Anticancer Drug DOX Research Articles

Multi-Stimuli-Responsive and Cell Membrane Camouflaged Aggregation-Induced Emission Nanogels for Precise Chemo-photothermal Synergistic Therapy of Tumors.

Targeted and controllable drug release at lesion sites with the aid of visual navigation in real-time is of great significance for precise theranostics of cancers. Benefiting from the marvelous features (e.g., bright emission and phototheranostic effects in aggregates) of aggregation-induced emission (AIE) materials, constructing AIE-based multifunctional nanocarriers that act as all-arounders to integrate multimodalities for precise theranostics is highly desirable. Here, an intelligent nanoplatform (P-TN-Dox@CM) with homologous targeting, controllable drug release, and in vivo dual-modal imaging for precise chemo-photothermal synergistic therapy is proposed. AIE photothermic agent (TN) and anticancer drug (Dox) are encapsulated in thermo-/pH-responsive nanogels (PNA), and the tumor cell membranes are camouflaged onto the surface of nanogels. Active targeting can be realized through homologous effects derived from source tumor cell membranes, which advantageously elevates the specific drug delivery to tumor sites. After being engulfed into tumor cells, the nanogels exhibit a burst drug release at low pH. The near-infrared (NIR) photoinduced local hyperthermia can activate severe cytotoxicity and further accelerate drug release, thus generating enhanced synergistic chemo-photothermal therapy to thoroughly eradicate tumors. Moreover, P-TN-Dox@CM nanogels could achieve NIR-fluorescence/photothermal dual-modal imaging to monitor the dynamic distribution of therapeutics in real-time. This work highlights the great potential of smart P-TN-Dox@CM nanogels as a versatile nanoplatform to integrate multimodalities for precise chemo-photothermal synergistic therapy in combating cancers.

NIR light-activated upconversion POP nanofiber composite; an effective carrier for targeted photodynamic therapy and drug delivery

Covalently linked porous organic polymers featuring a large surface area, low toxicity, and excellent stability is an emerging class of porous material that has drawn immense attention in the area of cancer therapy. However, the development of NIR light excitable nanoscale POP with available surface functional groups for active cancer cell targeting is still a great promise for chemotherapy and PDT. Herein, we have fabricated folic acid (FA) encapsulated upconversion nanoparticle embedded porous organic polymeric nanofiber (POP nanofiber) composite (UCNPs@TPDABA@FA) for cell imaging, targeted drug delivery, and photodynamic therapy. PEI-coated upconversion nanoparticle is attached with imine linked –COOH functionalized POP nanofiber in a single step to achieve highly porous composite UCNPs@TPDABA. Then functionalized folic acid has been attached with the composite which effectively targets cancer cell A549. The composite delivers the anticancer drug DOX and shows significant results for in-vitro lung cancer treatment. Besides the fluorescence imaging property, UCNPs serve as FRET donor to the photosensitizer methylene blue and then generates ROS upon photoexcitation. ROS generation is also detected in A549 cancer cells. So, the smart composite UCNPs@TPDABA@FA could open a new door in serving as an effective carrier for chemotherapeutic drug and PDT.

Multi-stimuli responsive Cu-MOFs@Keratin drug delivery system for chemodynamic therapy.

Although the potential of metal-organic framework (MOF) nanoparticles as drug delivery systems (DDS) for cancer treatment has been established by numerous studies, their clinical applications are still limited due to relatively poor biocompatibility. We fabricated a multifunctional Cu-MOFs@Keratin DDS for loaded drug and chemodynamic therapy (CDT) against tumor cells. The Cu-MOFs core was prepared using a hydrothermal method, and then loaded with the anticancer drug DOX and wrapped in human hair keratin. The Cu-MOFs@Keratin was well characterized by transmission electron microscopy (TEM), fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and X-ray photoelectron spectroscopy (XPS). Characterization and pharmacokinetic studies of Cu-MOFs@Keratin were performed in vitro and in vivo. The keratin shell reduced the cytotoxicity and potential leakage of Cu-MOFs to normal cells, and allowed the drug-loaded nanoparticles to accumulate in the tumor tissues through enhanced permeability and retention effect (EPR). The particles entered the tumor cells via endocytosis and disintegrated under the stimulation of intracellular environment, thereby releasing DOX in a controlled manner. In addition, the Cu-MOFs produced hydroxyl radicals (·OH) by consuming presence of high intracellular levels of glutathione (GSH) and H2O2, which decreased the viability of the tumor cells.

