NIR‐Induced Disintegration of CuS‐Loaded Nanogels for Improved Tumor Penetration and Enhanced Anticancer Therapy

Nanocarrier‐based cancer therapy suffers from poor tumor penetration and unsatisfied therapeutical efficacy, as its vascular extravasation efficiency is often compromised by the intrinsic physiological heterogeneity in tumor tissues. In this work, novel near infrared (NIR)‐responsive CuS‐loaded nanogels are prepared to deliver anticarcinogen into the tumor. These hybrid polymeric nanogels possess high photothermal conversion efficiency, and are able to load a large amount of antitumor drug (e.g., doxorubicin [DOX]). More importantly, the thermal heat could induce self‐destruction of the big‐size framework of hybrid nanogels into small nanoparticles, which greatly facilitates tumor penetration to release DOX deep inside the tumor, as validated by photoacoustic (PA) imaging which exhibits 26.3 times enhancement at the interior region compared to signals of groups without laser irradiation. Such structural alteration, combined with strong photothermal and chemotherapy effects, leads to remarkable inhibition of tumor growth in mice. As a result, this NIR‐induced disintegration of CuS‐loaded nanogels provides a novel drug delivery strategy and might open a new window for clinical cancer treatment.     

Near-infrared light (NIR)-responsive nanoliposomes combining photodynamic therapy and chemotherapy for breast tumor control

Light-responsive carriers have been used for the controlled release of antitumor drugs in recent years. However, most light-responsive vectors require high-energy ultraviolet or visible light to achieve local drug release, and ultraviolet light would cause cellular damage. Near-infrared light has a deeper tissue-penetration depths and minimal harm to tissues, but it is difficult to cleave the chemical bond directly. The aim of this study is to develop a novel near-infrared light-responsive carrier for local release of antitumor drugs. Unsaturated phospholipids can be oxidized by singlet oxygen to achieve liposomal drug release, and singlet oxygen can be produced by photosensitizer under light irradiation. A new near-infrared light-responsive nanoliposome was designed that imparts light-triggered local drug release. Nanoliposomes, which were composed of matrix phospholipids and unsaturated phospholipids, were prepared by ammonium sulfate gradient method, and loaded with antitumor drug doxorubicin (DOX) and photosensitizer 1,4,8,11,15,18,22,25-octabutoxypalladium phthalocyanine. Under near-infrared light, photosensitizers could produce singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the unsaturated phospholipids were oxidized by singlet oxygen and result in DOX release, causing sustained cell damage by chemotherapy. Near-infrared light-responsive nanoliposomes exhibit enhanced anticancer activity owing to combined treatment of photodynamic therapy and chemotherapy. A new platform is thus offered for designing effective intracellular drug-release systems, holding great promise for future cancer therapy.     

Short and simple peptide-based pH-sensitive hydrogel for antitumor drug delivery

Since self-assembled peptide hydrogels can solve the problems such as low solubility, poor selectivity and serious adverse effects of traditional chemotherapy drugs, they have been widely used as carrier materials for drug delivery. In this study, we developed a novel and injectable drug delivery platform for the antitumor drug doxorubicin(DOX) using a p H-responsive ionic-complementary octapeptide FOE.This octapeptide could self-assemble into stable hydrogel under neutral conditions, while disa...     

A DNA–Azobenzene Nanopump Fueled by Upconversion Luminescence for Controllable Intracellular Drug Release

Stimulus‐responsive drug release possesses considerable significance in cancer therapy. This work reports an upconversion‐luminescence‐fueled DNA–azobenzene nanopump for rapid and efficient drug release. The nanopump is constructed by assembling the azobenzene‐functionalized DNA strands on upconversion nanoparticles (UCNPs). Doxorubicin (DOX) is loaded in the nanopump by intercalation in the DNA helix. Under NIR light, the UCNPs emit both UV and visible photons to fuel the continuous photoisomerization of azo, which acts as an impeller pump to trigger cyclic DNA hybridization and dehybridization for controllable DOX release. In a relatively short period, this system demonstrates 86.7 % DOX release. By assembling HIV‐1 TAT peptide and hyaluronic acid on the system, targeting of the cancer‐cell nucleus is achieved for perinuclear aggregation of DOX and enhanced anticancer therapy. This highly effective drug delivery nanopump could contribute to chemotherapy development.     

