Anticancer Drug Delivery System Research Articles

Novel borospherenes as cisplatin anticancer drug delivery systems

Here we report a density functional theory (DFT) study on the endohedral metalloborospherenes Li@X4B32 (X = C and Si) as high-performance materials for drug delivery applications. The main objective of the present work is to investigate the interaction of pristine X4B32 and Li@X4B32 nanoclusters with an anticancer drug (cisplatin) by means of the DFT. Our ultraviolet–visible calculations reveal that the electronic spectra of the drug/nanocluster complexes show a blue shift toward lower wavelengths (higher energies). In order to go further and gain insight into the binding features of the studied nanoclusters with cisplatin drug, the FMO analysis was performed. Our results determine the high orbital overlapping between cisplatin and C4B32 cluster. Our calculations also show that the interactions between the drug and C4B32 in the acidic environment become weak; thus, the drug can be released from the carrier. Moreover, the higher values of adsorption energies in the aqueous phase reveal that the considered nanoclusters can increase their solubility and modify their interaction with the drug. Consequently, our results represented that the C4B32 could be used as potential carriers for the delivery of cisplatin drug.

The influence of carboxylate moieties for efficient loading and pH-controlled release of doxorubicin in Fe3O4 magnetic nanoparticles

One of the significant challenges in a nanoparticles-based anticancer drug delivery system for cancer therapy application is to design nanoparticles with specific functionality for efficient drug conjugation and release. In the present study, different carboxylate molecules, i.e., succinic acid (SA), ascorbic acid (AA), and citric acid (CA), were used as surface modifiers for delivery of an anticancer drug, doxorubicin (DOX), using Fe3O4 magnetic nanoparticles (MNPs). Here, a simple one-pot co-precipitation method was successfully used to fabricate monodisperse and uniform carboxylates functionalized Fe3O4 nanoparticles with excellent superparamagnetic properties and colloidal stabilities. Based on the result, the as-prepared MNPs exhibited high drug loading due to the formation of intermolecular forces between DOX and carboxylates moieties or MNPs surface. Besides, the release of the loaded DOX could quickly be released by simply reducing the pH of the suspension. However, it was observed that both loading efficiency and release of DOX were significantly affected by the type of carboxylate moieties. Finally, in vitro MTT assay of HeLa cell lines also revealed that the as-prepared DOX-loaded nanoparticles were able to induce the death of the cancer cell efficiently.

Redox-Sensitive Hyaluronic Acid Polymer Prodrug Nanoparticles for Enhancing Intracellular Drug Self-Delivery and Targeted Cancer Therapy.

Currently, available nanoscale anticancer drug delivery systems have low targeting and release efficiency, limiting their therapeutic effects. Thus, tumor-targeting nanocarriers for self-assembly of amphiphilic polymer-drug conjugates are urgently needed to improve drug targeting and treatment efficacy. Here, we report the construction of a stable, reduction-sensitive prodrug conjugate based on hyaluronic acid-grafted pH-sensitive doxorubicin (DOX). The amphiphilic prodrug copolymer self-assembled into spherical nanoparticles in aqueous solution and exhibited an average diameter of 150 nm. Prodrug micelles were stable in a normal physiological environment and achieve selective and rapid release under acidic pH and/or high reduction conditions. Cell Counting Kit-8, flow cytometry, and live cell imaging assays showed that the prodrug had high targeting and antitumor activity against CD44 receptors. Moreover, in vivo pharmacokinetics and biodistribution studies showed that the prodrug had a longer circulation time in BALB/c mice and higher accumulation in 4T1 tumors. Interestingly, the prodrug could effectively treat tumors with few side effects. These results showed that the DOX prodrug micelles developed in this study may have great potential in targeted therapy.

Withdrawal Notice: Application of Nanomaterials in Development of Electrochemical Sensors and Drug Delivery Systems for Anticancer Drugs

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Synthesis and Characterization of Carboxymethyl Chitosan–Methyl Cellulose Containing Drug Loaded Ag2O–Fe3O4 Nanocomposites as a Drug Delivery System

Fe3O4 and Ag2O nanoparticles have good bio-compatibility and chemical stability properties, the possibility of these nanomaterials could be applied as a carrier in anti-cancer drug delivery system. In this project, Curcumin, an anti-cancer compound drug, loaded on Ag2O–Fe3O4/carboxymethyl chitosan–methyl cellulose (Ag2O–Fe3O4/CMCS–MCS) was studied at changing pH amounts for significance drug delivery. The samples were studied by scanning electron microscope, Fourier transform infrared spectroscopy, dynamic light scattering, energy dispersive spectra analysis (EDS), and diffraction X-ray. The weight amount of the prepared nanocomposites was also characterized by thermal gravimetric method. The release of curcumin were tested by UV–Vis spectroscopy in pH 7.8 and pH 5.4 media, respectively. The outcomes confirm suitable and gradual curcumin release in times 150 min.

