Efficient Doxorubicin Research Articles

Synthesis of self-assemble pH-responsive cyclodextrin block copolymer for sustained anticancer drug delivery

Well-defined pH-responsive poly(e-caprolactone)-graft-β-cyclodextrin-graft-poly(2-(dimethylamino)ethylmethacrylate)-co-poly(ethylene glycol) methacrylate amphiphilic copolymers (PCL-g-β-CD-g-P(DMAEMA-co-PEGMA)) were synthesized using a combination of atom transfer radical polymerization (ATRP), ring opening polymerization (ROP) and “click” chemistry. Successful synthesis of polymers was confirmed by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H-NMR), and gel permeation chromatography (GPC). Then, the polymers could selfassemble into micelles in aqueous solution, which was demonstrated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The pH-responsive self-assembly behavior of these copolymers in water was investigated at different pH values of 7.4 and 5.0 for controlled doxorubicin (DOX) release, and these results revealed that the release rate of DOX could be effectively controlled by altering the pH, and the release of drug loading efficiency (DLE) was up to 88% (W/W). CCK-8 assays showed that the copolymers had low toxicity and possessed good biodegradability and biocompatibility, whereas the DOX-loaded micelles remained with high cytotoxicity for HeLa cells. Moreover, confocal laser scanning microscopy (CLSM) images revealed that polymeric micelles could actively target the tumor site and the efficient intracellular DOX release from polymeric micelles toward the tumor cells further confirmed the anti-tumor effect. The DOX-loaded micelles could easily enter the cells and produce the desired pharmacological action and minimize the side effect of free DOX. These results successfully indicated that pH-responsive polymeric micelles could be potential hydrophobic drug delivery carriers for cancer targeting therapy with sustained release.

Grafted copolymer micelles with pH triggered charge reversibility for efficient doxorubicin delivery

ABSTRACTThe instability and premature charge reversal at pH 7.4 have become the major limitations of charge‐reversal delivery systems. To address this problem, graft copolymer of poly(butylene succinate)‐g‐cysteamine‐bi‐poly(ethylene glycol) (PBS‐g‐CS‐bi‐PEG, bi = benzoic imine bond) was designed and synthesized through facile thiol‐ene click reaction and subsequent Schiff's base reaction. Then, PBS‐g‐CS‐bi‐PEG and carboxyl‐functionalized polyester of poly(butylene succinate)‐g‐3‐mercaptopropionic acid (PBS‐g‐MPA) co‐assemble in aqueous solution to give PEG shell‐sheddable charge‐reversal micelles with sizes of 85–103 nm and low polydispersity of 0.11–0.12. Interestingly, the PBS‐g‐MPA/CS‐bi‐PEG micelles could sensitively and arbitrarily switch their surface charges between negative and positive status in response to pH fluctuation via reversible protonation and deprotonation of carboxyl and amino groups, which endows the desired stability of co‐assembly micelles either during long‐term storage or under physiological conditions. Doxorubicin (DOX) was loaded into PBS‐g‐MPA/CS‐bi‐PEG micelles with a high drug‐loading content of 10.2% and entrapment efficiency of 68% as a result of electrostatic attraction. In vitro release studies revealed that less than 25% of DOX was released within 24 h in the environment mimicking the physiological condition, whereas up to 81% of DOX was released in 24 h under weak‐acid condition resembling microenvironment in endosome/lysosome. In vitro cytotoxicity study suggested that blank PBS‐g‐MPA/CS‐bi‐PEG micelles possessed excellent biocompatibility, while DOX‐loaded PBS‐g‐MPA/CS‐bi‐PEG micelles showed significant cytotoxicity with half‐maximal inhibitory concentration (IC50) of 1.55–1.67 μg DOX equiv/mL. This study provides a facile and effective approach for the preparation of novel charge‐reversal micelles with switchable charges and excellent biocompatibility, which are highly promising to be used as safe nanocarriers for efficient intracellular drug delivery. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 2036–2046

ROS-Switchable Polymeric Nanoplatform with Stimuli-Responsive Release for Active Targeted Drug Delivery to Breast Cancer.

