Intelligent Drug Delivery Systems Research Articles

A pH/reduction dual-sensitive copolymer inserted in liposomal bilayer acts as a protective “umbrella”

Developing a targeted intelligent drug delivery system with excellent controllability of drug release remains an ongoing challenge in chemotherapy. A multistage responsive liposome was constructed by inserting a folate (FA) modified lipid and a pH/reduction dual-sensitive copolymer into the liposome bilayer. The properties of liposome were studied by fluorescence polarization, dynamic light scattering and in vitro drug release. Since the PDPA segment of the copolymer could embed in or escape from the liposomal bilayer depending on pH value, the membrane stability of the liposome was improved at pH 7.4 and decreased at pH 5.0. As a result, the drug leakage of the liposome was significantly suppressed at pH 7.4 but promoted at an acidic pH. Moreover, the liposome Lipo5-FA, which contained negatively charged FA groups protected by the longer PEG, was found to undergo membrane fusion with the positively charged Lipo(+) to verify the longer PEG was cut by GSH. All results indicated that the smart copolymer acted as a switch on liposomal bilayer for drug release and also a protective “umbrella” for FA.

Synthesis, characterization, and evaluation of a magnetic molecular imprinted polymer for 5-fluorouracil as an intelligent drug delivery system for breast cancer treatment

Magnetic carriers-based molecular imprinting has become one of the most interesting phenomena in the drug delivery field. In this study, we endeavor to devise an effective magnetic drug carrier via imprinting technology for 5-fluorouracil and investigate its anticancer activity toward breast cancer treatment. In this case, methacrylic acid and trimethylolpropane triacrylate were chosen for imprinting 5-fluorouracil on the magnetic fluorescent core. With this aim, fluorescein isothiocyanate was utilized as a fluorescent agent. FT-IR, EDX, XRD, VSM, FESEM, TEM, and BET analysis were used to characterize the synthesized carrier. According to adsorption studies, the adsorption of 5-fluorouracil was followed by Freundlich isotherm (QMAX: 121.6 mg/g) in a fast second-order kinetic model (6 min) in our proposed carrier. Afterward, based on the release studies the Higuchi dynamic model was suggested for leaching of 5-fluorouracil from the carrier. Eventually, the cytotoxicity effect of the projected carrier on MCF-10 and MCF-7 cell lines was investigated. In this case, the magnetic carrier has shown 61% cytotoxicity on cancer cells which were about 25 times greater than the pure drug, but it had no significant effect on normal cells. In all steps, the non-imprinted carrier was investigated as a comparison. This study has shown that our proposed magnetic nanocarrier can effectively be utilized in breast cancer treatment. The synthesis of magnetic molecular imprinted for 5-FU toward the breast cancer treatment eliminates the MDR of cancer cell toward the 5-FU.

Cathepsin B-responsive nanodrug delivery systems for precise diagnosis and targeted therapy of malignant tumors

The tumor microenvironment (TME) significantly influences cancer evolution and therapeutic efficacy. Targeting biofunctional molecules to the TME has long been appreciated as a means of raising local drug concentrations and reducing systemic toxicities. The booming nanotechnology field has realized the importance of cathepsin B to derive a variety of intelligent enzyme-responsive nanosized drug delivery systems (nanoDDS) to improve treatment responses and clinical outcomes. In this tutorial review, after introducing the molecular structure and physiological/pathological functions of cathepsin B, the outstanding achievements of cathepsin B-responsive nanoplatforms in the precise diagnosis, targeted therapy, and synergistic theranostics of malignant tumors are systematically described. Finally, the challenges of enzyme-substrate incompatibility, low diagnostic sensitivity, mass production and biocompatibility of multifunctional nanoDDS are considered in order to successfully promote them to clinical applications

PLGA-Based Drug Delivery Systems for Remotely Triggered Cancer Therapeutic and Diagnostic Applications.

