Dual‐Functional Nanographene Oxide as Cancer‐Targeted Drug‐Delivery System to Selectively Induce Cancer‐Cell Apoptosis

Construction of bioresponsive drug‐delivery nanosystems could enhance the anticancer efficacy of anticancer agents and reduce their toxic side effects. Herein, by using transferrin (Tf) as a surface decorator, we constructed a cancer‐targeted nanographene oxide (NGO) nanosystem for use in drug delivery. This nanosystem (Tf‐NGO@HPIP) drastically enhanced the cellular uptake, retention, and anticancer efficacy of loaded drugs but showed much lower toxicity to normal cells. The nanosystem was internalized through receptor‐mediated endocytosis and triggered pH‐dependent drug release in acidic environments and in the presence of cellular enzymes. Moreover, Tf‐NGO@HPIP effectively induced cancer‐cell apoptosis through activation of superoxide‐mediated p53 and MAPK pathways along with inactivation of ERK and AKT. Taken together, this study demonstrates a good strategy for the construction of bioresponsive NGO drug‐delivery nanosystems and their use as efficient anticancer drug carriers.     

Zeolitic Imidazolate framework-8 as efficient pH-sensitive drug delivery vehicle

Zeolitic Imidazolate Framework-8 (ZIF-8), for the first time for ZIFs, exhibits a remarkable capacity for the anticancer drug 5-fluorouracil (5-FU), around 660 mg of 5-FU/g of ZIF-8, and presents a pH-triggered controlled drug release property. These prove ZIF-8 to be a valuable candidate for delivery of anticancer agents and reveal its potential applications in the treatment of cancer.     

Revolutionizing Cancer Treatment: Biopolymer-Based Aerogels as Smart Platforms for Targeted Drug Delivery

Cancer stands as a leading cause of global mortality, with chemotherapy being a pivotal treatment approach, either alone or in conjunction with other therapies. The primary goal of these therapies is to inhibit the growth of cancer cells specifically, while minimizing harm to healthy dividing cells. Conventional treatments, often causing patient discomfort due to side effects, have led researchers to explore innovative, targeted cancer cell therapies. Thus, biopolymer-based aerogels emerge as innovative platforms, showcasing unique properties that respond intelligently to diverse stimuli. This responsiveness enables precise control over the release of anticancer drugs, enhancing therapeutic outcomes. The significance of these aerogels lies in their ability to offer targeted drug delivery with increased efficacy, biocompatibility, and a high drug payload. In this comprehensive review, the author discuss the role of biopolymer-based aerogels as an emerging functionalized platforms in anticancer drug delivery. The review addresses the unique properties of biopolymer-based aerogels showing their smart behavior in responding to different stimuli including temperature, pH, magnetic and redox potential to control anticancer drug release. Finally, the review discusses the application of different biopolymer-based aerogel in delivering different anticancer drugs and also discusses the potential of these platforms in gene delivery applications.     

Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.     

Near‐Infrared‐Controlled,Targeted Hydrophobic Drug‐Delivery System for Synergistic Cancer Therapy

Hydrophobicity has been an obstacle that hinders the use of many anticancer drugs. A critical challenge for cancer therapy concerns the limited availability of effective biocompatible delivery systems for most hydrophobic therapeutic anticancer drugs. In this study, we have developed a targeted near‐infrared (NIR)‐regulated hydrophobic drug‐delivery platform based on gold nanorods incorporated within a mesoporous silica framework (AuMPs). Upon application of NIR light, the photothermal effect of the gold nanorods leads to a rapid rise in the local temperature, thus resulting in the release of the entrapped drug molecules. By integrating chemotherapy and photothermotherapy into one system, we have studied the therapeutic effects of camptothecin‐loaded AuMP‐polyethylene glycol‐folic acid nanocarrier. Results revealed a synergistic effect in vitro and in vivo, which would make it possible to enhance the therapeutic effect of hydrophobic drugs and decrease drug side effects. Studies have shown the feasibility of using this nanocarrier as a targeted and noninvasive remote‐controlled hydrophobic drug‐delivery system with high spatial/temperal resolution. Owing to these advantages, we envision that this NIR‐controlled, targeted drug‐delivery method would promote the development of high‐performance hydrophobic anticancer drug‐delivery system in future clinical applications.     