Tumor microenvironment plays a vital role in the process of tumor development, proliferation, invasion, and metastasis. It is well acknowledged that reduction in pH, reactive oxygen species (ROS), and increased level of glucose transporter 1 (GLUT1) have become featured intracellular and extracellular biochemical markers of cancer owing to oncogenic transformation and abnormal metabolism. To establish a distinctive drug delivery system directed against the tumor microenvironment features, we develop a newly engineered polymeric nanoplatform for efficient doxorubicin (DOX) delivery with reduced systemic toxicity and high antitumor efficiency. A thioketal cross-linker is used to improve the formulation's stability during circulation and to foster quick intracellular drug release in response to tumor's ROS potential. Furthermore, the low drug loading efficiency of conventional micelles is ameliorated in this polymeric nanoplatform via a drug-conjugation strategy with an acid-labile chemical bond. The optimized formulation, MPLs-sB-DOX micelles, possesses a high drug-loading efficiency (31%) within nanosize diameter (37.8 nm). In addition, this formulation shows significant improvement in the pharmacokinetics and biodistribution profiles with a 2.69-fold increase of tumor accumulation, while with largely reduced systemic toxicity in comparison with free DOX. With advantages of efficient cellular uptake, preferential tumor accumulation, and controlled release behaviors, MPLs-sB-DOX micelles demonstrate good tumor-targeting ability with reduced systemic toxicity, proving to be a promising formulation for breast cancer therapy.

Biocompatible Reduction and pH Dual-Responsive Core Cross-Linked Micelles Based on Multifunctional Amphiphilic Linear-Hyperbranched Copolymer for Controlled Anticancer Drug Delivery.

Novel strategy has been developed for fabricating the biocompatible reduction and pH dual-responsive core cross-linked (CCL) micelles as drug delivery system (DDS) for the controlled anticancer drug delivery, via the atom transfer radical polymerization (ATRP) of tert-butyl acrylate (tBA) with N,N'-bis(acryloyl)cystamine (BACy) as cross-linker and a multifunctional amphiphilic linear-hyperbranched copolymer as macroinitiator, which was synthesized via the self-condensing vinyl copolymerization (SCVCP) of tBA and p-chloromethylstyrene (CMS) with a poly(ethylene glycol) (PEG) based initiator (mPEG-Br). The hydrolyzed core cross-linked (HCCL) micelles were obtained as DDS for doxorubicin (DOX) by hydrolysis the tBA units into acrylic acid (AA) ones. The in vitro release performance showed that higher GSH concentration and/or lower pH value would lead to a faster and more efficient DOX release, meaning their reduction and pH dual-responsiveness. Therefore, the proposed HCCL micelles are expected to be potential anticancer drug-carriers for tumor microenvironment responsive controlled delivery.

Template-etching route to construct uniform rattle-type Fe3O4@SiO2 hollow microspheres as drug carrier

Template-etching strategy was put forward to synthesize rattle-type magnetic silica (Fe3O4@SiO2) hollow microspheres in a controlled way. During the experiment, monodisperse Fe2O3 microspheres were fabricated as physical template to generate uniform Fe2O3@SiO2 with controlled shell thicknesses through sol-gel method, and the subsequent Fe2O3 template etching process created variable space between Fe2O3 core and SiO2 shell, and the final calcination process transformed rattle-type Fe2O3@SiO2 hollow microspheres into corresponding Fe3O4@SiO2 product in hydrogen/nitrogen atmosphere. Compared with traditional physical template, here template-etching synthesis of rattle-type hollow microspheres saved the insertion of middle shells and their removal, which simplified the synthesis process with controllable core size and shell thickness. The rattle-type Fe3O4@SiO2 hollow microspheres as drug carrier show efficient doxorubicin (DOX) loading, and the release rate of DOX loaded the rattle-type Fe3O4@SiO2 hollow microspheres exhibit a surprising shell-thickness-dependent and a pH responsive drug release features. Additionally, MTT assays in HeLa cells demonstrated that the Fe3O4@SiO2 nanocarriers were non-toxic even at the concentration of 250µgmL−1 for 48h. Thus, our results revealed that the Fe3O4@SiO2-DOX could play an important role in the development of intracellular delivery nanodevices for cancer therapy.