Intelligent drug delivery systems based on nanotechnology have been widely developed and investigated in the field of nanomedicine since they were able to maximize the therapeutic efficacy and minimize the undesirable adverse effects. Among a variety of organic or inorganic nanomaterials available to fabricate drug delivery systems (DDSs) for cancer therapy and diagnosis, poly(D,L-lactic-co-glycolic acid) (PLGA) has been extensively employed due to its biocompatibility and biodegradability. In this paper, we review the recent status of research on the application of PLGA-based drug delivery systems (DDSs) in remotely triggered cancer therapy and the strategies for tumor imaging provided by PLGA-based DDSs. We firstly discuss the employment of PLGA-based DDSs for remotely triggered cancer therapy, including photo-triggered, ultrasound-triggered, magnetic field-triggered, and radiofrequency-triggered cancer therapy. Photo-triggered cancer therapy involves photodynamic therapy (PDT), photothermal therapy (PTT), and photo-triggered chemotherapeutics release. Ultrasound-triggered cancer therapy involves high intensity focused ultrasound (HIFU) treatment, ultrasound-triggered chemotherapeutics release, and ultrasound-enhanced efficiency of gene transfection. The strategies which endows PLGA-based DDSs with imaging properties and the PLGA-based cancer theranostics are further discussed. Additionally, we also discuss the targeting strategies which provide PLGA-based DDSs with passive, active or magnetic tumor-targeting abilities. Numerous studies cited in our review demonstrate the great potential of PLGA-based DDSs as effective theranostic agent for cancer therapy and diagnosis.

Injectable and Self-Healing Nanocomposite Hydrogels with Ultrasensitive pH-Responsiveness and Tunable Mechanical Properties: Implications for Controlled Drug Delivery.

Injectable, self-healing, and pH-responsive hydrogels are great intelligent drug delivery systems for controlled and localized therapeutic release. Hydrogels that show pH-sensitive behaviors in the mildly acidic range are ideal to be used for the treatment of regions showing local acidosis like tumors, wounds and infections. In this work, we present a facile preparation of an injectable, self-healing, and supersensitive pH-responsive nanocomposite hydrogel based on Schiff base reactions between aldehyde-functionalized polymers and amine-modified silica nanoparticles. The hydrogel shows fast gelation within 10 s, injectability, and rapid self-healing capability. Moreover, the hydrogel demonstrates excellent stability under neutral physiological conditions, while a sharp gel-sol transition is observed, induced by a faintly acidic environment, which is desirable for controlled drug delivery. The pH-responsiveness of the hydrogel is ultrasensitive, where the mechanical properties, hydrolytic degradation, and drug release behaviors can alter significantly when subjected to a slight pH change of 0.2. Additionally, the hydrogel's mechanical and pH-responsive properties can be readily tuned by its composition. Its excellent biocompatibility is confirmed by cytotoxicity tests toward human dermal fibroblast cells (HDFa). The novel injectable, self-healing, and sensitive pH-responsive hydrogel serves as a promising candidate as a localized drug carrier with controlled delivery capability, triggered by acidosis, holding great promise for cancer therapy, wound healing, and infection treatment.

Polymeric Nanocarriers of Drug Delivery Systems in Cancer Therapy.

Conventional chemotherapy is the most common therapeutic method for treating cancer by the application of small toxic molecules thatinteract with DNA and causecell death. Unfortunately, these chemotherapeutic agents are non-selective and can damage both cancer and healthy tissues, producing diverse side effects, andthey can have a short circulation half-life and limited targeting. Many synthetic polymers have found application as nanocarriers of intelligent drug delivery systems (DDSs). Their unique physicochemical properties allow them to carry drugs with high efficiency, specificallytarget cancer tissue and control drug release. In recent years, considerable efforts have been made to design smart nanoplatforms, including amphiphilic block copolymers, polymer-drug conjugates and in particular pH- and redox-stimuli-responsive nanoparticles (NPs). This review is focused on a new generation of polymer-based DDSs with specific chemical functionalities that improve their hydrophilicity, drug loading and cellular interactions.Recentlydesigned multifunctional DDSs used in cancer therapy are highlighted in this review.