Novel water-soluble and pH-responsive anticancer drug nanocarriers: doxorubicin-PAMAM dendrimer conjugates attached to superparamagnetic iron oxide nanoparticles (IONPs)

PH-responsive drug release system based on the conjugates of PAMAM dendrimers-doxorubicin (PAMAM-DOX) and superparamagnetic iron oxide (Fe(3)O(4)) nanoparticles (IONPs) has been constructed and characterized. The IONPs were stabilized by mPEG-G2.5 PAMAM dendrimers. The anticancer drug DOX was conjugated to the dendrimer segments of amino-stabilized IONPs using hydrazine as the linker via hydrazone bonds, which is acid cleavable and can be used as an ideal pH-responsive drug release system. The drug release profiles of DOX-PAMAM dendrimer conjugates were studied at pH 5.0 and 7.4. The results showed that the hydrolytic release profile can be obtained only at the condition of lysosomal pH (pH=5.0), and IONPs participated in carrying DOX to the tumor by the Enhanced Permeability and Retention (EPR) effect. These novel DOX-conjugated IONPs have the potential to enhance the effect of MRI contrast and cancer therapy in the course of delivering anticancer drugs to their target sites. Although the dendrimer-DOX-coated IONPs do not have any targeting ligands attached on their surface, they are potentially useful for cancer diagnosis in vivo.     

Development and physicochemical characterization of doxorubicin-encapsulated hydroxyapatite–polyvinyl alcohol nanocomposite for repair of osteosarcoma-affected bone tissues

Nowadays locoregional therapy for cancer treatment can be associated with nanocomposite drug delivery systems. Coated nanoparticles have versatile applications for delivering chemotherapeutic drugs to the targeted part of the body. In this study, a ceramic carrier like nanosized hydroxyapatite (HAp) was synthesized by the in situ precipitation method followed by coating with anticancer drug like doxorubicin (DOX) and polyvinyl alcohol (PVA) polymer. The physicochemical characterization of the prepared polymer-coated drug ceramic nanocomposite (DOX-HAp-PVA) was carried out using Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron spectroscopy, and particle size distribution. Furthermore, the biocompatibility and the anticancer activity of the nanocomposite were explored by MTT assay study. Successfully synthesized DOX-HAp-PVA nanocomposite exhibited a remarkable cytotoxicity toward osteosarcoma cells (MG 63), which may be potentially used as an anticancer agent against osteosarcoma.     

Zeolitic Imidazolate Frameworks: Synthesis,Functionalization, and Catalytic/Adsorption Applications

Zeolitic imidazolate frameworks (ZIFs) are comprised of transition metal ions (Zn, Co) and a range of imidazolate linkers in a tetrahedral coordination similar to that in crystalline aluminosilicate zeolites. The high surface area, tunable nanoporosity that can be subject to functionalization and the excellent thermal/chemical stability of ZIFs are attractive for heterogeneous catalysis and selective gas adsorption/separation. This review presents the current trends in synthesis, surface modification and catalytic reactions/adsorption of ZIF-based materials with particular emphasis on ZIF-8, which is the most widely studied structure among ZIFs.     

核酸适配体在肿瘤靶向治疗方面的研究进展

传统的抗肿瘤药物大多不具有选择性,在临床治疗中产生了严重的毒副作用。核酸适配体是一种小分子核酸,能够与靶标高亲和性、高特异性地结合。选择与癌症发生发展过程密切相关的生物标记物为靶标进行SELEX过程筛选出的核酸适配体自身可作为药物,也可与药物、siRNA、纳米粒等结合构成靶向给药体系,该体系能靶向作用于特定的肿瘤细胞,降低对正常细胞的毒性,用药量显著降低,药效提高。本文综述了近年来核酸适配体直接作为抗肿瘤药物、药物载体、siRNA载体以及作为纳米材料靶向剂构成多元复合靶向给药体系在肿瘤靶向治疗领域的研究进展。     

Enzyme and pH dual responsive l‐amino acid based biodegradable polymer nanocarrier for multidrug delivery to cancer cells

