release during circulation to conduct tumor site‐specific chemotherapy. The polymeric prodrug micelles combined with NIR laser irradiation could significantly enhance intracellular DOX accumulation and synergistically induce the cell apoptosis in DOX‐resistant MCF‐7/ADR cells. Meanwhile, the tumor site‐specific chemotherapy combined with hyperthermia effect induces significant inhibition of MCF‐7/ADR tumor growth in tumor‐bearing mice. These results demonstrate that the well‐designed IR‐780 loaded polymeric prodrug micelles for hyperthermia‐assisted site‐specific chemotherapy present an effective approach to reverse drug resistance.