Design, Synthesis and Characterization of a Novel Type of Thermo-Responsible Phospholipid Microcapsule-Alginate Composite Hydrogel for Drug Delivery.

Liposomes are extensively used in drug delivery, while alginates are widely used in tissue engineering. However, liposomes are usually thermally unstable and drug-leaking when in liquids, while the drug carriers made of alginates show low loading capacities when used for drug delivery. Herein, we developed a type of thermo-responsible liposome–alginate composite hydrogel (TSPMAH) by grafting thermo-responsive liposomes onto alginates by using Ca2+ mediated bonding between the phosphatidic serine (PS) in the liposome membrane and the alginate. The temperature-sensitivity of the liposomes was actualized by using phospholipids comprising dipalmitoylphosphatidylcholine (DPPC) and PS and the liposomes were prepared by a thin-film dispersion method. The TSPMAH was then successfully prepared by bridge-linking the microcapsules onto the alginate hydrogel via PS-Ca2+-Carboxyl-alginate interaction. Characterizations of the TSPMAH were carried out using scanning electron microscopy, transform infrared spectroscopy, and laser scanning confocal microscopy, respectively. Their rheological property was also characterized by using a rheometer. Cytotoxicity evaluations of the TSPMAH showed that the composite hydrogel was biocompatible, safe, and non-toxic. Further, loading and thermos-inducible release of model drugs encapsulated by the TSPMAH as a drug carrier system was also studied by making protamine–siRNA complex-carrying TSPMAH drug carriers. Our results indicated that the TSPMAH described herein has great potentials to be further developed into an intelligent drug delivery system.

Stimuli-responsive/smart tablet formulations (under simulated physiological conditions) for oral drug delivery system based on glucuronoxylan polysaccharide

Objective: Development of stimuli-responsive intelligent drug delivery system (based on a polysaccharide, glucuronoxylan [GX]) with on-off switching properties under physiological conditions.Significance: As GX exhibits high swelling index and stimuli-responsive swelling/de-swelling properties, therefore, this material appeared highly useful to design pH, solvent and ionic stress-sensitive oral tablet formulations, which offered on-off switching properties. In this way, we could design intelligent/smart drug delivery systems for levosulpiride (LS) and theophylline (TF) with valuable pharmaceutical properties.Methods: GX-based tablet formulations were explored for stimuli-responsive, reversible swelling–deswelling behavior, dynamic swelling, and its kinetics. Tablet surface and channeling after swelling were observed using scanning electron microscopy (SEM). Drug release study was performed mimicking the physiological conditions like pH and transit time of gastrointestinal tract (GIT). Radiographic images of tablet path (in vivo) were recorded.Results: GX-based formulations exhibited high swelling in deionized water (DW), pH 6.8 and 7.4 while negligible swelling at pH 1.2. SEM images discovered the presence of microcracks and nanopores on the surface of tablets and showed channeling after swelling of tablets in DW. Sustained drug release was observed and found directly proportional to the concentration of GX in the formulations with negligible release at pH 1.2. In vivo radiographic evaluation indicated the retention of tablets in GIT for 7 h. Hemocompatibility studies showed the non-thrombogenic and non-hemolytic nature of GX.Conclusions: GX-based smart/stimuli-responsive formulations can control/sustain the release of drugs in GIT.

"Smart" self-assembled structures: toward intelligent dual responsive drug delivery systems.

