Release Of Anticancer Drugs Research Articles

Enzymatic synthesis of PEG-poly(amine-co-thioether esters) as highly efficient pH and ROS dual-responsive nanocarriers for anticancer drug delivery.

Novel multifunctional drug nanocarriers have been successfully fabricated from a new type of enzymatically synthesized, biodegradable block copolymer, PEG-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-thiodipropionate) (PEG-PPMT), which was responsive to tumor-relevant acidic pH (5.0-6.5) and intracellular reactive oxygen species (ROS) of tumor cells. The PEG-PPMT copolymers could self-assemble to form nano-scaled particles in aqueous solutions, which are stable in physiological solutions, but swell substantially upon reducing the pH from 7.4 to 5.0 and/or in the presence of ROS on account of the protonation of the tertiary amino groups and oxidation of the thioether groups, causing a hydrophobic to hydrophilic transition in the nanoparticle cores. Consistently, docetaxel (DTX) encapsulated in PEG-PPMT nanoparticles can be triggered in a synergistic manner by acidic pH and a high-ROS environment in tumor cells to release the hydrophobic drug at accelerated rates for efficient tumor growth inhibition. In particular, DTX encapsulated in PEG-PPMT-11% PDL and PEG-PPMT-28% PDL nanoparticles exhibit extraordinarily enhanced potency (95% and 93% tumor-inhibiting efficiency, respectively) in inhibiting the growth of ROS-rich CT-26 tumors xenografted in mice. Importantly, biosafety analyses show minimal toxicity of DTX-loaded PEG-PPMT nanoparticles toward normal organs including liver and kidneys during the in vivo antitumor treatments. These results demonstrate that the PEG-PPMT nanoparticles are promising pH and ROS dual-responsive multifunctional nanocarriers for tumor site specific, controlled release of anticancer drugs to treat ROS-rich tumors.

Programmed supramolecular nanoassemblies: enhanced serum stability and cell specific triggered release of anti-cancer drugs

A bolaamphiphilic cross-linked nanoassembly endowed with pH responsive degradation features has been designed and fabricated for stable noncovalent guest encapsulation and controlled release. The self-assembled bolaamphiphile is utilized to prepare cross-linked nanoassemblies to further stabilize the noncovalent guest encapsulation at a concentration below its critical aggregation concentration (CAC) in a large volume of water or serum for drug delivery applications. Thus, this system can simultaneously address premature drug release and safety issues. The nanoassemblies integrated with a β-thioester linker, which can be hydrolyzed selectively under mildly acidic conditions (pH ∼ 5.3) at a slow rate, thus enable controlled release of guest molecules. Biological evaluation revealed that doxorubicin loaded cross-linked nanoassemblies (CNs–DOX) are nontoxic to normal cells such as HEK-293 or PBMC, but in contrast, showed a robust apoptotic effect on colon cancer cells, HCT-116, indicating excellent specificity. Thus, the fabrication reproducibility, robust stability, triggered drug release and cell selective toxicity behavior make this small molecular system very promising in the field of chemotherapeutic applications.

Preparation of Responsive Carbon Dots for Anticancer Drug Delivery.

Fluorescent carbon dots (CDs) have been extensively utilized as responsive drug nanocarriers to deliver anticancer agents, owing to their facile preparation, excellent water solubility, good photostability, and high quantum yield. Herein, we summarize the protocols for the synthesis and application of responsive CDs toward anticancer drug delivery both in vitro and in vivo. Specially, this chapter includes the preparation and structural characterization of CDs and anticancer prodrug-loaded CDs, in vitro anticancer drug release, in vitro and in vivo fluorescence imaging, and toxicity studies.

