Dual-responsive Drug Release Research Articles

Fabrication of functionalized layered double hydroxide/chitosan nanocomposite with dual responsive drug release for the targeted therapy of breast cancer

The DDS based on isocyanato functionalized layered double hydroxide (LDH-NCO), folic acid conjugated thiolated chitosan (TCS) and gold nanoparticle (AuNp) was used for actively targeted chemophotothermal therapy of breast cancer. The LDH-NCO was conjugated to TCS and forming LDH-NCO-TCS composite. The AuNp are appended on the surface of the LDH-NCO-TCS by electrostatic and soft acid soft base interaction and LDH-NCO-TCS/AuNp nanocomposite was formed. Doxorubicin (DOX) was loaded in LDH-NCO-TCS/AuNp through hydrogen bonding and static interactions. The presence of AuNps withstands high temperature by the near-infrared (NIR) light irradiation, which enhances the photothermal therapy. Besides stimuli responsive drug release was studied at two pHs 5.5 and 7.4. Toxicity studies of DOX loaded LDH-NCO-TCS/AuNp were carried out using breast cancer (MCF7) cells. Blood compatibility studies show the negligible haemolytic activity of the carrier. Flow cytometry analysis showed the significant cell death in G0/G1 phase after treatment with DOX loaded LDH-NCO-TCS/AuNp.

Construction of Ginsenoside Nanoparticles with pH/Reduction Dual Response for Enhancement of Their Cytotoxicity Toward HepG2 Cells

The aim of this study is to construct a pH- and reduction-responsive nanodrug delivery system to effectively deliver a ginsenoside (Rh2) and enhance its cytotoxicity against human hepatocarcinoma cells (HepG2). Here, pullulan polysaccharide was grafted by urocanic acid and α-lipoic acid (α-LA) to obtain a copolymer, α-LA-conjugated N-urocanyl pullulan (LA-URPA), which was expected to have pH and redox dual response. Then, the copolymer LA-URPA was used to encapsulate ginsenoside Rh2 to form Rh2 nanoparticles (Rh2 NPs). The results showed that Rh2 NPs exhibited an average size of 119.87 nm with a uniform spherical morphology. Of note, Rh2 NPs showed a high encapsulation efficiency of 86.00%. Moreover, Rh2 NPs possessed excellent pH/reduction dual-responsive drug release under acidic conditions (pH 5.5) and glutathione (GSH) stimulation with a low drug leakage of 14.8% within 96 h. Furthermore, Rh2 NPs with pH/reduction dual response had higher cytotoxicity than Rh2 after incubation with HepG2 cells for 72 h, indicating that Rh2 NPs had a longer circulation time. After the treatment with Rh2 NPs, the excessive increase of reactive oxygen species and the decrease of superoxide dismutase, glutathione (GSH), and mitochondrial membrane potential suggested that the mitochondrial pathway mediated by oxidative stress played a role in this Rh2 NP-induced apoptosis. In conclusion, this study provides a new strategy for improving the application of ginsenoside Rh2 in the food and pharmaceutical fields.

PH/Reduction dual-responsive comet-shaped PEGylated CQD-DOX conjugate prodrug: Synthesis and self-assembly as tumor nanotheranostics.

Carbon quantum dots (CQDs) show promising potential for tumor imaging owing to their unique superior fluorescent properties. However, the small particle size limits their practical application. Here, pH/reduction dual-responsive comet-shaped PEGylated CQD-DOX conjugate prodrug, DOX-Hy-CQD-SS-PEG with DOX content of 28.5%, was designed with the hydrophobic acid-labile DOX conjugated CQDs as comet nucleus and the few hydrophilic bioreducible detachable PEG brushes as comet tails. The comet-shaped DOX-Hy-CQD-SS-PEG prodrug could self-assemble into unique micelles with mean diameter of 127nm. The DOX-Hy-CQD-SS-PEG micelles possessed excellent pH/reduction dual-responsive drug release with low drug leakage of 9% in 150h. Furthermore, the fluorescent CQDs was recovered after DOX release and de-PEGylation, demonstrating their potential application for real-time response of therapy.

PH-Driven Targeting Nanoprobe with Dual-Responsive Drug Release for Persistent Luminescence Imaging and Chemotherapy of Tumor.