Combination of various polymeric blocks with distinct characteristics such as thermo-responsiveness, non-ionic nature and zwitterionic properties is an interesting approach toward fabricating copolymers undergoing a smart self-assembly process in an aqueous environment. In some cases, through a so-called "schizophrenic" self-assembly process, stimuli-induced self-assembly can occur from either double-hydrophilic or double hydrophobic polymers. In this process, the roles of the blocks forming the hydrophobic core and hydrophilic shell can be switched by changing the external conditions. This transformation in the solubilization profile leads to the fabrication of "smart" polymeric vehicles which could potentially control the release of their cargos as well as differentiate between encapsulated agents based on their charge and polarity properties. The aforementioned changes of the amphiphilicity of polymers in "schizophrenic" structures offer numerous self-assembly scenarios. In the current review, we summarize the polymer and peptide-based schizophrenic copolymers which could form micellar and vesicular (polymersome) systems providing novel structures with beneficial applications.

Hyaluronic acid reduction-sensitive polymeric micelles achieving co-delivery of tumor-targeting paclitaxel/apatinib effectively reverse cancer multidrug resistance

Multidrug resistance (MDR) of cancer cells is a significant challenge in chemotherapy, highlighting the urgent medical need for simple and reproducible strategies to reverse this process. Here, we report the development of an active tumor-targeting and redox-responsive nanoplatform (PA-ss-NP) using hyaluronic acid-g-cystamine dihydrochloride-poly-ε-(benzyloxycarbonyl)-L-lysine (HA-ss-PLLZ) to co-deliver paclitaxel (PTX) and apatinib (APA) for effective reversal of MDR. This smart nanoplatform specifically bound to CD44 receptors, leading to selective accumulation at the tumor site and uptake by MCF-7/ADR cells. Under high concentrations of cellular glutathione (GSH), the nanocarrier was degraded rapidly with complete release of its encapsulated drugs. Released APA effectively inhibited the function of the P-glycoprotein (P-gp) drug pump and improved the sensitivity of MDR cells to chemotherapeutic agents, leading to the recovery of PTX chemosensitivity in MDR cells. As expected, this newly developed intelligent drug delivery system could effectively control MDR, both in vitro and in vivo.

Liver-Targeting and pH-Sensitive Sulfated Hyaluronic Acid Mixed Micelles for Hepatoma Therapy.

BackgroundThe tumor-targeting ability and pH-sensitive properties of intelligent drug delivery systems are crucial for effective drug delivery and anti-tumor therapy.MethodsIn this study, sHA-DOX/HA-GA mixed micelles were designed with the following properties: sulfated hyaluronic acid (sHA) was synthesized to block cell migration by inhibiting HAase; sHA-DOX conjugates were synthesized via pH-sensitive hydrazone bond to realize DOX-sensitive release. The introduction of HA-GA conjugate could improve active-targeting ability and cellular uptake.ResultsThe results showed that the mixed micelles possessed a nearly spherical shape, nanoscale particle size (217.70±0.89 nm), narrow size distribution (PDI=0.07±0.04), negative zeta potential (−31.87±0.61 mV) and pH-dependent DOX release. In addition, the sHA-DOX/HA-GA micelles exhibited concentration-dependent cytotoxicities against liver carcinoma cells (HepG2) and HeLa cells, and were shown to be effectively taken up by HepG2 cells by confocal microscopy analysis. Furthermore, the in vivo anti-tumor study showed that mixed micelles had a superior anti-tumor effect compared to that of free DOX. Further evidence obtained from the hematoxylin–eosin staining and immunohistochemistry analysis also demonstrated that sHA-DOX/HA-GA exhibited stronger tumor inhibition and lower systemic toxicity than free DOX.ConclusionThe sHA-DOX/HA-GA mixed micelles could be a potential drug delivery system for anti-hepatoma therapy.