Injectable “cocktail” hydrogel with dual‐stimuli‐responsive drug release, photothermal ablation, and drug‐antibody synergistic effect

AbstractThe combination of the first‐line standard chemotherapeutic drug doxorubicin hydrochloride (DOX) and the molecular‐targeted drug Herceptin (HCT) has emerged as a promising strategy for human epidermal growth receptor 2 (HER‐2) overexpressing breast cancer treatment. However, insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application. Herein, an in situ forming gold nanorods (AuNRs)‐sodium alginate (ALG) hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable, dual‐stimuli‐responsive drug release, photothermal ablation, and drug‐antibody synergistic therapy. The photothermal agent AuNRs, anticancer drug DOX, and anticancer antibody HCT were mixed in ALG solution, and after injection, the soluble ALG was quickly transformed into a hydrogel in the presence of Ca2+ in the body. Significantly, the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70% under 808 nm laser irradiation. The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix. In addition, the drug release rate and the releasing degree are also sensitive to the pH. In vitro studies demonstrated that the PEI‐AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK‐BR‐3 cells. In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites. The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER‐2 overexpressing cancer therapy.

PH- and H2O2-sensitive drug delivery system based on sodium xanthate: Dual-responsive supramolecular vesicles from one functional group

Nano-drug delivery systems with multiple stimulus-responsive capabilities have superior response performance and efficient drug release. Nevertheless, it is sophisticated to construct multiple stimulus-responsive systems where the two or more functional groups need to be introduced simultaneously. Xanthate, one functional group with pH and H2O2 stimulus responsiveness, has significant potential applications for building dual-responsive drug delivery system. Herein, we present a novel dual stimuli-responsive supramolecular drug delivery system by using sodium xanthate derivative (SXD) as guest molecule and quaternary ammonium capped pillar[5]arene (QAP5) as host molecule through host-guest interaction on the basis of electrostatic interaction. The amphiphile QAP5⊃SXD could self-assemble into vesicles to efficiently load the anti-cancer drug DOX. The experimental results showed that QAP5⊃SXD nanoparticles could achieve efficient drug delivery and controlled release in the tumor microenvironment. Cytotoxicity experiments proved that DOX@QAP5⊃SXD nanoparticles could significantly improve the anticancer efficiency of free DOX on cancer cells. The present study provides an efficient strategy to develop supramolecular nanocarriers with dual-responsiveness in one functional group for controlled drug release.

Construction of a redox-responsive drug delivery system utilizing the volume of AS1411 spatial configuration gating mesoporous silica pores.

In recent years, diverse redox-responsive drug delivery systems have emerged to prevent premature drug release and reduce drug toxicity in the human body in cancer treatment. In this paper, we put forward a view of directly utilizing the spatial structure size of the AS1411 aptamer as the nano-gatekeeper on the pore openings of MCM-41 type mesoporous silica and thus constructed a redox-responsive drug delivery system named MCM-41-SS-AS1411. The particles obtained at each step were characterized by TEM, FTIR, SXRD, TGA and zeta potential measurement. The characterization data confirmed that the particles were successfully prepared. The binding amount of the aptamer was ca. 3.1 × 103 for each carrier particle averagely. The anticancer drug Dox was regarded as a drug model to investigate the redox-controlled drug release behavior by fluorescence measurements. The investigation results demonstrate that the spatial volume of aptamer AS1411 can block the mesopore, and this drug-carrier can realize controlled drug release by GSH. We hope this idea can play a prompt role in relevant research. Meanwhile, the preparation steps of this DDS are simplified.

Mesoporous Silica Nanoprodrug Encapsulated with Near-Infrared Absorption Dye for Photothermal Therapy Combined with Chemotherapy.