Multifunctional nanoprobes with both imaging and drug delivery capabilities represent an emerging approach to the diagnosis and treatment of tumor. However, poor accumulation in tumor cells and low drug availability are the main limitations for their further application. Here we show a pH-driven targeting nanoprobe with dual-responsive drug release for persistent luminescence imaging and chemotherapy of tumor. The nanoprobe is constructed by conjugating the pH-low-insertion-peptide (pHLIP) to the surface of the core-shell structure of mesoporous silica-coated persistent luminescence nanoparticles (MSPLNPs) with the peptide GFLG and disulfide bond as bridges. The pHLIP functionalized nanoprobe exhibits higher cellular uptake for A549 and HepG2 cells in an acidic extracellular microenvironment (pH < 6.5) than in normal physiological condition (pH 7.4). The nanoprobe possesses well-defined NIR persistent luminescence performance and can be effectively accumulated in the tumor site, leading to the visual HepG2 tumor target imaging without autofluorescence interference. Furthermore, the nanoprobe realizes the dual-responsive release of doxorubicin loaded in the mesoporous channels in systems containing cathepsin B and glutathione, and can effectively kill tumor cells and inhibit the growth of tumor. This integrated nanoprobe possesses great potential for the diagnosis and treatment of tumors with high specificity and efficiency.

Temperature-sensitive polypeptide brushes-coated mesoporous silica nanoparticles for dual-responsive drug release

A biopolymer-inorganic hybrid system (MSN@PBLGF) is designed and fabricated from mesoporous silica nanoparticles (MSNs) and folic acid (FA)-terminated temperature-sensitive synthetic polypeptide, i.e., poly(γ-benzyl-l-glutamate) (PBLG) derivative, through a thiol-disulfide exchange reaction, where MSNs with high drug loading capacity serve as drug nanocarriers and the biocompatible PBLG biopolymer brushes installed on MSN surface through disulfide bonds endow the system with tumor-specific recognition ability and GSH/temperature dual-stimuli responsiveness. Controlled drug release experiments indicate that DOX can be tightly hosted in the system with limited premature release, but efficiently released in response to an increased concentration of GSH and/or an elevated temperature. Intracellular experiments demonstrate that the DOX-loaded MSN@PBLGF nanohybrid shows outstanding cellular uptake and cell-growth inhibition effects on human lung cancer cell line A549 in comparison with healthy human cells such as hepatocyte cells LO2.

Tailored synthesis of hollow MOF/polydopamine Janus nanoparticles for synergistic multi-drug chemo-photothermal therapy

Elaborate design of multifunctional Janus nanoparticles (JNPs) with asymmetric compositions and independent functions has drawn extensive attention in biological fields. Here, a mild synthesis strategy is first explored for the preparation of spherical zeolitic imidazolate framework-8/polydopamine JNPs with hollow structure (H-ZIF-8/PDA JNPs). The resultant H-ZIF-8/PDA JNPs are further selectively functionalized on PDA sides with heptakis-(6-mercapto-6-deoxy)-β-cyclodextrin (CDs) to gain the capability of loading hydrophobic drug (H-ZIF-8/PDA-CD JNPs). Meanwhile, the ZIF-8 domains with hollow cavities can serve as reservoirs for loading hydrophilic drug molecules. Moreover, the pH-sensitive ZIF-8 and the strong near-infrared (NIR) absorption of PDA make the H-ZIF-8/PDA JNPs possess the conversion capacity from laser energy to heat and pH/NIR dual-responsive drug release behaviors. Besides, the Cell Counting Kit-8 (CCK-8), hemolysis and histological assays manifest the excellent biocompatibility of H-ZIF-8/PDA-CD JNPs. The therapeutic results in vitro and in vivo both reveal that the hydrophobic/hydrophilic drugs co-loaded H-ZIF-8/PDA-CD JNPs irradiated by 808 nm laser groups show the best therapeutic efficiency. Taken together, the H-ZIF-8/PDA-CD JNPs are capable of serving as promising platform for cancer treatment through collaborative photothermal and dual-drug chemical therapy.

PEGylated graphene oxide-capped gold nanorods/silica nanoparticles as multifunctional drug delivery platform with enhanced near-infrared responsiveness.

In this paper, near infrared (NIR)-responsive core-shell gold nanorods/mesoporous silica nanoparticles capped with PEGylated graphene oxide (GNRs/SiO2/GO-PEG) were prepared via electrostatic and physical absorption interactions. Hybrid nanoparticles display distinct photothermal stability in physiological environment and acidic media because of the introduction of biocompatible GO-PEG. In addition, due to the high specific surface area of GO-PEG and synergistically enhanced photothermal effect between GO-PEG and GNRs, GNRs/SiO2/GO-PEG nanoparticles exhibit excellent drug loading efficiency and superior photothermal conversion efficiency (39.53%). More importantly, significant pH-/NIR- dual responsive drug release upon NIR irradiation could be observed from GNRs/SiO2/GO-PEG nanoparticles due to the π-π cooperative interaction between GO-PEG and doxorubicin hydrochloride (DOX), and synergistically enhanced NIR-responsiveness derived from GNRs/GO-PEG. The present paper furnishes a green and feasible method to prepare smart core/shell hybrid nanoparticles with high drug loading efficiency and excellent photothermal conversion efficiency, which possess great perspectives as a multifunctional platform for remotely controllable drug delivery.