Multistimuli-responsive PEGylated polymeric bioconjugate-based nano-aggregate for cancer therapy

Molecular structure of pDHPMA-DOX-SS-mPEG, and schematic illustration of its self-aggregation into nano-aggregate for blood circulation and accumulation into tumors via the EPR effect. • Two functional polymer-DOX bioconjugates based nano-aggregates (NAs) were prepared. • NAs displayed pH and enzyme-responsive features and had excellent biocompatibility. • NAs entered into 4T1 cells through multiple endocytosis pathways. • NAs induced apoptosis by disrupting mitochondria function and actin cytoskeletons. • PEGylation for NA improved anti-tumor efficacy on 4T1 tumor bearing mice. Biocompatible, stimuli-responsive, intelligent and efficient drug delivery systems are essential for effectively suppressing cancer and reducing toxic side effects of chemotherapeutic drugs. Herein, two strategies have been employed to develop a N -(1,3-dihydroxypropan-2-yl) methacrylamide (DHPMA)-derived polymer carrier for doxorubicin (DOX) with a long circulation time: increasing molecular weight (MW) of the DHPMA polymer through an enzyme-responsive oligopeptide linker; and further grafting poly(ethylene glycol) (PEG) onto the polymer chain via a disulfide bond (pDHPMA-DOX-SS-mPEG), resulting in nano-aggregate. The nano-aggregate enters into 4T1 cells through multiple endocytosis pathways and DOX released in the presence of a low pH and reductive enzymes contribute to significant apoptosis by decreasing mitochondria membrane potential and disrupting actin cytoskeletons. Significantly enhanced tumor accumulation of the nano-aggregate is evidenced from ex vivo fluorescence imaging in comparison with the bioconjugate (pDHPMA-DOX) with no PEGylation. This is supported with a much longer terminal half-life time up to 16.9 h for pDHPMA-DOX-SS-mPEG, significantly higher than 10.4 h for pDHPMA-DOX and 2.7 h for free drug DOX. Accordingly, the best tumor inhibitive effect has been achieved by pDHPMA-DOX-SS-mPEG confirmed by significant reduction in tumor volumes and undetectable active proliferative cells and positive endotheliocytes from immunohistochemical staining of CD31 and Ki-67 in the 4T1 tumor tissue. The results demonstrate that increased MW through biodegradable linkers and grafted PEG significantly contribute to an extended circulation time, reduced systemic toxicity and an enhanced therapeutic efficacy. Tumor microenvironment-responsive PEGylated DHPMA-derived polymeric bioconjugate-based nano-aggregate offers the promising anti-tumor effect.

Drug self-gating fluorescent nanoparticles for pH-responsive doxorubicin delivery

Intelligent drug delivery systems have attracted great attention in the field of biomedicine and cancer diagnosis. In this work, a drug delivery system that can be gated by doxorubicin itself and together with pH-responsive ability has been designed and prepared based on the upconversion nanoparticles. The drug delivery system is a special core–shell structure, consisting of upconversion nanoparticle core and mesoporous silica shell. The new system tactfully bypasses the use of auxiliary capping agents and exhibits desirable drug release at pH = 5, enhancing HeLa cells inhibition. The introduction of Schiff base plays a key role in the process of achieving pH-responsive drug release. Moreover, upconversion nanoparticles could emit bright yellow-green fluorescence (540 nm) under the irradiation of near-infrared light (980 nm) for in vivo bioimaging. This characteristic provides the possibility of locating tumor tissues and real-time tracing drug delivery.

Temperature and CO2 Dual-Responsive Pickering Emulsions Using Jeffamine M2005-Modified Cellulose Nanocrystals

Cellulose nanocrystals (CNCs) with excellent biodegradability are promising biomaterials for use as responsive Pickering emulsifiers. However, the high hydrophilicity of CNCs limits their emulsification ability. Some existing studies have utilized complicated covalent modification procedures to increase the hydrophobicity of CNCs. To simplify the modification process, we prepared hydrophobically modified CNCs (CNCs-M2005) via simple and controllable electrostatic interactions with thermosensitive M2005. The obtained CNCs-M2005 exhibited temperature and CO2 dual-responsive properties. Subsequently, stable oil/water Pickering emulsions were prepared using the partially hydrophobic CNCs-M2005 at 20 °C. However, demulsification occurred when the temperature increased to 60 °C. This temperature-induced demulsification resulted from the dehydration of polyethylene oxide and polypropylene oxide, causing the aggregation of the CNCs-M2005, as shown by dynamic light scattering and transmission electron microscopy experiments. In addition, demulsification was also achieved after bubbling CO2, which was attributed to the dissociation of the partially hydrophobic CNCs-M2005. The temperature and CO2 dual-responsive biosafe Pickering emulsions open up opportunity for the design of intelligent food, cosmetic, and drug delivery systems.

