Drug Delivery In Tumor Therapy Research Articles

Rod-shaped mesoporous silica nanoparticles reduce bufalin cardiotoxicity and inhibit colon cancer by blocking lipophagy

BackgroundBufalin (BA) is a potent traditional Chinese medicine derived from toad venom. It has shown significant antitumor activity, but its use is limited by cardiotoxicity, which necessitates innovative delivery methods, such as rod-shaped mesoporous silica nanoparticles (rMSNs). rMSNs have been extensively employed for reducing drug toxicity and for controlled or targeted drug delivery in tumor therapy. However, their potential in delivering BA has not been completely elucidated. Therefore, in this study, BA-loaded rMSNs (BA-rMSNs) were developed to investigate their potential and mechanism in impairing colon cancer cells.MethodsrMSNs were developed via the sol‒gel method. Drug encapsulation efficiency and loading capacity were determined to investigate the advantages of the rMSN in loading BA. The antiproliferative activities of the BA-rMSNs were investigated via 5-ethynyl-2’-deoxyuridine and CCK-8. To evaluate cell death, Annexin V-APC/PI apoptotic and calcein-AM/PI double staining were performed. Western blotting, oil red O staining, and Nile red solution were employed to determine the ability of BA-rMSNs to regulate lipophagy.ResultsThe diameter of the BA-rMSNs was approximately 60 nm. In vitro studies demonstrated that BA-rMSNs markedly inhibited HCT 116 and HT-29 cell proliferation and induced cell death. In vivo studies revealed that BA-rMSNs reduced BA-mediated cardiotoxicity and enhanced BA tumor targeting. Mechanistic studies revealed that BA-rMSNs blocked lipophagy.ConclusionsrMSNs reduced BA-mediated cardiotoxicity and impaired the growth of colon cancer cells. Mechanistically, antitumor activity depends on lipophagy.

Controlled Release of the Anticancer Drug Cyclophosphamide from a Superparamagnetic β-Cyclodextrin Nanosponge by Local Hyperthermia Generated by an Alternating Magnetic Field.

A β-cyclodextrin (β-CD) nanosponge (NS) was synthesized using diphenyl carbonate (DPC) as a cross-linker to encapsulate the antitumor drug cyclophosphamide (CYC), thus obtaining the NSs-CYC system. The formulation was then associated with magnetite nanoparticles (MNPs) to develop the MNPs-NSs-CYC ternary system. The formulations mentioned above were characterized to confirm the deposition of the MNPs onto the organic matrix and that the superparamagnetic nature of the MNPs was preserved upon association. The association of the MNPs with the NSs-drug complex was confirmed through field emission scanning electron microscopy, energy dispersive spectroscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, dynamic light scattering, ζ-potential, atomic absorption spectroscopy, X-ray powder diffraction, selected area electron diffraction, and vibrating-sample magnetometer. The superparamagnetic properties of the ternary system allowed the release of CYC by utilizing magnetic hyperthermia upon the exposure of an alternating magnetic field (AMF). The drug release experiments were carried out at different frequencies and intensities of the magnetic field, complying with the "Atkinson-Brezovich criterion". The assays in AMF showed the feasibility of release by controlling hyperthermia of the drug, finding that the most efficient conditions were F = 280 kHz, H = 15 mT, and a concentration of MNPs of 5 mg/mL. CYC release was temperature-dependent, facilitated by local heat generation through magnetic hyperthermia. This phenomenon was confirmed by DFT calculations. Furthermore, the ternary systems outperformed the formulations without MNPs regarding the amount of released drug. The MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays demonstrated that including CYC within the magnetic NS cavities reduced the effects on mitochondrial activity compared to those observed with the free drug. Finally, the magnetic hyperthermia assays showed that the tertiary system allows the generation of apoptosis in HeLa cells, demonstrating that the MNPs embedded maintain their properties to generate hyperthermia. These results suggest that using NSs associated with MNPs could be a potential tool for a controlled drug delivery in tumor therapy since the materials are efficient and potentially nontoxic.