A dual-responsive hyaluronic acid nanocomposite hydrogel drug delivery system for overcoming multiple drug resistance

Chemotherapy is restricted by efficient drug outflow due to the multiple drug resistance (MDR) in heterogenous nature of tumor. Herein, we present a dual-responsive hyaluronic acid (HA) nanocomposite hydrogel that can not only response to the tumor microenvironment but also enhance chemotherapy. This HA hydrogel consists of a core-shell SiO₂ (GOD@SiO₂-Arg) and mesoporous silica nanoparticles (MSNs) with doxorubicin (DOX) as the cargo (DOX@MSN). It could rapidly release the GOD@SiO₂-Arg nanoparticles at the low pH tumor-specific environment due to the cleavage of imine bond. GOD@SiO₂-Arg activated by over-expressed glutathione (GSH) in tumor cells releases GOD due to the cleavage of disulfide bonds, which could oxidize glucose to produce hydrogen peroxide (H₂O₂) for in situ NO generation via reaction between Arg and H₂O₂. The validity of this study might provide a method to modulate the tumor microenvironment for enhancing chemotherapy.     

A pH‐Responsive Hydrogel Based on a Tumor‐Targeting Mesoporous Silica Nanocomposite for Sustained Cancer Labeling and Therapy

A facile strategy is presented to synthesize hyaluronic acid (HA) and a fluorescein isothiocyanate (FITC)‐conjugated mesoporous silica nanocomposite (MSN) with multiple functions of fluorescence, tumor‐cell targeting, pH‐triggered gelation, and enzyme‐responsive drug release. This injectable nanocomposite is able to indicate the entire tumor location and provides a microenvironment with rich anticancer drugs in and around tumor tissue for a long time, to avoid recrudescence. In this design, the mesoporous silica serves as the drug container, the FITC serves as a fluorescent probe, and the anchored HA plays multiple roles as drug‐release cap, tumor‐targeting points, and responsive gel matrix. Owing to the specific affinity between the HA on MSNs and the CD44 antigen over‐expressed on tumor cells, the MSNs can selectively attach to tumor cells. The nanocomposites then exploit the pH‐responsive interactions (hydrogen bonds) among the HA to self‐assemble in situ into a hydrogel around the tumor tissue. The resulting hydrogel gradually releases its payload (doxorubicin, anticancer drugs)‐loaded MSNs upon HA degradation in the presence of hyaluronidase‐1 (Hyal‐1), followed by endocytosis and intracellular drug release. All these properties have distinct benefits for tumor treatment, demonstrating that this device is a promising candidate for oncotherapy applications.

     

Preparation of Hyaluronic Acid Micro-Hydrogel by Biotin–Avidin-Specific Bonding for Doxorubicin-Targeted Delivery

Hyaluronic acid is a naturally ionic polysaccharide with cancer cell selectivity. It is an ideal candidate material for delivery of anticancer agents. In this study, hyaluronic acid (HA) micro-hydrogel loaded with anticancer drugs was prepared by the biotin–avidin system approach. Firstly, carboxyl groups on HA were changed into amino groups with adipic acid dihydrazide (ADH) to graft with biotin by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride named as HA–biotin. When HA–biotin solution mixed with doxorubicin hydrochloride (DOX·HCl) was blended with neutravidin, the micro-hydrogels would be formed with DOX loading. If excess biotin was added into the microgel, it would be disjointed, and DOX will be released quickly. The results of the synthesis procedure were characterized by ¹H-NMR and FTIR; ADH and biotin have been demonstrated to graft on the HA molecule. A field emission scanning electron microscope was used to observe morphologies of HA micro-hydrogels. Furthermore, the in vitro DOX release results revealed that the release behaviors can be adjusted by adding biotin. Therefore, the HA micro-hydrogel can deliver anticancer drugs efficiently, and the rate of release can be controlled by biotin-specific bonding with the neutravidin. Consequently, the micro-hydrogel will perform the promising property of switching in the specific site in cancer therapy.     