Multifunctional magnetic nanoparticles for controlled release of anticancer drug, breast cancer cell targeting, MRI/fluorescence imaging, and anticancer drug delivery

Anti-cancer drug, free base doxorubicin hydrophobic (DOX-HCL) or paclitaxel (PTX), EPPT-FITC and, oleic acid-Fe3O4 nanoparticles (OA-Fe3O4) were incorporated into the tree block PLA-PEG-PLA copolymer. Properties of these nanoparticles, such as structural, magnetic, drug-loading efficiency, drug release kinetics and in vitro cytotoxicity were evaluated in vitro for controlled drug release and targeted drug delivery. Transmission electron microscope (TEM) and dynamic light scattering (DLS) results showed that BMNPs/EPPT/drug have spherical morphology with diameters in the range of 179–203 nm. The release rate of drug from multifunctional nanoparticles was significantly increased with decreasing of the pH. Cytotoxicity assays with drug-loaded nanoparticles were performed in vitro using normal and breast tumor cell lines (MCF12-A and MCF-7 cells respectively), and in vivo evaluating antitumor activity in immunocompetent BABL/c mice. Neither in vitro nor in vivo cytotoxicity was observed for blank nanoparticles. In vitro cytotoxicity assay indicated that the IC50 values of BMNPs/EPPT/drug were significantly lower compared to other nanoparticles. Selectivity of interaction between receptors in breast cancer cells and EPPT peptides of multifunctional nanoparticles resulted in a significant decrease in cell viability in BMNPs/EPPT compared with other nanoparticles. Furthermore, drug-loaded BMNPs/EPPT produced significant decrease of tumor volumes compared with other nanoparticles.

Peptide functionalized dual-responsive chitosan nanoparticles for controlled drug delivery to breast cancer cells

In this work, we report K237-peptide functionalized hybrid chitosan/poly(N-isopropylacrylamide) nanoparticles (NPs) loaded with paclitaxel (PTX), and explore these for the active targeting and effective treatment of KDR/Flk-1-overexpressing human breast cancer. We find that the peptide-functionalized NPs have favorable pH and temperature-sensitive characteristics, with more rapid drug release at the slighly acidic pH of the tumor microenvironment, and accelerated release at higher temperatures. MTT assays showed that the K237-conjugated NPs could more effectively inhibit breast cancer cell growth than peptide-free NPs. Confocal microscopy experiments showed that the NPs could precisely target MDA-MB-231 human breast cancer cells, which over-express the KDR/Flk-1 protein. This shows that the enhanced efficacy of the K237-functionalized NPs in preventing cell proliferation is likely to be associated with specific recognition of KDR/Flk-1 on the cells by the K237 peptide. These results indicate that the peptide functionalized NPs have potential applications for targeted delivery and the controlled release of anticancer drugs.

Anionic carboxymethylagarose-based pH-responsive smart superabsorbent hydrogels for controlled release of anticancer drug

Herein, we demonstrate the preparation of superabsorbent hydrogel (CMA-g-PAm) materials using anionic and cold water soluble carboxymethyagarose (CMA, a seaweed polysaccharide-based derivative) with polyacrylamide (PAm) through rapid microwave assisted grafting technique. The successful fabrication of CMA-g-PAm was verified by FT-IR, SEM, XRD, TGA and CHN analyzer. Effects of initiator, crosslinker, and monomer on the swelling behavior and grafting parameters have been thoroughly investigated. Moreover, the swelling behavior of the resulting hydrogels was systematically studied, and the results suggested they exhibit excellent pH and salt responsive behavior. The drug delivery application of thus fabricated hydrogel was further evaluated using doxorubicin (Dox) as a model drug to explore its possible applications. Release study results revealed that Dox release was significantly accelerated with decrease in pH from 7.4 to 5.0. Toxicity assays confirmed that the blank hydrogels had negligible toxicity to normal cells (VERO), whereas the Dox-loaded hydrogels remained high in cytotoxicity for A549 and Hep-G2 cancer cells. All of these attributes implied that the new proposed hydrogel (HK11) serves as potential drug delivery platforms for cancer therapy.

Preparation and characterization of folic acid functionalized bioactive glass for targeted delivery and sustained release of methotrexate.