Ultrasound triggered local sequential reactive oxygen species and nitric oxide release for enhanced cerasomal drug delivery

Liposomal drug delivery for tumor therapy was still suffered from low stability, limited delivering efficiency and poor tumor penetration, greatly compromising the therapeutic efficacy. Herein, a stable and ultrasound triggered cerasomal drug delivery system was developed by loading doxorubicin (DOX) into stable liposomal cerasome, which was self-assembled from cerasome-forming lipid (CFL), sonosensitizer of porphyrin lipid (PL), nitric oxide (NO) donor of DSPE-PEG2000-SNO and unsaturated phospholipids DOPC, resulting in DOX@PC-SNO with stable siloxane network and S-nitrosothiol on surface, sonosensitizer in lipid bilayer and DOX in the core. DOX@PC-SNO can prevent drug leakage during blood circulation and efficiently accumulate at the tumor site at 24 h post-injection, while controllably generate reactive oxygen species (ROS) upon local ultrasound irradiation on tumor, which can not only use for SDT, but also operate as a switch for on-demand controlled release of internal DOX and external NO, resulting in specific delivery and high penetration of chemotherapeutic drug into the deep tumor, thus greatly improved antitumor efficacy without observed side effects.

Preparation and properties of chitosan/dialdehyde sodium alginate/dopamine magnetic drug-delivery hydrogels

The proportion of individuals with bladder cancer has drastically increased, thereby rendering bladder cancer a focus of social concern and great challenge for human health management. Hydrogels with three-dimensional network structures have attracted considerable attention in the field of drug delivery for tumor therapy. Therefore, exploring hydrogel drug-delivery systems with excellent biocompatibility and targeting ability is a current research hotspot. Herein, a chitosan/dialdehyde sodium alginate/magnetic dopamine hydrogel was investigated for this purpose. The hydrogel was prepared from chitosan using sodium dialdehyde alginate and dopamine via grafting, crosslinking, and compounding. Furthermore, characterization of the product structure, targeted adhesion, and evaluation of drug delivery properties were performed. The prepared wall-adherent hydrogel materials exhibited excellent targeted drug-delivery and controlled-release properties. In addition, the effect of dopamine dosage on the performance of drug-loaded hydrogels was examined. In conclusion, the drug-delivery materials exhibited strong organ-wall adhesion, hydrogel properties, targeting ability, antibacterial and antimicrobial abilities (98%), and biocompatibility (99%). Based on these excellent properties, the constructed targeted hydrogels demonstrate considerable potential for drug delivery and bladder cancer treatment.

Injectable thermo-sensitive hydrogel loaded hollow copper sulfide nanoparticles for ROS burst in TME and effective tumor treatment.

Introduction: Lung cancer the most prevalent cause of cancer-related deaths, and current therapies lack sufficient specificity and efficacy. This study developed an injectable thermosensitive hydrogel harboring hollow copper sulfide nanoparticles and β-lapachone (Lap) (CLH) for lung tumor treatment. Methods: The hydrogel-encapsulated CLH system can remotely control the release of copper ions (Cu2+) and drugs using photothermal effects for non-invasive controlled-release drug delivery in tumor therapy. The released Cu2+ consumes the overexpressed GSH in TME and the generated Cu+ further exploits the TME characteristics to initiate nanocatalytic reactions for generating highly toxic hydroxyl radicals. In addition, in cancer cells overexpressing Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase 1 (NQO1), Lap can catalyze the generation of hydrogen peroxide (H2O2) through futile redox cycles. H2O2 is further converted into highly toxic hydroxyl radicals via the Fenton-like reaction, leading to a burst of reactive oxygen species in TME, which further enhances the therapeutic effect of chemokines. Results: Analysis of the antitumor efficacy in a subcutaneous A549 lung tumor model mice showed a significant delay in tumor growth and no systemic toxicity was detected. Discussion: In conclusion, we have established a CLH nanodrug platform that enables efficient lung tumor therapy through combined photothermal/chemodynamic therapy (CDT) treatment and self-supplying H2O2 to achieve cascade catalysis, leading to explosive amplification of oxidative stress.

β-Cyclodextrin-Based Nanosponges Inclusion Compounds Associated with Gold Nanorods for Potential NIR-II Drug Delivery.