In Vitro and In Vivo Biocompatibility of Novel Zwitterionic Poly(Beta Amino)Ester Hydrogels Based on Diacrylate and Glycine for Site‐Specific Controlled Drug Release

AbstractNew (β‐aminoester) hydrogels (PBAE) based on di(ethylene glycol)diacrylate and glycine are successfully synthesized and characterized for the first time in this work. PBAE macromers are obtained using Michael addition. By changing the diacrylate/amine stoichiometric ratio, but maintaining it >1, samples with different chemical structure containing acrylate end‐groups are obtained. The hydrogels are synthesized from macromers utilizing free radical polymerization. Chemical structure of macromers and hydrogels is confirmed by proton nuclear magnetic resonance, and Fourier transform infra‐red spectroscopy. Swelling and degradation rates in physiological pH range change notably with pH and monomer molar ratio, validating pH sensitivity and zwitterionic behavior, which can be finely tuned by changing any of these parameters. In vitro cytotoxicity and in vivo acute embryotoxicity in zebrafish (Danio rerio) performed to assess the biocompatibility of the novel hydrogel materials and their degradation products reveal that materials are nontoxic and biocompatible. The Cephalexin in vitro drug release study, at pH values 2.20, 5.50, and 7.40, demonstrates pH‐sensitive delivery with the release profiles effectively controlled by pH and the hydrogel composition. PBAE hydrogels exhibit great potential for a variety of biomedical applications, including tissue regeneration and intelligent drug delivery systems.

Facile preparation of acid/CO2 stimuli-responsive sheddable nanoparticles based on carboxymethylated chitosan

The present study describes the facile preparation of acid/CO2 stimuli-responsive sheddable nanoparticles based on carboxymethylated chitosan (CMCS). Commercially available CMCS was grafted with monomethoxy polyethylene glycol (mPEG) chains via an acid/CO2 responsive linker, i.e., benzoic-imine, and then was used for the cross-linking with CaCl2. With a high CMCS concentration up to 7 mg/mL, stable nanoparticles were successfully prepared. The particle size grew slightly with increasing the molecular weight of mPEG. When the concentration of CaCl2 and the feed ratio of CMCS to mPEG increased, the particle size decreased at first and then increased after reaching a minimum size. When the particles were stimulated by CO2 or acid, benzoicimine cleaved quickly, and mPEG fell off the nanoparticles simultaneously, and then flocculation and precipitation occurred. These sheddable nanoparticles might have potential application in the biomedical field including the intelligent drug delivery system.

Tailored Design of an ROS-Responsive Drug Release Platform for Enhanced Tumor Therapy via "Sequential Induced Activation Processes".

The reactive oxygen species (ROS)-responsive intelligent drug delivery system has developed rapidly in recent years. However, because of the low concentration of ROS in most types of tumor cells, it is not possible to rapidly and effectively stimulate the drug delivery system to release the active drug. Here, we introduced "sequential induced activation processes" for efficient tumor therapy by designing a new ROS-responsive drug release platform. β-Lapachone, a positively charged nitrogen mustard (NM) prodrug, and two diblock molecules (mPEG-AcMH and PAsp-AcMH) are self-assembled to form prodrug primary micelles, which are further aggregated into nanoparticles that facilitate drug codelivery. When administered by intravenous injection, the nanoparticles reach the tumor site and enter the tumor cells by endocytosis. The β-lapachone released in the tumor cells induces a large amount of H2O2, and the ROS-responsive NM prodrug is activated to form activated NM, quinone methide, and boric acid under the induction of H2O2. The activated NM leads to tumor cell apoptosis.