Dual-Responsive Bola-Type Supra-Amphiphile Constructed from Water-Soluble Pillar[5]arene and Naphthalimide-Containing Amphiphile for Intracellular Drug Delivery.

Supramolecular construction of multistimuli platform for drug delivery is a challenging task. In this work, a pH and GSH (glutathione) dual-responsive bola-type supramolecular amphiphile was successfully fabricated by the complexation between a water-soluble pillar[5]arene (WP5) and a bolaform naphthalimide guest (G) in water. The resulting bola-type amphiphile further self-assembled into supramolecular binary vesicles, which could be disassembled by low pH, a high-GSH-concentration environment, or both. Furthermore, the results of drug loading and releasing tests showed that doxorubicin (DOX), the hydrophobic anticancer drug, could be successfully encapsulated into the Stern region of the obtained supramolecular vesicles and generated the DOX-loaded vesicles with good drug-loading efficiency. Moreover, the obtained DOX-loaded vesicles displayed efficient and rapid DOX release at a simulated tumor microenvironment with low-pH or excess-GSH conditions or both. Significantly, cytotoxicity experiments revealed that the DOX-loaded supramolecular vesicles could obviously improve the anticancer efficiency of free DOX for tumor cells while remarkably reducing its side effects for normal cells. In vitro cellular uptake and subcellular localization assays further proved that these smart drug nanovehicles, entering cancer cells mainly via endocytosis, could cause excellent drug accumulation in cancer cells. The present study provides a successful example with which to rational design an effective bola-type stimuli-responsive supramolecular nanocarrier, which might have wide potential applications in the construction of various controlled drug-delivery systems.

High efficient anti-cancer drug delivery systems using tea polyphenols reduced and functionalized graphene oxide.

Targeted drug delivery is urgently needed for cancer therapy, and green synthesis is important for the biomedical use of drug delivery systems in the human body. In this work, we report two targeted delivery systems for anticancer drugs based on tea polyphenol functionalized and reduced graphene oxide (TPGs). The obtained TPGs demonstrated an efficient doxorubicin loading capacity as high as 3.430 × 106 mg g-1 and 3.932 × 104 mg g-1, and exhibited pH-triggered release. Furthermore, the kinetic models, adsorption isotherms, and possible loading mechanisms were investigated in details. Compared to TPG1 and free doxorubicin, TPG2 is biocompatible to normal cells even at high concentrations and promotes tumor cells death by delivering the doxorubicin mainly to the nuclei. These results were confirmed using cell viability tests and confocal laser microscopy. Moreover, apoptosis tests showed that the mechanism of cancer cell death induced by TPG1 and TPG2 might follow the similar mechanisms. Taken together, these results demonstrate that TPGs provide a multifunctional drug delivery system with a greater loading capacity and pH-sensitive drug release for enhanced cancer therapy. The high drug payload capability and enhanced antitumor efficacy demonstrate that we developed systems are promising for various biomedical applications and cancer therapy.

Synthesis and evaluation of pH-sensitive, self-assembled chitosan-based nanoparticles as efficient doxorubicin carriers.