We report a new pH and enzyme dual responsive biodegradable polymer nanocarrier to deliver multiple anticancer drugs at the intracellular compartment in cancer cells. Natural l ‐aspartic acid was converted into multifunctional monomer and polymerized to yield new classes of biodegradable aliphatic polyester in‐build with pH responsiveness. The transformation of side chain BOC urethanes into cationic in the acidic endosomal environment disassembled the polymers nanoparticles (pH trigger‐1). The biodegradation of aliphatic polyester backbone by esterase enzyme ruptured the nanoassemblies and released the drugs in the cytoplasm (trigger‐2). The polymer scaffolds were capable of delivering multiple drugs such as doxorubicin, topotecan, and curcumin (CUR). The cytotoxicity of the nascent and drug‐loaded nanoparticles were tested in cervical (HeLa) and breast (MCF‐7) cancer cell lines. The nascent polymer nanoscaffolds were found to be nontoxic to cells whereas their drug‐loaded nanoparticles exhibited excellent killing. Confocal microscopic images revealed that the drug‐loaded polymer nanoparticles were taken up by the cells and the dual degradation process delivered the drugs to nucleus and established the proof‐of‐concept. The present investigation opens up new platform for l ‐amino acid based polyester scaffolds, for the first time, in the intracellular drug delivery in cancer treatment. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3279–3293     

Anticancer Drugs: Recent Strategies to Improve Stability Profile,Pharmacokinetic and Pharmacodynamic Properties

In past decades, anticancer research has led to remarkable results despite many of the approved drugs still being characterized by high systemic toxicity mainly due to the lack of tumor selectivity and present pharmacokinetic drawbacks, including low water solubility, that negatively affect the drug circulation time and bioavailability. The stability studies, performed in mild conditions during their development or under stressing exposure to high temperature, hydrolytic medium or light source, have demonstrated the sensitivity of anticancer drugs to many parameters. For this reason, the formation of degradation products is assessed both in pharmaceutical formulations and in the environment as hospital waste. To date, numerous formulations have been developed for achieving tissue-specific drug targeting and reducing toxic side effects, as well as for improving drug stability. The development of prodrugs represents a promising strategy in targeted cancer therapy for improving the selectivity, efficacy and stability of active compounds. Recent studies show that the incorporation of anticancer drugs into vesicular systems, such as polymeric micelles or cyclodextrins, or the use of nanocarriers containing chemotherapeutics that conjugate to monoclonal antibodies can improve solubility, pharmacokinetics, cellular absorption and stability. In this study, we summarize the latest advances in knowledge regarding the development of effective highly stable anticancer drugs formulated as stable prodrugs or entrapped in nanosystems.     

Effect of the Folate Ligand Density on the Targeting Property of Folated‐Conjugated Polymeric Nanoparticles

Targeted drug delivery systems have attracted increasing attention due to their ability for delivering anticancer drugs selectively to tumor cells. Folic acid (FA)‐conjugated targeted block copolymers, FA‐Pluronic‐polycaprolactone (FA‐Pluronic‐PCL) are synthesized in this study. The anticancer drug paclitaxel (PTX) is loaded in FA‐Pluronic‐PCL nanoparticles by nanoprecipitation method. The in vitro release of PTX from FA‐Pluronic‐PCL nanoparticles shows slow and sustained release behaviors. The effect of FA ligand density of FA‐Pluronic‐PCL nanoparticles on their targeting properties is examined by both cytotoxicity and fluorescence methods. It is shown that FA‐Pluronic‐PCL nanoparticles indicated better targeting ability than non‐targeted PCL‐Pluronic‐PCL nanoparticles. Furthermore, FA‐F127‐PCL nanoparticle with 10% FA molar content has more effective antitumor activity and higher cellular uptake than those with 50% and 91% FA molar content. These results prove that FA‐F127‐PCL nanoparticle with 10% FA molar content can be a better candidate as the drug carrier in targeted drug delivery systems.     