Mussel-Derived, Cancer-Targeting Peptide as pH-Sensitive Prodrug Nanocarrier

In this work, we prepared a novel cancer chemotherapeutic nanocarrier through the self-assembly of a mussel-derived, cancer-targeting peptide with a pH-sensitive conjugation of antitumor drugs. The biomimetic peptide was designed with a fluorescent molecule fluorescein isothiocyanate for imaging, a RGD sequence for cancer-targeting and tetravalent catechol groups for dynamic conjugation of the antitumor drug bortezomib via pH-cleavable boronic acid-catechol esters. Our study demonstrated that the peptide-based prodrug nanocarrier dramatically the enhanced specific cellular uptake and cytotoxicity toward human breast cancer cells in vitro in comparison with free drug and nontargeting control nanoparticles. Likewise, the prodrug nanocarrier showed improved therapeutic efficacy and low systematic toxicity in vivo. Considering highly biomimetic nature of the peptide-based nanocarriers, rapid drug release from the dynamically conjugated prodrugs, and convenience of introducing cancer-targeting activity onto this nanosystem, we believe our work would provide new ideas for the development of intelligent and biocompatible drug delivery systems to improve the chemotherapy efficacy in clinic. Furthermore, the pH-sensitive drug conjugation mechanism on peptide-based nanocarriers would provide a hint for the exploitation of dynamic prodrug strategies and the development of highly biocompatible nanocarriers using biogenic materials, e.g., the proteinogenic nanomaterials decorated with drugs through dynamic covalent chemistry.

Development of multifunctional cobalt ferrite/hydroxyapatite nanocomposites by microwave assisted wet precipitation method: A promising platform for synergistic chemo-hyperthermia therapy

Abstract Functional nanocomposites capable of multimodal therapy hold great potential to improve the efficiency of cancer therapy. Herein, we report a magnetic nanocomposite of cobalt ferrite/hydroxyapatite followed by loading a chemotherapeutic drug (5-fluorouracil, FU) to construct the intelligent drug delivery system and/or hyperthermia carrier. To do that, cobalt ferrite/hydroxyapatite nanocomposite was successfully synthesized by microwave assisted wet precipitation method, subsequently, FU loaded onto the formed composites through adsorption method. This nanocomposite exhibits ferromagnetic behaviour with a magnetic saturation value of approximately 2.5–8.2 emu/g. Upon alternating magnetic field, it could generate hyperthermia temperature within a short time (43°C in 4.5 min) and facilitate the release of encapsulated FU from the composite with enhanced release rate. These multifunctional carriers also demonstrate a noticeable proliferative activity against healthy fibroblast cells (L929) and suppressed growth against osteosarcoma cells (MG63). Therefore, this studied nanoplatform might be a promising candidate for synergistic chemo-hyperthermia therapy.

Engineered pH‐responsive hydrazone‐carboxylate complexes‐encapsulated 2D matrices for cathepsin‐mediated apoptosis in cancer

Spurred by the current advancements in engineering various intelligent nanoparticle-based drug delivery systems, conjugation of drugs with the stimuli-responsive molecular switches has become one of the most efficient approaches to deliver a drug cargo in spatiotemporal controlled fashions. In this study, we fabricated an innovative pH-triggered hydrazone-carboxylate complex of doxorubicin (Dox), which was subsequently encapsulated in the layered double hydroxide (LDH) nanoparticles for effective cancer therapeutics. These two-dimensional (2D) biodegradable matrices efficiently delivered Dox by pH-triggered release in the acidic lysosomal environment and their subsequent escape to cytosol. Moreover, the delivered Dox molecules and high positively-charged surfaces of LDHs facilitated the cancer cell ablation via enhancing the cathepsins-mediated cell apoptosis assisted by free radical species generation. The critical advancements in the nanoparticle-based designs and substantial ablation of tumor cells through a free radical attack indicate that the designed pH-triggered drug composites can be used for efficient cancer therapeutics. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1184-1194, 2019.