We have successfully prepared a novel targeted drug delivery system, composed of folic acid (FA) as targeting molecule, methotrexate (MTX) as anticancer drug, and bioactive glass (BG) as carrier. The BG nanoparticles were synthesized by sol-gel method with the dodecylamine as template. The surface of BG nanoparticles was grafted with amino groups by (3-aminopropyl) triethoxysilane, then, FA and MTX were covalently conjugated to the surface of modified BG through amidation reaction, so FA functionalized BG (BG-FA) and targeted drug delivery system (MTX-BG-FA) were prepared. The physicochemical properties of BG, BG-NH2 , and BG-FA were characterized by various methods, such as X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, ultraviolet-visible, and so on. Moreover, the drug release results showed that the MTX-BG-FA had sustained release property because of the peptide bond between MTX and BG-FA. And the cytocompatibility evaluation demonstrated that the BG and BG-FA were biocompatible and BG-FA even could promote cell proliferation, while the MTX-BG-FA had high cytotoxicity owning to the sustained release of anticancer drug. From the above, it could be concluded that MTX-BG-FA could kill tumor cells targetedly and sustainedly, which made it a good cancer targeted therapy material. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 319-329, 2019.

Magnetic DNA Nanogels for Targeting Delivery and Multistimuli-Triggered Release of Anticancer Drugs

DNA polymeric materials possess many unique properties such as programmable molecular sequences and excellent biocompatibility and have demonstrated a high potential in an assortment of biomedical applications. Herein, a magnetic DNA nanogel is constructed, aiming at the applications of targeting drug delivery and triggered drug release. Centering on magnetic nanoparticles, a DNA nanogel layer is synthesized via rolling circle amplification, which equips abundant sites for the loading of anticancer drugs. Guided by an external magnetic field, the magnetic DNA nanogel can target tumor cells efficiently. Moreover, DNA nanogel is responsive to multistimuli including temperature, pH, and nuclease, enabling a controlled release of anticancer drugs. Our system achieves magnet-controlled delivery and stimuli-triggered drug release and provides a new strategy for the development of precision medicine.

Injectable Hydrogel of Vitamin B9 for the Controlled Release of Both Hydrophilic and Hydrophobic Anticancer Drugs.

Folic acid (FA), vitamin B9 , is a good receptor of drugs triggering cellular uptake via endocytosis. FA is sparingly soluble in water. Herein, a new approach for the formation of FA hydrogel by the hydrolysis of glucono-δ-lactone in PBS buffer under physiological conditions has been reported. The gel has a fibrillar network morphology attributable to intermolecular H-bonding and π-stacking interactions. The thixotropic property of the gel is used for the encapsulation of both hydrophilic [doxorubicin (DOX)] and hydrophobic [camptothecin (CPT)] drugs. The loading of DOX and CPT into the gel is attributed to the H-bonding interaction between FA and drugs. The release of DOX is sustainable at pH 4 and 7, and the Peppas model indicates that at pH 7 the diffusion of the drug is Fickian but it is non-Fickian at pH 4. The release of CPT is monitored by fluorescence spectroscopy, which also corroborates the combined release of both drugs. The metylthiazolyldiphenyltetrazolium bromide assay of FA hydrogel demonstrates nontoxic behavior and that the cytotoxicity of the DOX-loaded FA hydrogel is higher than that of pure DOX, with a minimal effect on normal cells.

Squaric Acid-Coumarin-Chlorambucil: Photoresponsive Single-Component Fluorescent Organic Nanoconjugates for Self-Monitored Therapeutics

In this paper, we have developed photoresponsive fluorescent organic nanoconjugates based on a single-component system for effective cancer treatment by a synergistic combination of photodynamic therapy (PDT) and chemotherapy. Our single-component system was synthesized by coupling the squaric acid and the coumarin-chlorambucil conjugate. Next, multifunctional squaric acid-coumarin-chlorambucil (Sq-Cou-Cbl) nanoconjugates were prepared by “simple reprecipitation technique”. The unique properties of the newly designed Sq-Cou-Cbl nanoconjugates are (i) a phototrigger for controlled anticancer drug (chlorambucil) release and a photosensitizer for PDT upon visible light irradiation (ii) cellular imaging and self-monitoring of the drug release by a noninvasive fluorescent technique and (iii) PDT activity of the released photoproduct thereby resulting in the improved therapeutic efficiency. Further, in vitro studies showed that Sq-Cou-Cbl nanoconjugates exhibited an enhanced anticancer activity by synergistic c...