This article describes the synthesis and characterization of two nanocarriers consisting of β-cyclodextrin-based nanosponges (NSs) inclusion compounds (ICs) and gold nanorods (AuNRs) for potential near-infrared II (NIR-II) drug-delivery systems. These nanosystems sought to improve the stability of two drugs, namely melphalan (MPH) and curcumin (CUR), and to trigger their photothermal release after a laser irradiation stimulus (1064 nm). The inclusion of MPH and CUR inside each NS was confirmed by field emission scanning electron microscopy (FE-SEM), Raman spectroscopy, Fourier transform infrared spectroscopy, (FT-IR) differential scanning calorimetry (DSC), transmission electron microscopy (TEM), and proton nuclear magnetic resonance (1H-NMR). Furthermore, the association of AuNRs with both ICs was confirmed by FE-SEM, energy-dispersive spectroscopy (EDS), TEM, dynamic light scattering (DLS), ζ-potential, and UV–Vis. Moreover, the irradiation assays demonstrated the feasibility of the controlled-photothermal drug release of both MPH and CUR in the second biological window (1000–1300 nm). Finally, MTS assays depicted that the inclusion of MPH and CUR inside the cavities of NSs reduces the effects on mitochondrial activity, as compared to that observed in the free drugs. Overall, these results suggest the use of NSs associated with AuNRs as a potential technology of controlled drug delivery in tumor therapy, since they are efficient and non-toxic materials.

Targeted delivery and enhanced uptake of chemo-photodynamic nanomedicine for melanoma treatment

Nanoparticles (NPs) modified with targeting ligands have often shown great potential in targeted drug delivery for tumor therapy. However, the clearance of NPs by the monocyte-phagocyte system (MPS) and the relatively low cellular uptake by tumor cells have significantly limited the antitumor efficacy of a variety of nanomedicines. Tumor microenvironment-mediated multidrug resistance also reduces the antitumor efficacy of internalized nanomedicines. Herein, we developed an innovative nanomedicine for combined chemo-photodynamic therapy of melanoma through targeted drug delivery and significantly improved the cellular uptake of the nanomedicine through the charge-reversal phenomenon. An amphiphilic platinum (IV)-polyethylenimine-chlorin e6 (Pt(IV)-PEI-Ce6) polymer was designed, prepared, and self-assembled into NPs (PPC) in an aqueous solution, and these NPs were subsequently coated with hyaluronic acid (HA) to afford PPC@HA. The surface-coated HA provided PPC with a negatively charged surface potential to reduce the clearance by the MPS during systemic circulation and enhanced the targeted delivery of PPC to CD44-overexpressing melanoma cells. Upon accumulation in the tumor site, hyaluronidase overexpressed in the tumor induced HA degradation to release the positively charged PPC, resulting in an increased internalization of PPC into tumor cells. Bioactive Pt(II) was released in response to high glutathione level in the tumor cells for effective tumor chemotherapy. Under 650 nm laser irradiation, Ce6 produced reactive oxygen species (ROS), thus driving photodynamic therapy. Finally, PPC@HA exhibited combined photodynamic-chemotherapeutic antitumor efficacy against the melanoma cells in mice. Statement of significanceTumors are one of the greatest threats to human health, and chemotherapy has been one of the most common therapeutic modalities for treating tumors; however, many challenges related to chemotherapy remain, such as low delivery efficiency, side effects, and unsatisfactory therapeutic efficacy. Nanomedicines modified with targeting ligands have often shown great potential in improving targeted drug delivery for tumor therapy; however, the clearance of nanomaterials by the monocyte-phagocyte system and the relatively low cellular uptake by tumor cells have significantly limited the antitumor efficacy of a variety of nanomedicines. Herein, we developed a novel charge-reversal-based, hyaluronic acid-coated, Pt(IV) prodrug and chlorin e6-based nanomedicine to improve systemic circulation and targeted accumulation of the nanomedicine in the tumor tissue and to enhance its intracellular uptake. This nanomedicine may provide a potential new platform to improve the drug content inside tumor cells and to effectively inhibit tumor growth through combined chemotherapy and photodynamic therapy.

CRPC Membrane-Camouflaged, Biomimetic Nanosystem for Overcoming Castration-Resistant Prostate Cancer by Cellular Vehicle-Aided Tumor Targeting.