Multistimuli‐Responsive Bilirubin Nanoparticles for Anticancer Therapy

Although stimuli‐responsive materials hold potential for use as drug‐delivery carriers for treating cancers, their clinical translation has been limited. Ideally, materials used for the purpose should be biocompatible and nontoxic, provide “on‐demand” drug release in response to internal or external stimuli, allow large‐scale manufacturing, and exhibit intrinsic anticancer efficacy. We present multistimuli‐responsive nanoparticles formed from bilirubin, a potent endogenous antioxidant that possesses intrinsic anticancer and anti‐inflammatory activity. Exposure of the bilirubin nanoparticles (BRNPs) to either reactive oxygen species (ROS) or external laser light causes rapid disruption of the BRNP nanostructure as a result of a switch in bilirubin solubility, thereby releasing encapsulated drugs. In a xenograft tumor model, BRNPs loaded with the anticancer drug doxorubicin (DOX@BRNPs), when combined with laser irradiation of 650 nm, significantly inhibited tumor growth. This study suggests that BRNPs may be used as a drug‐delivery carrier as well as a companion medicine for effectively treating cancers.     

Targeted Drug Delivery Biopolymers Effectively Inhibit Breast Tumor Growth and Prevent Doxorubicin-Induced Cardiotoxicity

The anticancer agent doxorubicin(dox) has been widely used in the treatment of a variety of hematological malignancies and solid tumors. Despite doxorubicin’s efficiency in killing tumor cells, severe damage to healthy tissues, along with cardiotoxicity, limits its clinical use. To overcome these adverse side effects, improve patient safety, and enhance therapeutic efficacy, we have designed a thermally responsive biopolymer doxorubicin carrier that can be specifically targeted to tumor tissue by locally applying mild hyperthermia (41 °C). The developed drug vehicle is composed of the following: a cell penetrating peptide (SynB1) to promote tumor and cellular uptake; thermally responsive Elastin-like polypeptide (ELP); and the (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH) containing a pH-sensitive hydrazone linker that releases doxorubicin in the acidic tumor environment. We used the in vivo imaging system, IVIS, to determine biodistribution of doxorubicin-delivered ELP in MDA-MB-231 xenografts in nude mice. Tumor bearing mice were treated with a single IV injection of 10 mg/kg doxorubicin equivalent dose with free doxorubicin, thermally responsive SynB1 ELP 1-DOXO, and a thermally nonresponsive control biopolymer, SynB1 ELP 2-DOXO. Following a 2 h treatment with hyperthermia, tumors showed a 2-fold higher uptake when treated with SynB1 ELP 1-DOXO compared to free doxorubicin. Accumulation of the thermally non-responsive control SynB1 ELP2 –DOXO was comparable to free doxorubicin, indicating that an increase in dox accumulation with ELP is due to aggregation in response to thermal targeting. Higher levels of SynB1 ELP1–DOXO and SynB1 ELP2 –DOXO with respect to free doxorubicin were observed in kidneys. Fluorescence intensity from hearts of animals treated with SynB1 ELP1–DOXO show a 5-fold decrease in accumulation of doxorubicin than the same dose of free doxorubicin. SynB1-ELP1-DOXO biopolymers demonstrated a 6-fold increase in tumor/heart ratio in comparison to free doxorubicin, indicating preferential accumulation of the drug in tumors. These results demonstrate that thermally targeted polymers are a promising therapy to enhance tumor targeting and uptake of anticancer drugs and to minimize free drug toxicity in healthy tissues, representing a great potential for clinical application.     

Multivalent Aptamer-modified DNA Origami as Drug Delivery System for Targeted Cancer Therapy

In spite of great development in nanoparticle-based drug delivery systems(DDSs)for improved therapeutic efficacy,it remains challenging for effective delivery of chemotherapeutic drugs to targeted tumor cells.In this work,we report a triangle DNA origami as targeted DDS for cancer therapy.DNA origami shows excellent biocompatibility and stability in cell culture medium for 24 h.In addition,the DNA origami structures conjugated with multivalent aptamers enable for efficient delivery of anticancer drug doxorubicin(Dox)into targeted cancer cell due to their targeting function,reducing side effects associated with nonspecific distribution.Moreover,we also demonstrated that the multivalent aptamer-modified DNA origami loading Dox exhibits prominent therapeutic efficacy in vitro.Accordingly,this work provides a good paradigm for the development of DNA origami nanostructure-based targeted DDS for cancer therapy.     