A novel pH-responsive polymer based on amphiphilic N-acetyl histidine and arginine-grafted chitosan was synthesized using N-acetyl histidine as hydrophobic segment and arginine as hydrophilic segment by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-mediated coupling reactions as anticancer drug delivery system for doxorubicin. The structure of the synthesized polymer was confirmed by Fourier transform infrared and 1H nuclear magnetic resonance analysis. Due to self-association behavior, N-acetyl histidine and arginine-grafted chitosan structured nanoparticles with in size range of 204 nm. N-acetyl histidine and arginine-grafted chitosan with different substitution degree of N-acetyl histidine were initially prepared and characterized. The critical micelle concentration decreased with increasing substitution degree of N-acetyl histidine. Furthermore, N-acetyl histidine and arginine-grafted chitosan nanoparticles exhibited an acidic pH-triggered aggregation and disassembling nature. The doxorubicin-encapsulated nanoparticles based on synthesized conjugate ( N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles) showed a sustained drug release pattern, which could be hastened under acidic pH conditions but delayed with increasing substitution degree of N-acetyl histidine. Anticancer effects demonstrated that N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles could suppress both sensitive and resistant human breast tumor cell line (MCF-7) efficiently in a dose- and time-dependent pattern. Confocal microscopy results evidenced increased cellular uptake and enhanced retention of the synthesized nanoparticles in drug-resistant cells demonstrating better efficacy of nanoparticles over native doxorubicin. These results suggest that N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles might be promising carriers for delivery of hydrophobic drug doxorubicin against drug-resistant tumors.

PH-Responsive Triblock Copolymeric Micelles Decorated with a Cell-Penetrating Peptide Provide Efficient Doxorubicin Delivery.

This study developed novel triblock pH-responsive polymeric micelles (PMs) using cholic acid-polyethyleneimine-poly-l-arginine (CA-PEI-pArg) copolymers. PEI provided pH sensitivity, while the hydrophilic cell-penetrating pArg peptide promoted cellular PM internalization. The copolymers self-assembled into PMs in aqueous solution at above the critical micelle concentration (2.98 × 10−7 M) and encapsulated doxorubicin in the core region, with a 34.2% (w/w) entrapment efficiency. PMs showed pH-dependent swelling, increasing in size by almost sevenfold from pH 7.4 to 5.0. Doxorubicin release was pH-dependent, with about 65% released at pH 5.0, and 32% at pH 7.4. Cellular uptake, assessed by confocal microscopy and flow cytometry, was enhanced by using doxorubicin-loaded CA-PEI-pArg PMs, as compared to free doxorubicin and DOX-loaded CA-PEI PMs. Moreover, 24-h incubation of these PMs with a human breast cancer cell line produced greater cytotoxicity than free doxorubicin. These results indicate that pH-responsive CA-PEI-pArg micelles could provide a versatile delivery system for targeted cancer therapy using hydrophobic drugs.Graphical Graphical of CA-PEI-pArg polymeric micelles as a pH-responsive drug delivery system.

Modular Design and Facile Synthesis of Enzyme-Responsive Peptide-Linked Block Copolymers for Efficient Delivery of Doxorubicin.

Construction of efficient doxorubicin (DOX) delivery systems addressing a cascade of physiological barriers remains a great challenge for better therapeutic efficacy of tumors. Herein, we design well-defined enzyme-responsive peptide-linked block copolymer, PEG-GPLGVRGDG-P(BLA-co-Asp) [PEG and P(BLA-co-Asp) are poly(ethylene glycol) and partially hydrolyzed poly(β-benzyl l-aspartate) (PBLA), respectively] (P3), with modular functionality for efficient delivery of DOX. The block copolymers were successfully obtained via click reaction to introduce peptide (alkynyl-GPLGVRGDG) into the end of PEG for initiating ring-opening polymerization of β-benzyl l-aspartate N-carboxyanhydride (BLA-NCA) by terminal amino groups followed by partial hydrolysis of PBLA segments. P3 micelle was demonstrated to encapsulate DOX efficiently through synergistic effect of benzyl group-based hydrophobic and carboxyl moiety-based electrostatic interactions. Effective matrix metalloproteinase-2 (MMP-2)-triggered cleavage of peptide for dePEGylation of P3 micelles was confirmed and residual RGD ligands were retained on the surfaces. Against HT1080 cells overexpressing MMP-2, DOX-loaded P3 micelles showed approximately 4-fold increase of the cellular internalization amount as compared with free DOX and half maximal inhibitory concentration (IC50) value of DOX-loaded P3 micelles was determined to be 0.38 μg/mL compared with 0.66 μg/mL of free DOX due to MMP-triggered dePEGylation, RGD-mediated cellular uptake, and rapid drug release inside cells. Binding and penetration evaluation toward HT1080 multicellular tumor spheroids (MCTs) confirmed high affinity and deep penetration of P3 micelles in tumor tissues. This modular design of enzyme-responsive block copolymers represents an effective strategy to construct intelligent drug delivery vehicles for addressing a cascade of delivery barriers.