Poly (ε-caprolactone)/poly (N-vinyl-2-pyrrolidone) core–shell nanofibers loaded by multi-walled carbon nanotubes and 5-fluorouracil: an anticancer drug delivery system

Cancer is one of the most fatal diseases in the world. Chemotherapy and radiation therapy are conventional cancer treatments affecting healthy tissues and also have many side effects. Drug delivery systems based on nanofibers can be used as cancer drug carrier with the least side effects. 5FU is one of the most common medicines for many types of cancer. In this study, PCL/PVP core–shell nanofibers containing MWCNTs were performed as 5FU carrier, which was loaded in core of these nanofibers. FESEM images showed all these core–shell nanofibers are uniform and the average diameter was 300–400 nm. There was no interaction between components of nanofibers, and the presence of 5FU in nanofibers was confirmed. The presence of MWCNTs loaded in shell improved the tensile properties. The degradability of nanofibers was investigated, and it was improved by increasing PVP in nanofibers. The morphology change in nanofibers was investigated by FESEM images after degradation. The release behavior of nanofibers was studied. These nanofibers had sustained and prolonged release, and the optimum sample in which 85% of drug released after 528 h was used for cytotoxicity test. The drug release mechanism was modeled by various mathematical models and followed Fick's law. MTT assay on HeLa cell line showed that cell cytotoxicity of 5FU loaded nanofibers was 50.35% after 72 h. The non-toxicity of carrier and efficacy of the drug loaded nanofibers mat on cervical cancer cell line were confirmed. This drug delivery system has the potential to perform as post-surgical anticancer drug delivery system.

Preparation and evaluation of long circulating erythrocyte membrane-cloaked anti-cancer drug delivery system.

Recently, biomimetic hybrid drug delivery systems, especially erythrocyte membrane-based drug delivery systems, have been utilized to achieve high bioavailability, and biocompatibility, in the meantime, to reduce immunogenicity and effectively evade phagocytosis of the host immune system. Here, we developed a novel drug delivery system of red blood cell membrane-derived vesicles (RDVs) cloaked poly (acrylic acid)-cystamine hydrochloride-D-α-tocopherol succinate (PAAssVES) nanoparticles. The PAAssVES nanoparticles were prepared via emulsification and solvent volatilization method, followed by loading of the model anti-cancer drug, sorafenib (SFN). Then RDVs and SFN-PAAssVES nanoparticles were uniformly mixed and co-extruded through polycarbonate membrane. The prepared RDV-coated nanoparticles (RDV-NPs) had good stability, with a zeta potential of - 10.7mV and particle size of 113.5nm. MTT assay was used to analyze the effects of RDV-NPs on cell viability in two kinds of gastric cancer cell lines BGC-823 and MKN-45. The results showed that RDV-NPs significantly decreased cell viability. In vitro drug release investigation showed that RDV-NPs had good sustained release properties and the cumulative release was 71.5% in 72h. In pharmacokinetic studies, SD male rats' intravenous injection with RDV-NP solution showed a more smooth plasma concentration-time profile. Compared with free SFN treatment and SFN-PAAssVES group, RDV-NPs enhanced the AUC by about 4.1-fold and 2.0-fold. The MRT and t1/2 of RDV-NPs were increased to 23.670 ± 2.347h and 24.450 ± 2.652h. Our study demonstrated the promise of using RDV-NPs as a long circulating anti-cancer drug delivery system. Graphical abstract.

PH/GSH-Dual-Sensitive Hollow Mesoporous Silica Nanoparticle-Based Drug Delivery System for Targeted Cancer Therapy.

The purpose of developing novel anticancer drug delivery systems (DDSs) is to efficiently carry and release drugs into cancer cells and minimize side effects. In this work, based on hollow mesoporous silica nanoparticle (HMSN) and the charge-reversal property, a pH/GSH-dual-sensitive DDS named DOX@HMSN-SS-PLL(cit) was reported. HMSN encapsulated DOX with high efficacy and was then covered by the "gatekeeper" β-cyclodextrin (β-CD) through the glutathione (GSH)-sensitive disulfide bond. Thereafter, adamantine-blocked citraconic-anhydride-functionalized poly-l-lysine (PLL(cit)-Ad) was decorated on the surface of the particles via host-guest interaction. The negatively charged carriers were stable in the neutral environment in vivo and could be effectively transported to the tumor site. The surface charge of the nanoparticles could be reversed in the weakly acidic environment, which increased the cellular uptake ability of the carriers by the cancer cells. After cellular internalization, β-CD can be removed by breakage of the disulfide bond in the presence of a high concentration of GSH, leading to DOX release. The preparation process of the carriers was monitored. The charge-reversal capability and the controlled drug-release behavior of the carriers were also investigated. In vitro and in vivo experiments demonstrated the excellent cancer therapy effect with low side effects of the carriers. It is expected that dual-sensitive DOX@HMSN-SS-PLL(cit) could play an important role in cancer therapy.