Castration-resistant prostate cancer (CRPC) is the most common malignant tumor of the male urinary system. Nanodrug delivery systems (NDDS) have been widely applied in drug delivery for tumor therapy; however, nanotherapeutics encounter various biological barriers that prevent successful accumulation of drugs, specifically at diseased sites. Therefore, there is an urgent need to develop a CRPC-targeting nanocomposite with fine biocompatibility for penetrating various biological barriers, delivering sufficient drugs to the targeting site and improving therapeutic efficiency. In this work, CRPC cell membranes were firstly adapted as biomimetic vectors for the encapsulating PEG−PLGA polymer containing the chemotherapy drug docetaxel (DTX). The CRPC membrane-camouflaged nanoparticles can easily escape early recognition by the immune system, penetrate the extracellular barrier, and evade clearance by the circulatory system. In addition to the characteristics of traditional nanoparticles, the CRPC cell membrane contains an arsenal of highly specific homotypic moieties that can be used to recognize the same cancer cell types and increase the targeted drug delivery of DTX. In vivo fluorescence and radionuclide dual-model imaging were fulfilled by decorating the biomimetic nanosystem with near-infrared dye and isotope, which validated the homotypic targeting property offered by the CRPC cell membrane coating. Importantly, remarkably improved therapeutic efficacy was achieved in a mice model bearing CRPC tumors. This homologous cell membrane enabled an efficient drug delivery strategy and enlightened a new pathway for the clinical application of tumor chemotherapy drugs in the future.

Chitosan and fullerene hybrid hydrogel for drug delivery system with enhanced antitumor cell effects

Fullerene is a spherical hollow structure composed of carbon atoms. It has emerged in the new development of numerous fullerene-based compounds with a variety of biological targets such as anticancer, cytoprotection, tissue regeneration, and controlled drug delivery. Because of its biodegradable property of chitosan hydrogels, fullerine can function as a drug delivery system for implants with optimal degradation profiles that result in the proper rates of drug release. In this study, a chitosan-fullerene hybrid hydrogel was fabricated, and chemical and biological tests were performed to characterize it. We have shown that the incorpration of fullerene into the hydrogel decreased the degradation and swelling rate of the hydrogel. A rheology test showed that the addition of fullerene increased the elastic modulus of the hydrogel. Chitosan hydrogel containing fullerene reduced the releasing rate of methotrexate (MTX) loaded in the hydrogel. A cell viability assay showed that fullerene in the hydrogel was not toxic to the cultured cells. The fullerene in the chitosan hydrogel significantly enhanced the anti-tumor cell effect. This study implies that the combined application of fullerene and chitosan hydrogel is a promising strategy for drug delivery in tumor therapy.

Bioscaffold-based study of glioblastoma cell behavior and drug delivery for tumor therapy

Glioblastoma multiforme (GBM) is a severe form of brain cancer with an average five-year survival rate of 6.7%. Current treatment strategies include surgical resection of the tumor area and lining the lesion site with therapeutics, which offer only a moderate impact on increasing survival rates. Drug-testing models based on the monolayer cell culture method may partially explain the lack of advancement in effective GBM treatment, because this model is limited in its ability to show heterogeneous cell-cell and cell-environment interactions as tumor cells in the in vivo state. The development of bioscaffold-based culture models is an important improvement in GBM research, preclinical trials, and targeted drug testing, through better mimicking of the heterogeneity of tumor environmental conditions. A major hurdle towards better GBM outcomes is in delivering medication across the blood-brain barrier (BBB), which normally prevents the crossing of materials into the treatment site. The delivery of therapeutics using bioscaffolds is a potential means of overcoming the BBB and could potentially facilitate long-lasting drug release. A number of natural and synthetic materials have been studied for their biodegradability, toxicity, distribution, and pharmaceutical stability, which are needed to determine the overall effectiveness and safety of glioblastoma treatment. This review summarizes advancements in the research of bioscaffold-based GBM cell growth systems and the potential of using bioscaffolds as a carrier for drug delivery.

Captopril improves tumor nanomedicine delivery by increasing tumor blood perfusion and enlarging endothelial gaps in tumor blood vessels