Facile Synthesis of Reductively Degradable Biopolymers Using Cystamine Diisocyanate as a Coupling Agent.

Reductively degradable biopolymers have emerged as a unique class of smart biomedical materials. Here, a functional coupling agent, cystamine diisocyanate (CDI), was designed to offer a facile access to reductively degradable biopolymers via polycondensation with various diols. CDI was readily obtained with a decent yield of 46% by reacting cystamine dihydrochloride with triphosgene. The polycondensation of oligo(ethylene glycol) diol (Mn = 0.4 or 1.5 kg/mol) or oligo(ε-caprolactone) diol (Mn = 0.53 kg/mol) with CDI in N,N-dimethylformamide at 60 °C using dibutyltin dilaurate as a catalyst afforded reductively degradable poly(ethylene glycol) (SSPEG, Mn = 6.2-76.8 kg/mol) or poly(ε-caprolactone) (SSPCL, Mn = 6.8-16.3 kg/mol), in which molecular weights were well controlled by diol/CDI molar ratios. Moreover, PEG-SSPCL-PEG triblock copolymers could be readily prepared by reacting dihydroxyl-terminated SSPCL with PEG-isocyanate derivative. PEG-SSPCL-PEG with an Mn of 5.0-16.3-5.0 kg/mol formed small-sized micelles with an average diameter of about 85 nm in PB buffer. The in vitro release studies using doxorubicin (DOX) as a model drug showed that, in sharp contrast to reduction-insensitive PEG-PCL(HDI)-PEG controls, drug release from PEG-SSPCL-PEG micelles was fast and nearly complete in 24 h under a reductive condition containing 10 mM glutathione. The confocal microscopy experiments in drug-resistant MCF-7 cells (MCF-7/ADR) displayed efficient cytoplasmic DOX release from PEG-SSPCL-PEG micelles. MTT assays revealed that DOX-loaded PEG-SSPCL-PEG micelles were much more potent against MCF-7/ADR cells than reduction-insensitive PEG-PCL(HDI)-PEG controls (IC50: 6.3 vs 55.4 μg/mL). It should further be noted that blank PEG-SSPCL-PEG micelles were noncytotoxic up to a tested concentration of 1 mg/mL. Hence, cystamine diisocyanate appears to be an innovative coupling agent that facilitates versatile synthesis of biocompatible and reductively degradable biopolymers.

Mixed Micelles for Targeted and Efficient Doxorubicin Delivery to Multidrug-Resistant Breast Cancer Cells.

For efficient treatment of multidrug-resistance (MDR) breast cancer cells, design of biocompatible mixed micelles with diverse functional moieties and superior stability is needed for targeted delivery of chemical drugs. In this study, polypropylene glycol (PPG)-grafted hyaluronic acid (HA) copolymers (PPG-g-HA) are used to make mixed micelles with different amounts of pluronic L61, named PPG-g-HA/L61 micelles. Optimized PPG-g-HA/L61 micelles with 3% pluronic L61 exhibit great stability in aqueous solution, superior biocompatibility, and significantly increased uptake into MCF-7 MDR cells via HA-CD44-specific interactions when compared to free doxorubicin (DOX) and other types of micelles. In addition, DOX in PPG-g-HA/L61 micelles with 3% pluronic L61 have toxicity in MCF-7 MDR cells but significantly lower toxicity in fibroblast L929 cells compared to free DOX. Thus, PPG-g-HA/L61 micelles with 3% pluronic L61 content can be a promising nanocarrier to overcome MDR and release DOX in a hyaluronidase-sensitive manner without any toxicity to normal cells.