Preparation of polyprenol/poly (β-amino ester)/galactose targeted micelle carrier for enhancing cancer therapy

Lacking of substantial physiological activity and low utilization remains a problem for most conventional drug carriers. Polyprenol with beneficial medical effects and high availability could be an ideal candidate for solving this issue. Here, Ginkgo biloba leaves polyprenol (GBP)-based derivative was prepared by Michael addition reaction of poly (β-amino esters) (PBAE) with GBP and galactose (Gal). The intervention of poly (β-amino ester) and galactose promoted GBP-PBAE-Gal to depict as micellar carrier, enhancing the loading of hydrophobic DOX and the sensitivity to the specific tumor microenvironment, with the largest DOX loading of 28.62 ± 1.49 % and the efficient DOX release rate of 90.30 %. In the meantime, GBP-PBAE-Gal exhibited enhanced colloidal stability at 640-folds of dilution and in the presence of serum and realized the possibility of long-term storage at room temperature. Additionally, GBP-PBAE-Gal was safe for human red blood cells and human normal liver cells HL-7702. When applied for DOX delivery to HepG2 cells, GBP-PBAE-Gal increased the targeting of DOX to intensify its inhibition on HepG2 cells. Compared to free DOX, the DOX loaded into GBP-PBAE-Gal presented stronger anticancer activity, with IC₅₀ of 0.56 μg/mL at 72 h. Besides, the anticancer mechanism study revealed that GBP-PBAE-Gal arrested the cell cycle in HepG2 cells, suggesting the potential of GBP-based carrier for intensive treatment. This research evidenced the feasibility and high availability of the GBP to use as a drug carrier, providing a novel candidate for drug delivery systems.     

Synthesis and characterization of biodegradable pH and reduction dual‐sensitive polymeric micelles for doxorubicin delivery

Novel pH and reduction dual‐sensitive biodegradable polymeric micelles for efficient intracellular delivery of anticancer drugs were prepared based on a block copolymer of methyloxy‐poly(ethylene glycol)‐b‐poly[(benzyl‐l ‐aspartate)‐co‐(N‐(3‐aminopropyl) imidazole‐l ‐aspartamide)] [mPEG‐SS‐P(BLA‐co‐APILA), MPBA] synthesized by a combination of ring‐opening polymerization and side‐chain reaction. The pH/reduction‐responsive behavior of MPBA was observed by both dynamic light scattering and UV–vis experiments. The polymeric micelles and DOX‐loaded micelles could be prepared simply by adjusting the pH of the polymer solution without the use of any organic solvents. The drug release study indicated that the DOX‐loaded micelles showed retarded drug release in phosphate‐buffered saline at pH 7.4 and a rapid release after exposure to weakly acidic or reductive environment. The empty micelles were nontoxic and the DOX‐loaded micelles displayed obvious anticancer activity similar to free DOX against HeLa cells. Confocal microscopy observation demonstrated that the DOX‐loaded MPBA micelles can be quickly internalized into the cells, and effectively deliver the drugs into nuclei. Thus, the pH and reduction dual‐responsive MPBA polymeric micelles are an attractive platform to achieve the fast intracellular release of anticancer drugs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1771–1780     

Well‐Defined Poly(Ortho Ester Amides) for Potential Drug Carriers: Probing the Effect of Extra‐ and Intracellular Drug Release on Chemotherapeutic Efficacy

To compare the chemotherapeutic efficacy determined by extra‐ and intracellular drug release strategies, poly(ortho ester amide)‐based drug carriers (POEAd‐C) with well‐defined main‐chain lengths, are successfully constructed by a facile method. POEAd‐C3‐doxorubicin (DOX) can be rapidly dissolved to release drug at tumoral extracellular pH (6.5–7.2), while POEAd‐C6‐DOX can rapidly release drug following gradual swelling at intracellular pH (5.0–6.0). In vitro cytotoxicity shows that POEAd‐C3‐DOX exhibits more toxic effect on tumor cells than POEAd‐C6‐DOX at extracellular pH, but POEAd‐C6‐DOX has stronger tumor penetration and inhibition in vitro and in vivo tumor models. So, POEAd‐C6‐DOX with the intracellular drug release strategy has stronger overall chemotherapeutic efficacy than POEAd‐C3‐DOX with extracellular drug release strategy. It is envisioned that these poly(ortho ester amides) can have great potential as drug carriers for efficient chemotherapy with further optimization.