Based on the tumor microenvironment with weak acidic characteristics, a nano-drug delivery system that achieves controlled release of drugs through the pH response has been a popular strategy to improve the effectiveness of tumor therapy and reduce toxic side effects, and combining photothermal therapy (PTT) on this basis can help improve the antitumor effect. In this study, mesoporous silica nanoparticles (MSNs) were surface-modified with polymer poly(PEGMA-co-HEMA) via surface-initiated atom transfer radical polymerization, and a multifunctional nanoplatform MSN@poly(PEGMA-co-HEMA-g-doxorubicin (DOX)/indocyanine green (ICG) was designed for effective photothermal/chemotherapy combination therapy. The anticancer drug DOX was anchored to the polymer on the surface of MSN by reversible covalent bond cis-aconitic anhydride with a drug loading of 10%. Meanwhile, the small-molecule dye was loaded into the pores of MSN, and PTT mediated by near-infrared (NIR) radiation could further kill cancer cells. Under low-pH stimulation, the cis-aconitic anhydride bond breaks and DOX is released, with a 65% increase in cumulative drug release over 50 h compared to that at pH 7.4 (normal physiological environment). The high temperature induced by photothermal conversion accelerated the reversible covalent bond breakage, and the cumulative drug release at pH 5.0 for 3 h at elevated temperature up to 50 °C increased by 24.3% compared with that under normal physiological conditions (T = 37 °C), demonstrating that increasing the temperature can reduce the time required to reach blood drug concentration. In vitro cytotoxicity results revealed that the prodrug delivery system showed stronger cytotoxicity under NIR light irradiation compared with free DOX, with more than 90% of tumor cells killed after 48 h. Therefore, MSN@poly(PEGMA-co-HEMA-g-DOX)/ICG enhanced the synergistic effect of chemotherapy through photothermal action and accelerated reversible chemical bond cleavage, which has great potential in the combined therapy of cancer.

Biocompatible Eu doped mesoporous calcium silicate nanospheres for pH-responsive drug release

Calcium silicate is a kind of inorganic biomaterial containing Si, Ca, O elements, they have been widely investigated and applied in a variety of medical applications in the past four decades. Herein, Europium (Eu) doped mesoporous calcium silicate nanoparticles (Eu-MCS) with sizes ranging from 60 nm to 110 nm were prepared via a simple hydrothermal synthesis method. The morphology, structure, texture and optical property were characterized by SEM, TEM, XRD, N2 adsorption/desorption and PL spectra, respectively. The prepared material emits strong red luminescence at 613 nm upon UV irradiation and is cytocompatible at a wide range of concentrations, exibiting promising application in bioimaging. The Eu-MCS has a high loading capacity of 356.67 μg/mg for the anticancer drug DOX, and the drug loaded material DOX@Eu-MCS showed pH-controlled drug release behaviour. Moreover, both of the biocompatibility tests on normal human cells HEK293 and human colon cancer cells HT29 indicate a low cytotoxicity of Eu-MCS. The cell cytotoxity assays of the DOX loaded nanomaterial (DOX@Eu-MCS) on Hela cancer cells prove a high cancer cell mortality. Therefore, the as-prepared red emissive nanocarrier Eu-MCS has great potential to be used as an integrated platform for cancer diagnosis and therapy.

Aptamer-mediated synthesis of multifunctional nano-hydroxyapatite for active tumour bioimaging and treatment.

ObjectivesThe nano‐hydroxyapatite (nHAp) is widely used to develop imaging probes and drug carriers due to its excellent bioactivity and biocompatibility. However, traditional methods usually need cumbersome and stringent conditions such as high temperature and post‐modification to prepare the functionalized nHAp, which do not benefit the particles to enter cells due to the increased particle size. Herein, a biomimetic synthesis strategy was explored to achieve the AS1411‐targeted tumour dual‐model bioimaging using DNA aptamer AS1411 as a template. Then, the imaging properties and the biocompatibility of the synthesized AS‐nFAp:Gd/Tb were further investigated.Materials and methodsThe AS‐nFAp:Gd/Tb was prepared under mild conditions through a one‐pot procedure with AS1411 as a template. Besides, the anticancer drug DOX was loaded to AS‐nFAp:Gd/Tb so as to achieve the establishment of a multifunctional nano‐probe that integrated the tumour diagnosis and treatment. The AS‐nFAp:Gd/Tb was characterized by transmission electron microscopy (TEM), energy disperse X‐ray Spectroscopy (EDS) mapping, X‐ray photoelectron spectroscopy (XPS) spectrum, X‐ray diffraction (XRD), fourier‐transformed infrared (FTIR) spectroscopy, capillary electrophoresis analyses, zeta potential and particle sizes. The in vitro magnetic resonance imaging (MRI) and fluorescence imaging were performed on an MRI system and a confocal laser scanning microscope, respectively. The potential of the prepared multifunctional nHAp for a targeted tumour therapy was investigated by a CCK‐8 kit. And the animal experiments were conducted on the basis of the guidelines approved by the Animal Care and Use Committee of Sichuan University, China.ResultsIn the presence of AS1411, the as‐prepared AS‐nFAp:Gd/Tb presented a needle‐like morphology with good monodispersity and improved imaging performance. Furthermore, due to the specific binding between AS1411 and nucleolin up‐expressed in cancer cells, the AS‐nFAp:Gd/Tb possessed excellent AS1411‐targeted fluorescence and MRI imaging properties. Moreover, after loading chemotherapy drug DOX, in vitro and in vivo studies showed that DOX@AS‐nFAp:Gd/Tb could effectively deliver DOX to tumour tissues and exert a highly effective tumour inhibition without systemic toxicity compared with pure DOX.ConclusionsThe results indicated that the prepared multifunctional nHAp synthesized by a novel biomimetic strategy had outstanding capabilities of recognition and treatment for the tumour and had good biocompatibility; hence, it might have a potential clinical application in the future.