Evaluation and live monitoring of pH-responsive HSA-ZnO nanoparticles using a lung-on-a-chip model.

One of the key problems that have hindered the development and approval of anticancer nanoparticle drug delivery systems is the limited predictability of 2D cell culture and animal models. Here, we describe a biomimetic alveolus-epithelium-on-a-chip (AEOC) model with in-built sensors for monitoring and evaluating pH-responsive zinc oxide quantum dots (QDs)-loaded human serum albumin nanoparticles. This AEOC model closely represents the cancerous alveolus epithelium, which comprises lung cancer cells, as well as stromal cells, such as fibroblasts along with extracellular matrix (ECM) in the form of collagen. ZnO QDs were encapsulated in the HSA nanoparticles with a diameter of 60 nm. The physicochemical properties, quantum dots release, in vitro cytotoxicity, and cellular uptake of HSA-ZnO were evaluated. HSA-ZnO showed higher ZnO loading and encapsulation efficacy. TEER and pH sensors were used to monitor the cells over three days, and real-time data with and without nanoparticle treatment were obtained. Cell viability after treatment with 10 and 50 µg/mL of HSA-ZnO nanoparticles and confocal imaging data confirmed the significant internalization of the nanoparticles under co-culture cellular conditions in the AEOC model. Our designed organ-on-a-chip model has potentially expanded the capabilities of cell culture in biomimetic conditions, and therefore, can provide a low-cost alternative to expensive and tedious animal models for the evaluation of nanomedicines.

Novel 3D printed device with integrated macroscale magnetic field triggerable anti-cancer drug delivery system

With the growing demand for personalized medicine and medical devices, the impact of on-demand triggerable (e.g., via magnetic fields) drug delivery systems increased significantly in recent years. The three-dimensional (3D) printing technology has already been applied in the development of personalized dosage forms because of its high-precision and accurate manufacturing ability. In this study, a novel magnetically triggerable drug delivery device composed of a magnetic polydimethylsiloxane (PDMS) sponge cylinder and a 3D printed reservoir was designed, fabricated and characterized. This system can realize a switch between “on” and “off” state easily through the application of different magnetic fields and from different directions. Active and repeatable control of the localized drug release could be achieved by the utilization of magnetic fields to this device due to the shrinking extent of the macro-porous magnetic sponge inside. The switching “on” state of drug-releasing could be realized by the magnetic bar contacted with the side part of the device because the times at which 50%, 80% and 90% (w/w) of the drug were dissolved are observed to be 20, 55 and 140 min, respectively. In contrast, the switching “off” state of drug-releasing could be realized by the magnetic bar placed at the bottom of the device as only 10% (w/w) of the drug could be released within 12 h. An anti-cancer substance, 5-fluorouracil (FLU), was used as the model drug to illustrate the drug release behaviour of the device under different strengths of magnetic fields applied. In vitro cell culture studies also demonstrated that the stronger the magnetic field applied, the higher the drug release from the deformed PDMS sponge cylinder and thus more obvious inhibition effects on Trex cell growth. All results confirmed that the device can provide a safe, long-term, triggerable and reutilizable way for localized disease treatment such as cancer.

Galactosamine-Conjugating Zwitterionic Block Copolymer for Reduction-Responsive Release and Active Targeted Delivery of Doxorubicin to Hepatic Carcinoma Cells

Nanocarriers with integrated advantage, such as excellent stealth property, active targeting function, and rapid intracellular drug release, are significant for cancer treatment. Herein, a biodegradable zwitterionic triblock copolymer containing disulfide-linked poly-ε-caprolactone and polycarboxybetaine methacrylate (PCB-SS-PCL-SS-PCB) was first synthesized and then partly modified with galactosamine (GAL) for constructing polymeric micelle drug carrier with multifunctionality. Polymeric micelles showed ultralow protein absorption in serum and obvious reduction-responsiveness in the presence of glutathione, provided by the zwitterionic polymer shell and the disulfide bond, respectively. Furthermore, active targeting of the carrier to hepatic carcinoma cells was achieved via GAL ligands on PCB shells due to their specific binding to asialoglycoprotein receptors on the cell surface. As expected, in vivo competition studies demonstrated that doxorubicin- (DOX-) loaded GAL-modified micelles have better anticancer effect in hepatic tumor-bearing mice than free DOX and nontargetable micelles. As a result, this novel multifunctional carrier provides a valuable strategy to design promising anticancer drug delivery systems for liver cancer treatment.