Amphiphilic Diblock Terpolymer PMAgala-b-P(MAA-co-MAChol)s with Attached Galactose and Cholesterol Grafts and Their Intracellular pH-Responsive Doxorubicin Delivery.

In this work, a series of diblock terpolymer poly(6-O-methacryloyl-D-galactopyranose)-b-poly(methacrylic acid-co-6-cholesteryloxy hexyl methacrylate) amphiphiles bearing attached galactose and cholesterol grafts denoted as the PMAgala-b-P(MAA-co-MAChol)s were designed and prepared, and these terpolymer amphiphiles were further exploited as a platform for intracellular doxorubicin (DOX) delivery. First, employing a sequential RAFT strategy with preliminarily synthesized poly(6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose) (PMAIpGP) macro-RAFT initiator and a successive trifluoroacetic acid (TFA)-mediated deprotection, a series of amphiphilic diblock terpolymer PMAgala-b-P(MAA-co-MAChol)s were prepared, and were further characterized by NMR, Fourier transform infrared spectrometer (FTIR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and a dynamic contact angle testing instrument (DCAT). In aqueous media, spontaneous micellization of the synthesized diblock terpolymer amphiphiles were continuously examined by critical micellization concentration assay, dynamic light scattering (DLS), and transmission electron microscopy (TEM), and the efficacies of DOX loading by these copolymer micelles were investigated along with the complexed nanoparticle stability. Furthermore, in vitro DOX release of the drug-loaded terpolymer micelles were studied at 37 °C in buffer under various pH conditions, and cell toxicities of as-synthesized diblock amphiphiles were examined by MTT assay. Finally, with H1299 cells, intracellular DOX delivery and localization by the block amphiphile vectors were investigated by invert fluorescence microscopy. As a result, it was revealed that the random copolymerization of MAA and MAChol comonomers in the second block limited the formation of cholesterol liquid-crystal phase and enhanced DOX loading efficiency and complex nanoparticle stability, that ionic interactions between the DOX and MAA comonomer could be exploited to trigger efficient DOX release under acidic condition, and that the diblock terpolymer micellular vector could alter the DOX trafficking in cells. Hence, these suggest the pH-sensitive PMAgala-b-P(MAA-co-MAChol)s might be further exploited as a smart nanoplatform toward efficient antitumor drug delivery.

Multifunctional PLGA Nanobubbles as Theranostic Agents: Combining Doxorubicin and P-gp siRNA Co-Delivery Into Human Breast Cancer Cells and Ultrasound Cellular Imaging.

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. One of the effective approaches to overcome MDR is to use nanoparticle-mediated the gene silence of chemotherapeutic export proteins by RNA interference to increase drug accumulation in drug resistant cancer cells. In this work, a new co-delivery system, DOX-PLGA/PEI/P-gp shRNA nanobubbles (NBs) around 327 nm, to overcome doxorubicin (DOX) resistance in MCF-7 human breast cancer was designed and developed. Positively charged polyethylenimine (PEI) were modified onto the surface of DOX-PLGA NBs through DCC/NHS crosslinking, and could efficiently condense P-gp shRNA into DOX-PLGA/PEI NBs at vector/shRNA weight ratios of 70:1 and above. An in vitro release profile demonstrated an efficient DOX release (more than 80%) from DOX-PLGA/PEI NBs at pH 4.4, suggesting a pH-responsive drug release for the multifunctionalized NBs. Cellular experimental results further showed that DOX-PLGA/PEI/P-gp shRNA NBs could facilitate cellular uptake of DOX into cells and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The IC50 of DOX-PLGA NBs against MCF-7/ADR cells was 2-fold lower than that of free DOX. The increased cellular uptake and nuclear accumulation of DOX delivered by DOX-PLGA/PEI/P-gp shRNA NBs in MCF-7/ADR cells was confirmed by fluorescence microscopy and fluorescence spectrophotometry, and might be owning to the down-regulation of P-gp and reduced the efflux of DOX. The cellular uptake mechanism of DOX-PLGA/PEI/P-gp shRNA NBs indicated that the macropinocytosis was one of the pathways for the uptake of NBs by MCF-7/ADR cells, which was also an energy-dependent process. Furthermore, the in vitro cellular ultrasound imaging suggested that the employment of the DOX-PLGA/PEI/P-gp shRNA NBs could efficiently enhance ultrasound imaging of cancer cells. These results demonstrated that the developed DOX-PLGA/PEI/P-gp shRNA NBs is a potential, safe and efficient theranotic agent for cancer therapy and diagnostics.