Infrared Responsive Choline Phosphate Lipids for Synergistic Cancer Therapy.

Choline phosphate lipids have been designed and developed as new-generation zwitterionic nanocarriers with excellent biocompatibility and bioorthogonality to provide a more programmable performance for cancer therapy. However, there is a lack of spatiotemporal and reversible control for drug release at target tumor cells, which can lead to severe adverse effects to normal tissue and discounted treatment outcome. Here, light-inducible Lip-cRGDfk/ICG/Dox liposomes were developed for synergistic cancer therapy. ICG can effectively convert light energy into selective heating in a local environment upon laser irradiation, thus inducing thermal ablation of tumor cells, and further reversibly trigger the spatiotemporal release of anticancer drugs (Dox) at tumor cells due to the conformation transformation of CP lipids to synergistically kill tumor cells. That Lip-cRGDfk/ICG/Dox exhibited a significant improvement for breast cancer therapy in vitro and in vivo is also demonstrated, thus it can serve as an efficient platform to noninvasively and spatiotemporally control the activation of cytotoxicity at tumor cells for precision cancer therapy.

Multifunctional Plasmonic Core-Satellites Nanoprobe for Cancer Diagnosis and Therapy Based on a Cascade Reaction Induced by MicroRNA.

Constructing multifunctional plasmonic core-satellites (CS) nanoassembly for clinical cancer diagnosis and therapy has gained vast attention. Herein, we reported a doxorubicin (Dox)-loaded CS nanoprobe for microRNA (miRNA) detection, targeting drug release, and therapy evaluation. The plasmonic CS nanoprobe was constructed with uniformly distributional 50 nm (core) and 13 nm (satellites) gold nanoparticles (AuNPs), which were functionally assembled with a specific sequence of DNA and peptides. Anticancer drug Dox was loaded by intercalating into the GC-rich double strands. In the presence of target miRNA (miRNA-21 used as model), the constructed CS nanostructure was disassembled, producing characteristic localized surface plasmon resonance (LSPR) signals and releasing Dox. With the increase of the miRNA-21 concentration ranging from 0.01 to 1000 fM, a distinct blue shift of scattering spectra peak occurred, along with obvious color change from orange to green under a dark-field microscope (DFM), which can be used to detect miRNA at single-particle level. Meanwhile, it released Dox-induced apoptosis. Caspase-3 involved in apoptosis was then activated to cleave the specific peptide substrate, releasing fluorophore FAM from AuNPs. As a result, caspase-3 was detected based on restored fluorescence intensity, which was used to evaluate the therapy effectiveness. In a word, the multifunctional plasmonic CS nanoprobe can be used not only to image cellular miRNA-21 to distinguish tumor cells from normal cells, but also to release drugs and monitor the apoptotic process in situ by confocal imaging.

Doxorubicin-Loaded MnO2@Zeolitic Imidazolate Framework-8 Nanoparticles as a Chemophotothermal System for Lung Cancer Therapy.