Poor tumor perfusion and unfavorable vessel permeability compromise nanomedicine drug delivery to tumors. Captopril dilates blood vessels, reducing blood pressure clinically and bradykinin, as the downstream signaling moiety of captopril, is capable of dilating blood vessels and effectively increasing vessel permeability. The hypothesis behind this study was that captopril can dilate tumor blood vessels, improving tumor perfusion and simultaneously enlarge the endothelial gaps of tumor vessels, therefore enhancing nanomedicine drug delivery for tumor therapy. Using the U87 tumor xenograft with abundant blood vessels as the tumor model, tumor perfusion experiments were carried out using laser Doppler imaging and lectin-labeling experiments. A single treatment of captopril at a dose of 100 mg/kg significantly increased the percentage of functional vessels in tumor tissues and improved tumor blood perfusion. Scanning electron microscopy of tumor vessels also indicated that the endothelial gaps of tumor vessels were enlarged after captopril treatment. Immunofluorescence-staining of tumor slices demonstrated that captopril significantly increased bradykinin expression, possibly explaining tumor perfusion improvements and endothelial gap enlargement. Additionally, imaging in vivo, imaging ex vivo and nanoparticle distribution in tumor slices indicated that after a single treatment with captopril, the accumulation of 115-nm nanoparticles in tumors had increased 2.81-fold with a more homogeneous distribution pattern in comparison to non-captopril treated controls. Finally, pharmacodynamics experiments demonstrated that captopril combined with paclitaxel-loaded nanoparticles resulted in the greatest tumor shrinkage and the most extensive necrosis in tumor tissues among all treatment groups. Taken together, the data from the present study suggest a novel strategy for improving tumor perfusion and enlarging blood vessel permeability simultaneously in order to improve nanomedicine delivery for tumor therapy. As captopril has already been extensively used clinically, such a strategy has great therapeutic potential.

Biomacromolecule/lipid hybrid nanoparticles for controlled delivery of sorafenib in targeting hepatocellular carcinoma therapy.

Hybrids composed of various materials are highly versatile for drug delivery in tumor therapy including hepatocellular carcinoma. Herein, a sorafenib (SF)-loaded biomacromolecule hyaluronic acid (HA)/lipid hybrid nanoparticles (HA/SF-cLNS) were developed for targeting drug delivery. In vitro assays determined HA/SF-cLNS release behavior, enzymatic degradation, uptake and cytotoxicity. H22-bearing liver cancer xenograft murine models were used to evaluate the biodistribution and therapeutic efficacy in vivo. HA/SF-cLNS could be disassembled and drug was released in response to hyaluronidase. In vivo imaging results demonstrated HA/cLNS could enhance drug accumulation at tumor site. Meanwhile, HA/SF-cLNS exhibited improved antitumor efficacy in vitro and in vivo. HA/SF-cLNS demonstrated the potential to enhance antitumor efficacy of SF.

Formation and characterization of β-cyclodextrin (β-CD) - polyethyleneglycol (PEG) - polyethyleneimine (PEI) coated Fe3O4 nanoparticles for loading and releasing 5-Fluorouracil drug.

In this work, β-cyclodextrin (β-CD) - polyethyleneglycol (PEG) - polyethyleneimine (PEI) coated iron oxide nanoparticles (Fe3O4-β-CD-PEG-PEI) were developed as drug carriers for drug delivery applications. The 5- Fluorouracil (5-FU) was chosen as model drug molecule. The developed nanoparticles (Fe3O4-β-CD-PEG-PEI) were characterized by various techniques such as Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), Scanning electron microscopy (SEM), transmission electron microscopy (TEM) and vibrating sample magnetometry (VSM). The average particles size range of 5-FU loaded Fe3O4-β-CD, Fe3O4-β-CD-PEG and Fe3O4-β-CD-PEG-PEI nanoparticles were from 151 to 300nm and zeta potential value of nanoparticles were from -43mV to -20mV as measured using Malvern Zetasizer. Finally, encapsulation efficiency (EE), loading capacity (LC) and in-vitro drug release performance of 5-FU drug loaded Fe3O4-β-CD, Fe3O4-β-CD-PEG and Fe3O4-β-CD-PEG-PEI nanoparticles was evaluated by UV-vis spectroscopy. In-vitro cytotoxicity tests investigated by MTT assay indicate that 5-FU loaded Fe3O4-β-CD-PEG-PEI nanoparticles were toxic to cancer cells and non-toxic to normal cells. The in-vitro release behavior of 5-FU from drug (5-FU) loaded Fe3O4-β-CD-PEG-PEI composite at different pH values and temperature was studied. It was found that 5-FU was released faster in pH 6.8 than in the acidic mediums (pH 1.2), and the released quantity was higher. Therefore, the newly prepared Fe3O4-β-CD-PEG-PEI carrier exhibits a promising potential capability for anticancer drug delivery in tumor therapy.