Efficient Doxorubicin Delivery Using Deaggregated and Carboxylated Nanodiamonds for Cancer Cell Therapy

Efficient Doxorubicin Delivery Using Deaggregated and Carboxylated Nanodiamonds for Cancer Cell Therapy

Supramolecular Prodrug Micelles Constructed by Drug‐Drug Conjugate with Water Soluble Pillar[6]arene for Controllable and Rapid Drug Release

AbstractThe first attempt of constructing supramolecular prodrug micelles based on the host‐guest interaction between water‐soluble pillar[6]arene (WP6) and a novel doxorubicin (DOX)‐based drug‐drug conjugate (G) is reported, in which the drug‐drug conjugate is synthesized by conjugating anticancer drug DOX with another drug isoniazide via the acid‐cleavable hydrazone bond. The obtained WP6⊃G micelles are stable under physiological conditions, whereas the cumulative release of DOX is approximate to 100% within 30 min at pH 5.5 by simulating the endo‐lysosomal environment at 37°C. Therefore, this WP6‐based prodrug micelles can achieve efficient DOX accumulation in the acidic tumor cells within a short period of time, which is very important and valuable; meanwhile it can also reduce the unexpected premature burst release under physiological condition. Furthermore, cellular internalization and localization experiments demonstrated that these prodrug micelles enter cancer cells mainly via endocytosis and can lead to significant drug accumulation in SKOV3 cancer cells, implying its promising future for cancer therapy.

Supramolecular Nanoparticles Constructed by DOX-Based Prodrug with Water-Soluble Pillar[6]arene for Self-Catalyzed Rapid Drug Release

The constructing of novel supramolecular prodrug nanoparticles based on the host–guest interaction of water-soluble pillar[6]arene (WP6) and novel doxorubicin (DOX)-based prodrugs (G1 or G2) is reported, in which these two kinds of prodrugs are synthesized by conjugating DOX with a flexible alkyl chain or a short EGn chain via an acid-cleavable hydrazone bond. The obtained supramolecular nanoparticles are stable under physiological conditions, whereas the cumulative release of DOX is approximate to 100% within 30 min at pH 5.5 by simulating the endolysosomal environment at 37 °C. It is noteworthy that WP6 can efficiently catalyze the cleavage of hydrazone bond of the prodrug G1 or G2 via a favored intramolecular process under acidic conditions. Moreover, intracellular localization experiments demonstrated that these two nanoparticles, taken up by cancer cells via endocytosis, can lead to efficient DOX accumulation in SKOV3 cancer cells. Cytotoxicity experiments further suggest that these nanoparticles can efficiently inhibit the proliferation of cancer cells and exhibit potent antitumor activity.

Tailor-made magnetic nanocarriers with pH-induced charge reversal and pH-responsiveness to guide subcellular release of doxorubicin