Doxorubicin-loaded MnO2@zeolitic imidazolate framework-8 (DOX/MnO2@ZIF-8) nanoparticles, a smart multifunctional therapeutic platform, were prepared for the treatment of lung cancer. The morphology, structure, and redox and photothermal properties of MnO2@ZIF-8 were characterized by the corresponding methods. The anticancer drug DOX released from the DOX/MnO2@ZIF-8 nanoparticles was measured. The cell viability of Lewis lung cancer (LLC) cells treated with MnO2@ZIF-8 or DOX/MnO2@ZIF-8 nanoparticles was determined using the cell counting kit-8 (CCK-8) method. The cellular uptake of DOX/MnO2@ZIF-8 nanoparticles into LLC cells was observed using a confocal laser scanning microscope. TUNEL staining was performed to evaluate the in vivo therapeutic efficacy of DOX/MnO2@ZIF-8 nanoparticles. The results showed that the as-prepared MnO2@ZIF-8 nanoparticles had an average particle size of 155.59 ± 13.61 nm and the DOX loading efficiency was 12 wt %. MnO2@ZIF-8 could react with H2O2 to generate O2 and showed a great photothermal conversion effect both in vitro and in vivo. Up to 82% of total DOX could be released from DOX/MnO2@ZIF-8 nanoparticles at pH = 5.0. The CCK-8 assay showed that MnO2@ZIF-8 had low cytotoxicity to LLC cells, while DOX/MnO2@ZIF-8 can significantly reduce the cell viability. DOX/MnO2@ZIF-8 can be accumulated in LLC cells over time. Compared with PBS and DOX/MnO2@ZIF-8 groups, the mice in the DOX/MnO2@ZIF-8 + NIR group had the most apoptotic cells and significantly reduced tumor volume. In conclusion, these findings suggest that the as-prepared MnO2@ZIF-8 nanoparticles with synergetic therapeutic effects by photothermal therapy and improved tumor microenvironment and as a pH-responsive nanocarrier for delivering the nonspecific anticancer drug DOX might be applied in the treatment of lung cancer.

Intelligent Nanoprobe: Acid-Responsive Drug Release and In Situ Evaluation of Its Own Therapeutic Effect.

The design of an intelligent nanoprobe capable of intracellular controlled release of apoptosis inducers and subsequent high-fidelity imaging of the drug-induced apoptosis is highly desirable for precise cancer treatment. Herein, we report an intelligent nanoprobe that combined therapeutic and imaging functions in one agent. Briefly, a gold nanoparticle is designed to be conjugated with acid-responsive DNA duplexes (Dox intercalates in this region) and caspase-3-specific cleavable peptides (labeled with fluorophore). We demonstrated that the nanoprobe could efficiently deliver an anticancer drug (Dox) into cancer cells and achieve acid-responsive drug release. Furthermore, the apoptotic process was in situ-monitored by detection of fluorescence through the cleavage of the peptide linker by caspase-3, which is one of the executioner caspases involved in apoptosis. This newly developed nanoprobe could serve as a theranostic agent for targeted responsive chemotherapy and also provide feedback apoptosis imaging of the self-therapeutic effect.

Injectable redox and light responsive MnO2 hybrid hydrogel for simultaneous melanoma therapy and multidrug-resistant bacteria-infected wound healing

The recurrence of cutaneous cancer and multidrug-resistant (MDR) bacteria infected-wound healing after surgical excision remains a great challenge for both clinic and research. In this study, we developed an injectable redox and light responsive bio-inspired MnO2 hybrid (BMH) hydrogel for effective melanoma photothermo-chemotherapy and MDR bacteria infected-wound healing. The BMH hydrogel was ingeniously fabricated via non-covalent self-assembly and MnO2 nanosheets mediated covalent oxidative polymerization of the catechol functionalized chitosan for the first time. The BMH hydrogel displayed excellent shear-thinning, injectable, adhesive, redox/light responsive and contact-active antibacterial capabilities. Remarkably, our rationally designed BMH hydrogel could alleviate the hypoxic tumor microenvironment (TME) by decomposing the endogenous H2O2 into O2, and simultaneously release anticancer drug DOX. Increasing the local availability of O2 enhanced the cytotoxicity of DOX against melanoma in a highly site-specific manner. By further combining with a spatiotemporal controllable photothermal hyperthermia, we demonstrated a near-complete tumor suppression both in vitro (98.6%) and large solid tumors in vivo (96.2%). Moreover, BMH hydrogel could significantly promote the MDR-infected wound healing in vivo by efficiently eradicating bacterial invasion and perpetually ameliorating the oxidative and inflammatory wound microenvironment. Collectively, BMH hydrogel indicated great therapeutic potentials for both cancer therapy and tissue engineering.