Preparation of a Camptothecin Prodrug with Glutathione‐Responsive Disulfide Linker for Anticancer Drug Delivery

We present here a novel camptothecin (CPT) prodrug based on polyethylene glycol monomethyl ether‐block‐poly(2‐methacryl ester hydroxyethyl disulfide‐graft‐CPT) (MPEG‐SS‐PCPT). It formed biocompatible nanoparticles (NPs) with diameters of approximately 122 nm with a CPT loading content as high as approximately 25 wt % in aqueous solution. In in vitro release studies, these MPEG‐SS‐PCPT NPs could undergo triggered disassembly and much faster release of CPT under glutathione (GSH) stimulus than in the absence of GSH. The CPT prodrug had high antitumor activity, and another anticancer drug, doxorubicin hydrochloride (DOX ? HCl), could also be introduced into the prodrug with a high loading amount. The DOX ? HCl‐loaded CPT prodrug could deliver two anticancer drugs at the same time to produce a collaborative cytotoxicity toward cancer cells, which suggested that this GSH‐responsive NP system might become a promising carrier to improve drug‐delivery efficacy.     

Enhanced Anticancer Efficacy by ATP‐Mediated Liposomal Drug Delivery

A liposome‐based co‐delivery system composed of a fusogenic liposome encapsulating ATP‐responsive elements with chemotherapeutics and a liposome containing ATP was developed for ATP‐mediated drug release triggered by liposomal fusion. The fusogenic liposome had a protein–DNA complex core containing an ATP‐responsive DNA scaffold with doxorubicin (DOX) and could release DOX through a conformational change from the duplex to the aptamer/ATP complex in the presence of ATP. A cell‐penetrating peptide‐modified fusogenic liposomal membrane was coated on the core, which had an acid‐triggered fusogenic potential with the ATP‐loaded liposomes or endosomes/lysosomes. Directly delivering extrinsic liposomal ATP promoted the drug release from the fusogenic liposome in the acidic intracellular compartments upon a pH‐sensitive membrane fusion and anticancer efficacy was enhanced both in vitro and in vivo.     

Role of Calixarene in Chemotherapy Delivery Strategies

Since cancer is a multifactorial disease with a high mortality rate, the study of new therapeutic strategies is one of the main objectives in modern research. Numerous chemotherapeutic agents, although widely used, have the disadvantage of being not very soluble in water or selective towards cancerous cells, with consequent side effects. Therefore, in recent years, a greater interest has emerged in innovative drug delivery systems (DDSs) such as calixarene, a third-generation supramolecular compound. Calixarene and its water-soluble derivatives show good biocompatibility and have low cytotoxicity. Thanks to their chemical–physical characteristics, calixarenes can be easily functionalized, and by itself can encapsulate host molecules forming nanostructures capable of releasing drugs in a controlled way. The encapsulation of anticancer drugs in a calixarene derivate improves their bioavailability and efficacy. Thus, the use of calixarenes as carriers of anticancer drugs could reduce their side effects and increase their affinity towards the target. This review summarizes the numerous research advances regarding the development of calixarene nanoparticles capable of encapsulating various anticancer drugs.     

A new Dy(III)-based metal-organic framework with polar pores for pH-controlled anticancer drug delivery and inhibiting human osteosarcoma cells

Anticancer drug delivery is considered as the most common and patient acceptable drug administration with reduced side effects. In general, an ideal drug carrier for anticancer drug delivery should have high drug loading capacity, good biocompatibility, and avoid drug delivery in normal tissue (neutral conditions) and promoting the drug release in cancerous tissue (acidic condition). Herein, we synthesize a new porous Dy(III)-based metal-organic framework, [Dy(HABA)(ABA)](DMA)₄] (1, H₂ABA = 4,4'-azanediyldibenzoic acid, DMA = N,N-dimethylacetamide) with uncoordinated N donor sites in the porous surroundings using a bent polycarboxylic acid linker under solvothermal conditions. The structure of the obtained crystalline product has been determined by X-ray single-crystal diffraction, elemental analysis, TGA, XRD, and gas sorption measurement. Due to the suitable window size and polar atom functionalized 1D channels, the activated 1 (1a) was used for anticancer drug 5-Fu loading. A moderately high drug loading and pH-dependent drug-release behavior could be observed for 1a. Furthermore, as demonstrated by the MTT assay, this drug/MOF composite shows low cytotoxicity, good biocompatibility, and anticancer activity against human osteosarcoma cell lines MG63.