     

刺激响应共负载药物/基因微载体的制备

合成了聚乙烯亚胺接枝二茂铁(PEI-Fc)两亲聚合物, 采用水包油法制备包埋疏水性抗癌药阿霉素(DOX)的载药胶束, 并利用胶束表面正电荷的PEI链段有效缔合DNA, 获得尺寸合适、 表面带正电荷的阿霉素与基因共负载微载体. 在磷酸盐(PBS)缓冲溶液中, 共负载微载体能够缓慢释放出DOX. 在硝酸铈铵存在下, 二茂铁从疏水性转变为亲水性, 使载药胶束完全解离, 由于PEI-Fc与DNA之间的静电作用, 使基因超分子组装体稳定存在, 显示出很好的氧化响应特性. 细胞培养结果表明, 表面带正电荷的共负载微载体易被HepG2细胞内吞, 并可转染, 且随着DOX的释放逐渐杀死HepG2肝癌细胞, 为安全稳定、 具有刺激响应的药物与基因共负载微载体的制备提供了可行的途径.     

Fabrication of a polypseudorotaxane nanoparticle with synergistic photodynamic and chemotherapy

Polypseudorotaxane (PPR) nanoparticles were fabricated by the self-assembly of mPEG-protoporphyrin IX (PpIX) conjugate and a-CDs via the hostguest interaction for achieving synergistic photodynamic and chemotherapy.     

Tracing drug release process with dual-modal hyperbranched polymer-gold nanoparticle complexes

Dual-modal surface enhanced Raman spectrum(SERS)-fluorescence polymer/metal hybrid complexes have been prepared for tracing drug release process in tumor cells. Firstly, the hyperbranched poly((S-(4-vinyl) benzyl S′-propyltrithiocarbonate)-co-(poly(ethylene glycol) methacrylate))(HPVBEG) was synthesized via the combination of reversible addition-fragmentation chain-transfer(RAFT) polymerization and self-condensing vinyl polymerization(SCVP). Subsequently, the anticancer drug doxorubicin(DOX) was linked to HPVBEG via pH sensitive Schiff base bonds to form HPVBEG-g-DOX conjugates.Through aminolysis reaction, HPVBEG-g-DOX was coordinated with gold nanoparticles(GNP), resulting in the formation of HPVBEG-g-DOX/GNP complexes. In neutral condition, the HPVBEG-g-DOX/GNP complexes were stable, and DOX was bound to the surface of GNPs. Therefore, the SERS of DOX could be observed, while the fluorescence of DOX was quenched by GNPs. Under an acidic environment, DOX was released from the surface of GNPs with breakage of Schiff base bonds.Thus, the SERS signal of DOX was gradually reduced. Correspondingly, the fluorescence signal of DOX was enhanced.Through dual-modal SERS-fluorescence technique, the DOX delivery and release process was traced in tumor cells. Moreover,the viability of MCF-7 cells incubated with HPVBEG-g-DOX/GNP complexes was investigated by Cell Counting Kit-8(CCK-8) assay. The experimental results showed that HPVBEG-g-DOX/GNP complexes had similar proliferation inhibition effect compared with free DOX. Definitely, the dual-modal SERS-fluorescence complexes for tracing drug delivery and release will have promising prospects on tumor diagnosis and therapy.     

NIR-triggered drug delivery system based on phospholipid coated ordered mesoporous carbon for synergistic chemo-photothermal therapy of cancer cells