New organic/inorganic nanohybrids of targeted pullulan derivative/gold nanoparticles for effective drug delivery systems

This study aimed to develop new organic/inorganic nanohybrids of targeted pullulan derivative/gold nanoparticles (FA-PABA-Q188-PUL@AuNPs) to improve the selectivity and efficacy of drugs. The chemical structure of targeted pullulan derivative, folic acid-decorated para-aminobenzoic acid-quat188-pullulan (FA-PABA-Q188-PUL), was designed for reducing, stabilizing, capping, and functionalizing AuNPs. Here, the key factors, including pH, temperature, and FA-PABA-Q188-PUL concentrations, were systematically optimized to control the morphology, size, and functionalization of multifunctional FA-PABA-Q188-PUL@AuNPs. Spherical FA-PABA-Q188-PUL@AuNPs obtained by a green, simple, and bio-inspired strategy under the optimum conditions were thoroughly characterized and had an average size of 12.6 ± 1.5 nm. The anticancer drug DOX was successfully loaded on monodispersed FA-PABA-Q188-PUL@AuNPs and the system exhibited excellent intracellular uptake, specificity, and physicochemical properties. The pH-responsive DOX release from FA-PABA-Q188-PUL@AuNPs-DOX showed fast release (85% after 72 h) under acidic conditions. Furthermore, FA-PABA-Q188-PUL@AuNPs-DOX enhanced the anticancer activity of DOX toward Chago-k1 cancer cells up to 4.8-fold and showed less cytotoxicity toward normal cells than free DOX. The FA-PABA-Q188-PUL@AuNPs-DOX induced the death of cells by increasing late apoptotic cells (26.4%) and arresting the cell cycle at S-G2/M phases. These results showed that innovative FA-PABA-Q188-PUL@AuNPs should be considered as new candidate platforms for anticancer drug delivery systems.

Ultra-small MoS2 nanodots-incorporated mesoporous silica nanospheres for pH-sensitive drug delivery and CT imaging

Functionalization of mesoporous silica spheres with well-dispersed and ultra-small nanodots to exert their synergistic effects for biomedical applications has been considered to be an urgent challenge. Herein, homogeneously incorporation of ultra-small and monodispersed MoS2 nanodots in the mesoporous silica nanospheres (MSN) was achieved by a facile one-step solvothermal reaction. The as-synthesized UsMSND@MSN possessed uniform size (∼115 nm) and favorable biocompatibility inherited from MSN. The dispersed UsMSND within MSN could act as anchoring sites for aromatic anti-cancer drug DOX loading, and consequently achieved pH-responsive release based on the special π-π/electrostatic interactions with the DOX molecules. More importantly, the well-dispersed UsMSND in MSN could function as the non-toxic contrast agent for the sensitive in vivo CT imaging in various tumors including breast cancer and glioma with different sections. This work promises a good strategy for dispersed incorporation of UsMSND into MSN as an excellent pH-responsive platform for simultaneous cancer imaging and therapy.

GSH‐responsive polyglutamic acid nanocarriers for dual targeted cancer therapy

AbstractIn order to reduce the toxic side effects of chemotherapeutic drugs and improve the targeting and efficiency of cancer treatment, the development of drug delivery system has received great attention. In this study, second generation polyglutamic acid dendrimers (G2) are used as basic materials to produce porous nanoparticles through cross link by crosslinkers containing disulfide bonds. The crosslinked products (G2)n have negative electricity and abundant voids, which enable them to adsorb the electronegative anticancer drug DOX. At the same time, in order to transport DOX to the tumor site, we modified FA on DOX and encapsulated it in magnetic mesoporous silica (FA‐DOX‐MSNs). Therefore, the final nanoparticles (FA‐DOX‐MSNs/(G2)n) not only have dual targeting ability to transport DOX to the tumor site, but also have reductive responsiveness that can release drugs responsively in the tumor cells. In addition, it has good biocompatibility and endocytosis ability.