Synthesis of stimuli-responsive chitosan nanocomposites via RAFT copolymerization for doxorubicin delivery

In this study, a unique stimuli-responsive hydrogel nanocomposite was prepared via surface reversible addition fragmentation chain transfer (RAFT) copolymerization of acrylic acid and N‑isopropyl acrylamide onto chitosan and subsequent in situ synthesis of magnetic Fe3O4 nanoparticles. In the next age, the structure and morphology of synthetic magnetic nanocomposite were characterized by FTIR, XRD, VSM, SEM, and TEM techniques. The modified hydrogel nanocomposite was employed as an excellent carrier for controlled releasing of anticancer drug doxorubicin (DOX). The results indicated that the maximum of DOX loading efficiency of nanocomposite was 89%. Notably, in vitro drug release studies showed that DOX was released in a sustained-release manner for the nanocomposites. From the results of in vitro release studies, dual temperature and pH responsiveness of the nanocomposite was demonstrated, and 82% of total DOX was released from the hydrogel within 2 days. Due to the unique structures and properties, the chitosan-based nanocomposite may be utilized as a promising drug carrier for controlled and sustained release of anticancer drugs.

Cover Feature: Improvement of Anticancer Drug Release by Cobalt Ferrite Magnetic Nanoparticles through Combined pH and Temperature Responsive Technique (ChemPhysChem 21/2018)

Cover Feature: Improvement of Anticancer Drug Release by Cobalt Ferrite Magnetic Nanoparticles through Combined pH and Temperature Responsive Technique (ChemPhysChem 21/2018)

Glycol chitin/PAA hydrogel composite incorporated bio-functionalized PLGA microspheres intended for sustained release of anticancer drug through intratumoral injection

A novel anti-hepatoma drug release hybrid system is prepared by using poly(acrylic acid) (PAA) and glycol chitin as substrate in combination with Paclitaxel (PTX)-loaded bio-biofunctionalized poly(lactic-co-glycolic acid) (PLGA) micro-particles, which is intended for cancer therapy through intratumoral injection. The rheological behavior of glycol chitin (7 wt%)/PAA illustrates that it has low gelling temperature (i.e. 17 °C at pH 7.56) which ensures that the formulation turns to gel at physiological condition. The gelling time of glycol chitin/PAA is 16 minutes at 25 °C and 3 minutes at 37 °C, which is convenient for doctors to inject the in-situ gel formulations into the tumor location of patient. The drug release behavior reveals that the system can dramatically postpone the drug release. The cell viability test indicates that the micro-particles with drug still have 62% inhibitory effect on hepatoma cells in the fourteenth day after combing with hydrogel. This system is a promising approach for cancer therapy through intratumoral injection of in-situ gel formulations to extend retention time at tumor sites.

Improvement of Anticancer Drug Release by Cobalt Ferrite Magnetic Nanoparticles through Combined pH and Temperature Responsive Technique.

This work reports the application possibilities of cobalt ferrite (CoFe2 O4 ) magnetic nanoparticles (CFMNPs) for stimuli responsive drug delivery by magnetic field induced hyperthermia technique. The CFMNPs were characterized by X-ray diffraction (XRD) with Rietveld analysis, field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), selected area electron diffraction (SAED), fourier transform infrared spectroscopy (FTIR), thermogravimetry and differential thermal analysis (TG-DTA), vibrating sample magnetometer (VSM) and superconducting quantum interference device (SQUID) magnetometry. Particles were functionalized with folic acid (FA) by EDC-NHS coupling method and loaded with anticancer drug (DOX) by activated folate ions. The drug release was studied as a function of time at two different temperatures (37 and 44 °C) under pH∼5.5 and 7. It was observed that the drug release rate is higher at elevated temperature (44 °C) and acidic pH∼5.5 as compared to our normal body temperature and pH∼7 using the CFMNPs. This way, we have developed a pH and temperature sensitive drug delivery system, which can release the anticancer drug selectively by applying ac magnetic field as under ac field particles are heated up. We have calculated the amount of heat generation by the particles around 1.67 °C per second at ∼600 Hz frequency. By MTT assay on cancer cell and normal cell, it was confirmed that CFMNPs are nontoxic and biocompatible in nature, which assures that our synthesized particles can be successfully used in localized cancer treatment by stimuli responsive drug delivery technique.