Deposition of gadolinium onto the shell structure of micelles for integrated magnetic resonance imaging and robust drug delivery systems.

Selective deposition of Gd(iii) ions onto the shell structure of complex micelles was achieved to yield Gd decorated hybrid micelles for integrated magnetic resonance imaging and drug delivery. The complex micelles were engineered by the hydrophilic-hydrophobic self-assembly of two kinds of amphiphilic polymers, pluronic F127 and a peptide-amphiphile (PA), via a facile, environmentally benign strategy. These core-shell complex micelles provide a robust multifunctional platform for theranostic applications. The hydrophobic core of micelles allows us to compartmentalize anti-cancer drugs, while the shell structure with a mixed poly(ethylene-oxide) (PEO) and peptide composition provides chelation capacity for the MRI contrast agent Gd(iii). The nanoscaled hybrid micelles are not only developed to address the challenges of small molecular Gd(iii)-chelates, but also be integrated with the capability of anticancer drug delivery for tumor therapy. More importantly, a synergy effect was observed such that the coordination effect of Gd(iii) with the shell enhanced the micellar stability and retarded the DOX release behavior. In vitro and in vivo experiments of MRI contrast enhancement and therapy clearly evidenced that the DOX loaded hybrid micelles can serve as efficient theranostic agents.

A hybrid actuated microrobot using an electromagnetic field and flagellated bacteria for tumor-targeting therapy.

In this paper, we propose a new concept for a hybrid actuated microrobot for tumor-targeting therapy. For drug delivery in tumor therapy, various electromagnetic actuated microrobot systems have been studied. In addition, bacteria-based microrobot (so-called bacteriobot), which use tumor targeting and the therapeutic function of the bacteria, has also been proposed for solid tumor therapy. Compared with bacteriobot, electromagnetic actuated microrobot has larger driving force and locomotive controllability due to their position recognition and magnetic field control. However, because electromagnetic actuated microrobot does not have self-tumor targeting, they need to be controlled by an external magnetic field. In contrast, the bacteriobot uses tumor targeting and the bacteria's own motility, and can exhibit self-targeting performance at solid tumors. However, because the propulsion forces of the bacteria are too small, it is very difficult for bacteriobot to track a tumor in a vessel with a large bloodstream. Therefore, we propose a hybrid actuated microrobot combined with electromagnetic actuation in large blood vessels with a macro range and bacterial actuation in small vessels with a micro range. In addition, the proposed microrobot consists of biodegradable and biocompatible microbeads in which the drugs and magnetic particles can be encapsulated; the bacteria can be attached to the surface of the microbeads and propel the microrobot. We carried out macro-manipulation of the hybrid actuated microrobot along a desired path through electromagnetic field control and the micro-manipulation of the hybrid actuated microrobot toward a chemical attractant through the chemotaxis of the bacteria. For the validation of the hybrid actuation of the microrobot, we fabricated a hydrogel microfluidic channel that can generate a chemical gradient. Finally, we evaluated the motility performance of the hybrid actuated microrobot in the hydrogel microfluidic channel. We expect that the hybrid actuated microrobot will be utilized for tumor targeting and therapy in future.

Magnetothermally responsive star-block copolymeric micelles for controlled drug delivery and enhanced thermo-chemotherapy

Magnetothermally responsive drug-loaded micelles were designed and prepared for cancer therapy. These specially designed micelles are composed of the thermo-responsive star-block copolymer poly(ε-caprolactone)-block-poly(2-(2-methoxyethoxy)ethyl methacrylate-co-oligo(ethylene glycol)methacrylate) and Mn, Zn doped ferrite magnetic nanoparticles (MZF-MNPs). The thermo-responses of 6sPCL-b-P(MEO2MA-co-OEGMA) copolymers were shown to be dependent on the MEO2MA to OEGMA ratio. The lower critical solution temperature (LCST) of the star-block copolymers was controlled at 43 °C by adjusting the feed molar ratios of MEO2MA/OEGMA at 92 : 8. With the anti-tumor drug doxorubicin (DOX) self-assembling into the carrier system, the thermo-responsive micelles exhibited excellent temperature-triggered drug release behavior. In vitro cytotoxicity results showed high biocompatibility of the polymer micelles. Efficient cellular proliferation inhibition by the drug-loaded micelles was found on the HepG2 cells under different treatments. The thermo-responsive polymer micelles are promising for controlled drug delivery in tumor therapy under an alternating magnetic field.

Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery.

A novel amphiphilic triblock pH-sensitive poly(β-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-g-MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation–deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX) was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE-g-MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy.

Controlled release of doxorubicin from graphene oxide based charge-reversal nanocarrier

A number of anticancer drugs, such as doxorubicin (DOX), operate only after being transported into the nucleus of cancer cells. Thus it is essential for the drug carriers to effectively release the anticancer drugs into the cytoplasm of cancer cells and make them move to nucleus freely. Herein, a pH-responsive charge-reversal polyelectrolyte and integrin αⅤβ3 mono-antibody functionalized graphene oxide (GO) complex is constituted as a nanocarrier for targeted delivery and controlled release of DOX into cancer cells. The DOX loading and releasing in vitro demonstrates that this nanocarrier cannot only load DOX with high efficiency, but also effectively release it under mild acidic pH stimulation. Cellular toxicity assay, confocal laser scanning microscopy and flow cytometer analysis results together confirm that with the targeting nanocarrier, DOX can be selectively transported into the targeted cancer cells. Then they will be effectively released from the nanocarriers in cytoplasm and moved into the nucleus subsequently, stimulating by charge-reverse of the polyelectrolyte in acidic intracellular compartments. The effective delivery and release of the anticancer drugs into nucleus of the targeted cancer cells will lead to a high therapeutic efficiency. Hence, such a targeting nanocarrier prepared from GO and charge-reversal polyelectrolytes is likely to be an available candidate for targeted drug delivery in tumor therapy.

Study of glycol chitosan-carboxymethyl β-cyclodextrins as anticancer drugs carrier

Efficient target delivery system for insoluble anticancer drugs to increase the intracellular drug concentration has become a focus in cancer therapy. Herein, glycol chitosan-carboxymethyl β-cyclodextrins (G-chitosan-CM-dextrins) was synthesized for delivering different hydrophobic anticancer drugs. Surface plasmon resonance and UV–vis spectroscopy results showed that all the three anticancer drugs (5-fluorouracil, doxorubicin, and vinblastine) could be successfully loaded into the cavities of the covalently linked CM-dextrins. Moreover, the free carboxymethyl groups could enhance the binding interactions between the covalently linked CM-dextrins and anticancer drugs. Release behaviors with pH changes of the three drugs were also explored, result showed different drugs would be released by different ways, as for doxorubicin, pH sensitive release has been realized. The obtained G-chitosan-CM-dextrins carrier has both mucoadhesive property of G-chitosan and hydrophobic cavities of β-cyclodextrins. Therefore, the new synthesized G-chitosan-CM-dextrins carrier exhibits a promising potential capability for anticancer drug delivery in tumor therapy.

Anti-tumor activity of paclitaxel through dual-targeting carrier of cyclic RGD and transferrin conjugated hyperbranched copolymer nanoparticles

Targeted delivery strategies are becoming increasingly important. Herein, a novel hyperbranched amphiphilic poly[(amine-ester)-co-(d,l-lactide)]/1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine copolymer (HPAE-co-PLA/DPPE) with RGD peptide (cRGDfK) and transferrin (Tf) on the periphery was synthesized and used to prepare paclitaxel-loaded nanoparticles (NPs) for dual-targeting chemotherapy. These NPs show satisfactory size distribution, high encapsulated efficiency and a pH-dependent release profile. The intrinsic fluorescence of the hyperbranched copolymer renders the detection and tracking of NPs in vitro and in vivo conveniently. In vitro cytotoxicity studies proved that the presence of cRGDfK enhanced the cytotoxic efficiency by 10 folds in ανβ3 integrin over-expressed human umbilical vein endothelial cells, while Tf improved cytotoxicity by 2 folds in Tf receptor over-expressed human cervical carcinoma cells. The drug-loaded NPs can be efficiently transported into the vascular endothelial cells and the target tumor cells. These results indicate that the cRGDfK and Tf decorated HPAE-co-PLA/DPPE could deliver chemotherapies specifically inside the cell via receptor-mediated endocytosis with greater efficacy. Therefore, such a fluorescent nanocarrier prepared from non-cytotoxic and biodegradable polymers is promising for drug delivery in tumor therapy.