Hyperthermia-Triggered On-Demand Biomimetic Nanocarriers for Synergetic Photothermal and Chemotherapy.

Nanoparticle‐based drug delivery systems with low side effects and enhanced efficacy hold great potential in the treatment of various malignancies, in particular cancer; however, they are still challenging to attain. Herein, an anticancer drug delivery system based on a cisplatin (CDDP) containing nanogel, functionalized with photothermal gold nanorods (GNRs) which are electrostatically decorated with doxorubicin (DOX) is reported. The nanoparticles are formed via the crosslinking reaction of hyaluronic acid with the ancillary anticarcinogen CDDP in the presence of DOX‐decorated GNRs. The nanogel is furthermore cloaked with a cancer cell membrane, and the resulting biomimetic nanocarrier (4T1‐HANG‐GNR‐DC) shows efficient accumulation by homologous tumor targeting and possesses long‐time retention in the tumor microenvironment. Upon near‐infrared (NIR) laser irradiation, in situ photothermal therapy is conducted which further induces hyperthermia‐triggered on‐demand drug release from the nanogel reservoir to achieve a synergistic photothermal/chemo‐therapy. The as‐developed biomimetic nanocarriers, with their dual‐drug delivery features, homotypic tumor targeting and synergetic photothermal/chemo‐therapy, show much promise as a potential platform for cancer treatment.

Comparison between novel star-like redox-sensitive amphiphilic block copolymer and its linear counterpart copolymer as nanocarriers for doxorubicin

Linear and star-like redox-sensitive amphiphilic block copolymers have been studied as anticancer drug delivery systems. However, few reports directly compared the properties of those two structures especially when they are used as nanocarriers for antitumor drugs. To address this, a novel star-like copolymer and its linear counterpart were synthesized with a hydrophobic/redox-responsive/hydrophilic structure. The overall molecular weight of the star-shaped copolymer was nearly equal to that of the linear counterpart. The star-like micelles exhibit size of 90 nm, which was smaller than that of linear copolymers (151.6 nm) and critical micelle concentration of 1 mg/L, which was lower than that of the linear micelles (8.9 mg/L). The disassembly behaviors and the redox-sensitivity of the nanoparticles to reductive stimuli of glutathione was evaluated from the changes of the micellar size and morphology. Furthermore, doxorubicin was physically loaded into the hydrophobic part of the copolymers. The drug-loading capacities in the star-like and linear micelles were 15.94 and 7.53 wt%, respectively. Drug release studies carried out at two different glutathione concentrations. A cytotoxicity study of the micelles was performed by MTT assay. The prepared star copolymer showed no significant toxicity against HDF cells while enhanced cytotoxicity of the DOX-loaded micelles against MCF-7 cells was observed. Therefore, developing sucrose-PCL-SS-PEG copolymer reported in this paper as an effective reduction-responsive carrier with excellent properties and cell biocompatibility is promising for the efficient intracellular delivery of hydrophobic chemotherapeutic drugs. This work also indicates that modification of the nanocarrier structure is a potential strategy for optimizing drug delivery.

Development of anticancer drug delivery system based on bone marrow-derived multipotent mesenchymal stem cells

Nowadays, a number of anticancer drugs are inadmissible due to their high toxicity. However, this matter can be addressed with improvements in pharmacokinetics, which would allow to generate localized high concentrations of antitumor drugs with minimal systemic toxicity. Such an effect can be achieved by utilizing high encapsulating properties of polyelectrolyte microcapsules with further modification of therapeutically relevant cells capable of pathotropism with these microcarriers. In the present work we studied the effect of drug carrier size on the migration properties of the human multipotent mesenchymal stromal cells (MMSCs). The conducted study included experiments on internalization efficiency, overall toxicity, migration index and speed in order to optimize the properties of the resulting cell-based drug delivery system. In addition to that the ability to directed migration of modified MMSCs along the gradient of tumor-associated chemokines (SDF-1) was explored using chemotaxis slides and 3D tumor tissue model. The results demonstrated that the combination of MMSCs and drug-loaded microcapsules resulted in a delivery system which possesses the ability to actively migrate into tumors, was not toxic towards cell carriers and overall had a therapeutic potential.