Reduction-responsive amphiphilic star copolymers with long-chain hyperbranched poly(ε-caprolactone) core and disulfide bonds for trigger release of anticancer drugs

In this contribution, the reduction-responsive star copolymers with long-chain hyperbranched poly(ε-caprolactone) (PCL) (HyperMacs) core and disulfide bonds were synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The HyperMacs core was constructed from disulfide-containing AB2-type PCL macromonomers, which possesses length-adjustable chain segments between branching points, large cavities, low degree of crystallinity, and reduction-responsivity. After grafted with poly(ethylene glycol), the reduction-responsive star copolymers can self-assemble into micelles in aqueous solution. The obtained micelles exhibited much lower critical micelle concentration (CMC) than their linear analogues. The reduction-responsivity from disulfide bonds makes them a promising carrier candidate for trigger release of anticancer drugs. The in vitro release results confirmed that their doxorubicin (DOX)-loaded micelles exhibited desirable reduction-triggered release performance. The cellular proliferation inhibition against HepG2 cells demonstrated that the DOX-loaded micelles showed a comparable anticancer activity with free DOX. Therefore, it can be expected that the reduction-sensitive micelles may serve as smart vehicles for intracellular delivery of anti-cancer drugs in tumour therapy.

Metal-Organic Framework-Based Nanoplatform for Intracellular Environment-Responsive Endo/Lysosomal Escape and Enhanced Cancer Therapy.

Nowadays, efficient endo/lysosomal escape and the subsequent release of drugs into the cytosol are the major obstacles for nanoplatform-based cancer therapy. Herein, we first report a metal-organic framework-based nanoplatform (doxorubicin@ZIF-8@AS1411) for intracellular environment-responsive endo/lysosomal escape and enhanced cancer therapy. In our system, the nanoplatform was first targeted toward the cancer cells. Then, it was entrapped in endo/lysosomes, where pH-responsive decomposition occurred and abundant Zn ions were released. The released Zn ions could induce an influx of counterions, promote reactive singlet oxygen (ROS) generation to rupture the endo/lysosomal membrane, and accelerate the release of anticancer drugs in the cytosol. Finally, the released drugs and the generation of ROS could synergistically enhance cancer therapy. With excellent biocompatibility, effective endo/lysosomal escape, and enhanced therapeutic effect, the novel drug delivery systems are supposed to become a promising anticancer agent for cancer therapy and bring more opportunities for biomedical application.

Enhanced anticancer effect of MAP30-S3 by cyclosproin A through endosomal escape.

Cyclosporin A (CsA) is a calcium antagonist and can enhance the efficacy of some protein drugs, but its mechanism remains unknown. In this study, MAP30, a ribosome-inactivating protein reported to have apoptotic effects on cancer cells, was fused with S3, an epidermal growth factor receptor (EGFR)-targeting peptide. In addition, CsA was used to investigate whether it can further promote the apoptotic effects of S3 fused MAP30 (MAP30-S3). Our result showed that the internalization of FITC-labeled MAP30-S3 was increased significantly by S3 in HeLa cells. Unexpectedly, MAP30-S3 only showed a minor decrease in the viability of EGFR-overexpressing cancer cells, including HeLa, SMMC-7721, and MGC803 (IC50>5 μmol/l). However, 2 μmol/l CsA significantly increased the cytotoxicity of MAP30-S3, especially for HeLa cells (IC50=40.3 nmol/l). In comparison, CsA did not further decrease the cytotoxicity of MAP30-S3 on MRC-5, an EGFR low-expressing cell line from normal lung tissue, indicating that CsA did not affect the cancer-targeting specificity of MAP30-S3. Our results also showed that CsA further increased the apoptotic activity of MAP30-S3 in HeLa cells. CsA could promote the endosomal escape of FITC-MAP30-S3 with a diffused pattern in the cytoplasm. Five endocytic inhibitors were used to investigate the cellular uptake mechanism of MAP30-S3, and the results showed that the endosomal escape-enhancing effect of CsA on MAP30-S3 may be associated with the clathrin-dependent endocytic pathways. Our study suggested that CsA could be a novel endosomal escape enhancer to potentiate the intracellular release of anticancer protein drugs, resulting in their improved therapeutic efficacy.