A charge reversible, magnetic-targeted, and pH-responsive nano therapy system assembled from citraconic-modified dextran (Dex–COOH), glycine-stabilized superparamagnetic iron oxide nanoparticles (SPION–NH2), and doxorubicin (DOX) through electrostatic interaction was designed for delivering therapeutics to tumor cells. Dex–COOH was first synthesized to build the pH-sensitive citraconic amide bond and further render charge reversal upon the cleavage of the linkage. The SPION–NH2 anchored in the nanocarrier endows the carrier with magnetic migration. The vibrating sample magnetometer analysis exhibits the superparamagnetic behavior, and the magnetic saturation value is estimated to be 39.6 emu (g Fe)−1. The change of size and the reversal of zeta potential from negative to positive in acidic environment confirmed these expected responsibilities. The DOX-loaded nanocarriers contain DOX up to 13.0 wt%. An in vitro release profile demonstrated an efficient DOX release of 80 % at pH 5.0 while of 27 % at pH 6.8 and 13 % at pH 7.4, suggesting a pH-induced release mechanism. Microscopic images of Prussian blue staining, quantification of cellular iron and protein concentration displayed apparent iron uptake by HeLa cells. Confocal laser scanning microscopy observations revealed that the nanocarriers could efficiently deliver and release DOX into the nuclei of HeLa cells. MTT assays testified that DOX-loaded nanocarrier exhibited high anti-tumor activity with IC50 of 0.7 μg mL−1, while plain nanocarriers were practically non-toxic. This drug delivery system has shown the ability to improve the chemotherapeutic efficacy and to reduce the side effects, indicating great potential for delivery of drugs to the targeted sites in patients.

Encapsulation of anticancer drug by hydrogen-bonded multilayers of tannic acid

Tannic acid (TA)-based multilayer assemblies have attracted increasing interest for biomedical applications. Here we explore properties of TA-poly(N-vinylpyrrolidone) (TA-PVPON) hydrogen-bonded multilayers for drug encapsulation and long-term storage. We demonstrate that the small molecular weight anticancer drug, doxorubicin (DOX), can be successfully loaded into (TA-PVPON) capsules with high encapsulation efficiency. We have also found that the encapsulated DOX can be efficiently stored inside the capsules for the pH range from pH = 7.4 to pH = 5. We show that the chemical and functional stability of TA at neutral and basic pH values is achieved through complexation with PVPON. The UV-vis spectrophotometry and in situ ellipsometry analyses of the hydrogen bonding interactions between TA and PVPON at different pH values reveal pH-dependent behavior of TA-PVPON capsules for the pH range from pH = 7.4 to pH = 5. Increasing deposition pH value from pH = 5 to pH = 7.4 leads to a 2-fold decrease in capsule thickness. However, this trend is reversed when salt concentration of the deposition solutions is increased from 0.01 M to 0.1 M NaCl. We have also demonstrated that the permeability of (TA-PVPON) capsules prepared using low salt deposition conditions and pH = 7.4 can be increased 2-fold by exposure of the capsules to 0.1 M NaCl salt solutions at the same pH. Our work opens new perspectives for design of novel polymer carriers for controlled drug delivery in cancer therapy.

Molecular structural transformation regulated dynamic disordering of supramolecular vesicles as pH-responsive drug release systems

The spontaneous release of drug payloads in the whole body always results in the compromised drug bioavailability and ultimate therapeutic efficacy. To achieve enhanced therapeutic efficacy and reduced side effects, pH-responsive targeted drug delivery systems have been studied due to their enhanced tumor accumulation and controllable maximum drug release feature. The present study described a co-assembly constructed by a pH responsive molecule (i.e., malachite green carbinol base (MG)) and liposome for highly efficient doxorubicin (DOX) release in tumor cells (MG–DOX⊂L). The structural transformation of MG effectively regulates the drug release profile in acidic environment. The pH-responsive sensitivity of co-assembly can be fine-tuned by altering the mixing ratios of building blocks with pH responders (i.e., MG molecules). MG–DOX⊂L was beneficial for the DOX release at pH5.0 and showed a higher cytotoxicity in KB cells owing to the pH-responsive drug release in acidic organelles following endocytosis pathway. In vivo tumor targetability and growth inhibition were evaluated in KB cell-xenografted nude mice. We have demonstrated that effective tumor growth inhibition in vivo is attributed to the synergistic contributions from highly efficient cellular entry and responsive intracellular release of DOX from MG–DOX⊂L.