Diterpenoids from Euphorbia royleana reverse P-glycoprotein-mediated multidrug resistance in cancer cells

Eight previously undescribed diterpenoids, euphoroyleans A−H, including two cembranes, three ingenanes, two ent-atisanes, and one ent-kaurane, along with 22 known analogues were isolated from the whole plants of Euphorbia royleana. The structures of euphoroyleans A−H, including the absolute configurations, were elucidated by extensive spectroscopic analyses, chemical transformation, and single crystal X-ray diffractions. All the isolates were screened for their chemoreversal abilities on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) cancer cell line HepG2/DOX, and eight compounds exhibited significant activities. Among them, ingol-3,7,12-triacetate-8-benzoate, the most active MDR modulator with no obvious cytotoxicity, could enhance the efficacy of anticancer drug DOX to ca. 105 folds at 10 μM, being stronger than the positive drug verapamil. Mechanistic study revealed that ingol-3,7,12-triacetate-8-benzoate could inhibit the transport activity of P-gp rather than its expression, and the possible recognition mechanism between compounds and P-gp was predicted by molecular docking.

PH-responsive DNA nanomicelles for chemo-gene synergetic therapy of anaplastic large cell lymphoma.

Chemo-gene therapy is an emerging synergetic modality for the treatment of cancers. Herein, we developed pH-responsive multifunctional DNA nanomicelles (DNMs) as delivery vehicles for controllable release of doxorubicin (Dox) and anaplastic lymphoma kinase (ALK)-specific siRNA for the chemo-gene synergetic therapy of anaplastic large cell lymphoma (ALCL).Methods: DNMs were synthesized by performing in situ rolling circle amplification (RCA) on the amphiphilic primer-polylactide (PLA) micelles, followed by functionalization of pH-responsive triplex DNA via complementary base pairing. The anticancer drug Dox and ALK-specific siRNA were co-loaded to construct Dox/siRNA/DNMs for chemo-gene synergetic cancer therapy. When exposed to the acidic microenvironment (pH below 5.0), C-G·C+ triplex structures were formed, leading to the release of Dox and siRNA for gene silencing to enhance the chemosensitivity in ALCL K299 cells. The chemo-gene synergetic anticancer effect of Dox/siRNA/DNMs on ALCL was evaluated in vitro and in vivo.Results: The pH-responsive DNMs exhibited good monodispersity at different pH values, good biocompatibility, high drug loading capacity, and excellent stability even in the human serum. With the simultaneous release of anticancer drug Dox and ALK-specific siRNA in response to pH in the tumor microenvironment, the Dox/siRNA/DNMs demonstrated significantly higher treatment efficacy for ALCL compared with chemotherapy alone, because the silencing of ALK gene expression mediated by siRNA increased the chemosensitivity of ALCL cells. From the pathological analysis of tumor tissue, the Dox/siRNA/DNMs exhibited the superiority in inhibiting tumor growth, low toxic side effects and good biosafety.Conclusion: DNMs co-loaded with Dox and ALK-specific siRNA exhibited significantly enhanced apoptosis of ALCL K299 cells in vitro and effectively inhibited tumor growth in vivo without obvious toxicity, providing a potential strategy in the development of nanomedicines for synergetic cancer therapy.

A tumor-sensitive biological metal-organic complex for drug delivery and cancer therapy.

Metal-organic complexes (MOCs) or metal-organic frameworks (MOFs) have attracted increasing interest for constructing nanoscale drug delivery systems for cancer therapy. However, conventional MOC/MOF materials usually contain toxic metals or low-biocompatible organic ligands. Also, current approaches for creating tumor-sensitive nanocarriers are always based on the instability of coordination bonds under acidic conditions, or through post-synthetic modification with sensitive molecules. As a matter of fact, it is more facile to fabricate tumor-sensitive MOCs/MOFs based on the stimuli-responsiveness of organic ligands. In this study, a novel tumor-sensitive biological MOC (bioMOC-Zn(Cys)) was created through the assembly of endogenous Zn2+ ions and the small biological molecule (l-cystine, Cys). The disulfide bond in l-cystine is cleavable by the overexpressed GSH in tumor cells, thus achieving rapid release of drugs from nanocarriers. By encapsulating doxorubicin (DOX) in bioMOC-Zn(Cys), DOX@bioMOC-Zn(Cys) displayed higher cellular uptake and cytotoxicity in cancer cells than free DOX. In vivo investigations indicated that DOX@bioMOC-Zn(Cys) largely inhibited tumor growth and reduced side effects. Remarkably, since both metal ions and organic ligands were obtained from biological sources, bioMOC-Zn(Cys) exhibited superior biocompatibility. This study presents a new method for fabricating MOC-based nanodrugs with high tumor-sensitivity and low toxicity.