The assembly and antitumor activity of lycium barbarum polysaccharide-platinum-based conjugates

In this work, the new polysaccharide-platinum conjugates of 5-aminosalicylic acid modified lycium barbarum polysaccharide linking platinum compounds were designed in order to construct an anticancer metal drug delivery system. The multiple analysis methods were used to describe the chemical structure and physical properties of the polysaccharide-metal conjugates. The results showed that 5-aminosalicylic acid successfully acted as linker which was covalently bound between polysaccharide and platinum compound. The morphology and rheological properties of polysaccharide have been changed by the formation of conjugates, which exhibited certain inhibition specificity to A549 (human lung cancer cell line). The agarose gel electrophoresis and fluorescence microscopy results demonstrated that such conjugates promoted the unwinding of DNA and could significantly damage the nucleus of A549 cells. Cell cycle analyzing the Pt complex of conjugates could cause intracellular DNA damage and induced G2 phase arrest. So, polysaccharide-platinum conjugates might find a range of applications, for example in metal anticancer drug delivery.

Optimal adaptive intuitionistic fuzzy logic control of anti-cancer drug delivery systems

This paper introduces a new closed loop fuzzy logic controller for regulating intravenous anti-cancer drug delivery, based on intuitionistic fuzzy sets and invasive weed optimization (IWO) algorithm. The developed intuitionistic fuzzy logic controller (IFLC) contributes the following advancements: First, the parameters of IFLC are adaptive and optimally tuned to achieve desired drug concentrations at the tumor site, killing almost all cancer cells at the end of treatment time. Second, drug delivery constraints; namely allowed levels of the drug dose and cumulative toxicity are naturally implied in the design of the optimized IFLC to ensure the clinical safety of cancer patients. Finally, the developed drug delivery control system is robust to handle all possible physiological conditions during treatment such as patient sensitivity in response to toxicity. To test and validate the performance of developed IFLC, extensive simulation results and comparative evaluation have been done on a mathematical patient model. It is proved that our optimal adaptive IFLC is superior to other methods in previous related studies, resulting in the best performance index and the minimum number of remaining cancer cells of 27.63 and 0.806, respectively.

Modification of multiwalled carbon nanotubes with a ruthenium drug candidate-indazolium[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 ).

Functionalized carbon nanotubes are interesting, promising and unique delivery systems for anticancer drugs, which are now in the spotlight of nanomedicine. Connecting nanotubes with anticancer drugs or new compounds with anticancer properties aims at improving their stability, efficiency and reduces the toxic side effects of cancer treatment. In our research, we are interested in connecting functionalized MWCNTs-NH2 with [InH][trans-RuCl4(In)2], (KP1019) which is one of the most promising anticancer ruthenium(iii) drug candidates, known mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers. As a result of the amidation of MWCNTs (1), MWCNTs-NH2 (2) were obtained. Then, they were modified with [InH][RuCl4(In)2] (4) and the nanosystem [MWCNT-NH3+][RuCl4(In)2-] (3) was obtained. The characterization of the resulting products was performed using IR, Raman spectroscopy, thermal gravimetric, XRD, STEM-EDX, ESI-MS, ICP-MS, and XPS analyses. The cytotoxic activity has been tested on human lung carcinoma (A549), chronic myelogenous leukemia (K562) and human cervix carcinoma (HeLa) cells which showed the higher toxicity of the nanosystem than the ruthenium complex.

Supramolecular assembly of calix[4]resorcinarenes and chitosan for the design of drug nanocontainers with selective effects on diseased cells

Effective delivery systems for anticancer drugs were prepared through the self-assembly of calix[4]resorcinarenes and chitosan in an aqueous medium.

A stimuli-responsive anticancer drug delivery system with inherent antibacterial activities.

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.

Ultrasound-responsive highly biocompatible nanodroplets loaded with doxorubicin for tumor imaging and treatment in vivo

As an injectable anticancer drug delivery system, the biological safety of nanocarriers is the most important prerequisite for their clinical application. The objective of our study was to synthesize special ultrasound-responsive highly biocompatible chitosan nanodroplets (BCNDs), observe their spatiotemporally control the delivery of doxorubicin (DOX) in vivo. The experimental results showed that the BCNDs were successfully prepared with high biosafety in vivo and great ultrasound imaging ability. DOX-BCNDs promoted the anticancer effects of DOX in vivo and inhibited the development of tumors. They also reduced the side effects to the heart and kidneys. In conclusion, BCNDs are a new type of smart nanocarrier with high biocompatibility and efficacy have great potential to be used in the clinic.