Chemo-photothermal treatment is one of the most efficient strategies for cancer therapy. However, traditional drug carriers without near-infrared absorption capacity need to be loaded with materials behaving photothermal properties, as it results in complicated synthesis process, inefficient photothermal effects and hindered NIR-mediated drug release. Herein we report a facile synthesis of a polyethylene glycol (PEG) linked liposome (PEG-liposomes) coated doxorubicin (DOX)-loaded ordered mesoporous carbon (OMC) nanocomponents (PEG-LIP@OMC/DOX) by simply sonicating DOX and OMC in PEG-liposomes suspensions. The as-obtained PEG-LIP@OMC/DOX exhibits a nanoscale size (600 ± 15 nm), a negative surface potential (−36.70 mV), high drug loading (131.590 mg/g OMC), and excellent photothermal properties. The PEG-LIP@OMC/DOX can deliver loaded DOX to human MCF-7 breast cancer cells (MCF-7) and the cell toxicity viability shows that DOX unloaded PEG-LIP@OMC has no cytotoxicity, confirming the PEG-LIP@OMC itself has excellent biocompatibility. The NIR-triggered release studies demonstrate that this NIR-responsive drug delivery system enables on-demand drug release. Furthermore, cell viability results using human MCF-7 cells demonstrated that the combination of NIR-based hyperthermal therapy and triggered chemotherapy can provide higher therapeutic efficacy than respective monotherapies. With these excellent features, we believe that this phospholipid coating based multifunctional delivery system strategy should promote the application of OMC in nanomedical applications.     

Drug pH-sensitive release in vitro and targeting ability of polyamidoamine dendrimer complexes for tumor cells

Recently, dendrimers have been widely used in medical applications such as drug delivery and gene transfection. In this study, a pH-sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and polyethylene glycol (PEG) modified by lactose (LA-PEG-b-PSD) was synthesized. The pK(a) value of the LA-PEG-b-PSD was also measured. Then, polyamidoamine (PAMAM) complexes were prepared with PAMAM (G4.0) and LA-PEG-b-PSD by electrostatic interaction. To investigate drug pH-sensitive release in vitro, doxorubicin (DOX) was loaded in PAMAM. A higher drug cumulative release from LA-PEG-b-PSD/PAMAM complexes in phosphate buffered saline (PBS) was found at pH 6.5 than at pH 7.4. The cytotoxicity and cellular uptake of PAMAM complexes were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and confocal microscopy. LA-PEG-b-PSD/PAMAM/DOX complexes were able to enhance the cytotoxicity of DOX against HepG2 cells at pH 7.4. Confocal microscopy showed a higher cellular uptake of PEG-b-PSD/PAMAM complexes at pH 6.5. PAMAM complexes modified by lactose showed a higher affinity for hepatic cancer cells than those without lactose at pH 7.4. These results suggest that LA-PEG-b-PSD/PAMAM complexes exhibit selective targeting and cytotoxicity against HepG2 cells. In vivo antitumor studies showed that the LA-PEG-b-PSD/PAMAM/DOX complexes displayed higher antitumor efficacy compared with non-targeted PAMAM/DOX and DOX solution. These results indicate that this strategy should be applicable to the treatment of liver cancers.     

pH/酶/光热多重响应的金纳米笼/透明质酸核壳结构纳米载体的制备与性能

以金纳米笼(AuNC)为核, 巯基化改性的透明质酸(LC-HA)为壳, 盐酸阿霉素(DOX)为药物模型, 通过简单的一锅法制备了核壳结构载药纳米粒子DOX@AuNC@HA(DAH). 金纳米笼为药物装载提供容器且赋予载体光热性能, 改性的透明质酸对金纳米笼进行包封并提供pH/酶响应及靶向介导功能. 对DAH的结构进行了表征, 并进行了载药、 控释性能以及细胞摄取和细胞毒性的研究. 结果表明, 核壳结构纳米微粒DAH具有较高的载药能力, 在激光源的照射下具有较好的循环稳定性和较高的光热转换率. 在pH=7.4的磷酸盐缓冲液中, DAH具有较高的稳定性, 20 h的药物泄露率低于20%; 而在酸性环境、 透明质酸酶(HAase)及光热作用下, DAH均能较快地释放出装载的药物, 展现出较好的刺激响应性. 此外, DAH能够更多地被肿瘤细胞摄取, 表现出一定的靶向性; 当化疗与光热疗法共同作用时, 肿瘤细胞的活性大大减弱, 展现出了联合疗法的优势及潜力.     