PH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogels via aza‐michael addition for anticancer drug delivery

ABSTRACTA pH and reduction dual‐stimuli‐responsive PEGDA/PAMAM injectable network hydrogel containing “acetals” as pH‐sensitive groups and “disulfides” as reducible linkages was designed and synthesized via aza‐Michael addition reaction between PAMAM and PEGDA diacrylates. The pore size and swelling ratio of hydrogels was varied from 14 ± 3 to 19 ± 4 μm and 214 ± 13 to 300 ± 19 μm, respectively, with varying ethylene glycol repeating units in diacrylates. The swelling ratio of PEGDA/PAMAM network hydrogel increased with increase in the molecular weight of PEG and with decrease in pH. The presence of different cationizable amino‐functionalities in PEGDA/PAMAM network hydrogel helped to enhance the swelling ability of hydrogel under the acidic conditions. The continuous increase in metabolically active live HeLa cells with time in MTT assay implied biocompatibility/noncytotoxicity of the synthesized PEGDA/PAMAM injectable network hydrogel. Furthermore, the prepared PEGDA/PAMAM hydrogel showed higher degradation at lower pH and at higher concentration of DTT. The burst release of doxorubicin from PEGDA/PAMAM hydrogel under the environment of the lower pH and in presence of DTT compared to the release at normal physiological pH and in absence of DTT suggested the potential ability of this model hydrogel system for targeted and selective anticancer drug release at tumor tissues. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 2080–2095

Regulating the anticancer drug release rate by controlling the composition of waterborne polyurethane

Water-based polyurethane (WPU) is an alternate green pathway which poses a minimum threat to the environment. In WPU, hard segments (HS) and soft segments (SS) have a pronounced effect on the physicochemical properties of the polymer. Therefore, the effect of a change in the size of HS and SS on the properties of WPU were studied in detailed. Size of HS and SS were varied by increasing the aliphatic chain length of chain extender and PEG respectively. WPU were prepared with different compositions and the effect on thermal stability, mechanical properties, chemical resistance, biodegradation, biocompatibility, the degree of swelling, and drug release rate was studied. For this purpose, two series of WPU were synthesized to study structure–property relationship. The first series of WPU were synthesized by varying molecular weights of polyethylene diol (PEG, Mn = 650, 1250, 1500, and 2000 g/mol) and the second series was synthesized by using diamine chain extenders (CE) with increasing aliphatic chain. All WPU did not show any cytotoxicity as evaluated by MTT assay and are designated as safe biomaterials.

Light-stimulus Dual-drug Responsive Nanoparticles for Photoactivated Therapy Using Mesoporous Silica Nanospheres

Photoactivated therapy is an exciting new method of cancer treatment. A new light-stimulus dual-drug responsive nanoparticles based on mesoporous silica nanoparticles(MSN) were developed to control cellular anticancer drug release. The prepared Curcumin(Cur)-loaded nanoparticles MSN-Pt-PEG@Cur[PEG=poly(ethylene glycol)] could be activated by photostimulation to generate reactive oxygen species(ROS) from Cur and Pt(II) from Pt(IV), respectively. Compared with free anti-cancer drugs’ chemotherapy and single photoactivated therapy, the prepared MSN-Pt-PEG@Cur displayed increased cytotoxicity. Therefore, the strategy of light-stimulus dual-drug responsive nanoparticles is a promising approach to photoactivated therapy.