NIR-triggered drug delivery system based on phospholipid coated ordered mesoporous carbon for synergistic chemo-photothermal therapy of cancer cells

Chemo-photothermal treatment is one of the most efficient strategies for cancer therapy. However, traditional drug carriers without near-infrared absorption capacity need to be loaded with materials behaving photothermal properties, as it results in complicated synthesis process, inefficient photothermal effects and hindered NIR-mediated drug release. Herein we report a facile synthesis of a polyethylene glycol (PEG) linked liposome (PEG-liposomes) coated doxorubicin (DOX)-loaded ordered mesoporous carbon (OMC) nanocomponents (PEG-LIP@OMC/DOX) by simply sonicating DOX and OMC in PEG-liposomes suspensions. The as-obtained PEG-LIP@OMC/DOX exhibits a nanoscale size (600±15 nm), a negative surface potential (-36.70 mV), high drug loading (131.590 mg/g OMC), and excellent photothermal properties. The PEG-LIP@OMC/DOX can deliver loaded DOX to human MCF-7 breast cancer cells (MCF-7) and the cell toxicity viability shows that DOX unloaded PEG-LIP@OMC has no cytotoxicity, confirming the PEG-LIP@OMC itself has excellent biocompatibility. The NIR-triggered release studies demonstrate that this NIR-responsive drug delivery system enables on-demand drug release. Furthermore, cell viability results using human MCF-7 cells demonstrated that the combination of NIR-based hyperthermal therapy and triggered chemotherapy can provide higher therapeutic efficacy than respective monotherapies. With these excellent features, we believe that this phospholipid coating based multifunctional delivery system strategy should promote the application of OMC in nanomedical applications.     

DNA-capped nanoparticles designed for doxorubicin drug delivery

The anticancer drug, doxorubicin (DOX), was loaded onto DNA-capped gold nanoparticles (AuNP) designed for specific DOX intercalation. Drug binding was confirmed by monitoring DNA melting temperature, AuNP plasmon resonance maximum, and hydrodynamic radius increase, as a function of [DOX]/[DNA] ratio. The capacity for drug release to target DNA was confirmed.     

Nanoparticles for Triple Drug Release for Combined Chemo- and Photodynamic Therapy

A pH-responsive drug delivery system (DDS) based on mesoporous silica nanoparticles (MSNs) has been prepared for the delivery of three anticancer drugs with different modes of action. The novelty of this system is its ability to combine synergistic chemotherapy and photodynamic therapy. A photoactive conjugate of a phthalocyanine (Pc) and a topoisomerase I inhibitor (topo-I), namely camptothecin (CPT), linked by a poly(ethylene glycol) (PEG) chain has been synthesized and then loaded into the mesopores of MSNs. Doxorubicin (DOX), which is a topoisomerase II inhibitor (topo-II), has also been covalently anchored to the outer surface of the MSNs through a dihydrazide PEG linker. In the acidic environment of tumor cells, selective release of the three drugs takes place. In vitro studies have demonstrated the endocytosis of the system into HeLa and HepG2 cells, and the subsequent release of the three drugs into the cytoplasm and nucleus. Furthermore, the cytotoxic effect of DOX, CPT and Pc has been assessed in vitro before and upon light irradiation.     

Liposomes‐Camouflaged Redox‐Responsive Nanogels to Resolve the Dilemma between Extracellular Stability and Intracellular Drug Release

Liposomes have shown great promises for pharmaceutical applications, but still suffer from the poor storage stability, undesirable drug leakage, and uncontrolled drug release. Herein, liposomes‐camouflaged redox‐responsive nanogels platform (denoted as “R‐lipogels”) is prepared to integrate the desirable features of sensitive nanogels into liposomes to circumvent their intrinsic issues. The results indicate that drug‐loaded R‐lipogels with controlled size and high stability not only can achieve a very high doxorubicin (DOX)‐loading capacity (12.9%) and encapsulation efficiency (97.3%) by ammonium sulfate gradient method and very low premature leakage at physiological condition, but also can quickly release DOX in the reducing microenvironment of tumor cells, resulting in effective growth inhibition of tumor cells. In summary, the strategy given here provides a facile approach to develop liposomes–nanogels hybrid system with combined beneficial features of stealthy liposomes and responsive nanogels, which potentially resolves the dilemma between systemic stability and intracellular rapid drug release.