NIR/pH dual-responsive polysaccharide-encapsulated gold nanorods for enhanced chemo-photothermal therapy of breast cancer.

Combination of different therapy modalities with multiple tumoricidal mechanisms has emerged as a promising anticancer strategy. Herein, we reported an aldehyde/catechol-functionalized hyaluronic acid (DAHA) and hydroxyethyl chitosan (HECS) decorated gold nanorod (GNR) platform for combined chemo-photothermal therapy of breast cancer. The DAHA was synthesized by conjugating dopamine onto oxidized hyaluronic acid. The nanoplatform was prepared by successively modifying GNR with DAHA via Au-catechol bonds, conjugating DOX onto DAHA moiety through Schiff base linkage, and coating HECS interlayer for charge-reversal and hyaluronic acid corona for tumor cell targeting. The resulting nanoplatform GNR-HADOXCH exhibited acid-triggered surface charge-reversal and pH/NIR dual-responsive drug release behaviors. The nanoplatform could be efficiently internalized into MCF-7 breast cancer cells and displayed greater cancer cell killing than individual modalities. Therefore, polysaccharide decoration could ensure the co-delivery of GNR and DOX into cancer cells, and the developed GNR-HADOXCH holds great potential for breast cancer treatment.

Nanoscale Metal-Organic-Frameworks Coated by Biodegradable Organosilica for pH and Redox Dual Responsive Drug Release and High-Performance Anticancer Therapy.

Responsive nanocarriers with biocompatibility and precise drug releasing capability have emerged as a prospective candidate for anticancer treatment. However, the challenges imposed by the complicated preparation process and limited loading capacities have seriously impeded the development of novel multifunctional drug delivery systems. Here, we developed a novel and dual-responsive nanocarrier based on a nanoscale ZIF-8 core and an organosilica shell containing disulfide bridges in its frameworks through a facile and efficient strategy. The prepared ZIF-8@DOX@organosilica nanoparticles (ZDOS NPs) exhibited a well-defined structure and excellent doxorubicin (DOX) loading capability (41.2%) with pH and redox dual-sensitive release properties. The degradation of the organosilica shell was observed after 12 h incubation with a 10 mM reducing agent. Confocal imaging and flow cytometry analysis further proved that the nanocarriers can efficiently enter cells and complete intracellular DOX release under the low pH and high glutathione concentrations, which resulted in an enhanced cytotoxicity of DOX for cancer cells. Meanwhile, subcellular localization experiments revealed that the ZDOS NPs entered cells mainly by endocytosis and then escaped from lysosomes into the cytosol. Moreover, in vivo assays also demonstrated that the ZDOS NPs exhibited negligible systemic toxicity and significantly enhanced anticancer efficiencies compared with free DOX. In summary, our prepared pH and redox dual-responsive nanocarriers provide a potential platform for controlled release and cancer treatment.

Multifunctional PEG-b-polypeptide-decorated gold nanorod for targeted combined chemo-photothermal therapy of breast cancer

The combination of chemotherapy and photothermal therapy is acknowledged as one of the most promising approaches in cancer treatment. Targeted delivery and controlled drug release are two important factors for combined chemo-photothermal therapy. In this study, a multifunctional nanoplatform based on gold nanorod (GNR) decorated with folate-conjugated poly(ethylene glycol)-b-poly(L-γ-glutamylhydrazine) (FEGGH) containing disulfide linker and dihydroxyphenyl groups was developed for targeted combined chemo-photothermal therapy of breast cancer. FEGGH was synthesized by ring-opening polymerization of γ-benzyl-l-glutamate-N-carboxyanhydride using folate/cystamine-heterobifunctionalized poly(ethylene glycol) as an initiator, following by hydrazinolysis and carbodiimide reactions. FEGGH was decorated onto GNR through Au-catechol bonds. Chemotherapeutic drug doxorubicin (DOX) was loaded onto the nanoplatform through pH-sensitive hydrazone linkage, obtaining final product FEGGHDOX-GNR. The DOX-loaded nanoplatform displayed excellent photostability and reduction/pH dual-responsive drug release behavior. Cytological studies demonstrated the effective internalization of FEGGHDOX-GNR into MCF-7 cells via folate-mediated endocytosis and additive therapeutic effect of combined photothermal-chemotherapy. These results indicate that our nanoplatform may be a promising strategy for targeted combined chemo-photothermal therapy of breast cancer.

Octreotide-Conjugated Core-Cross-Linked Micelles with pH/Redox Responsivity Loaded with Etoposide for Neuroendocrine Neoplasms Therapy and Bioimaging with Photoquenching Resistance.

The study of multifunctional polymer micelles combined with chemotherapy due to reduced systemic toxicity and enhanced efficacy has attracted intensive attention. Herein, a multifunctional core-cross-linked hybrid micelle system based on mPEG- b-PGu(BA-TPE) and OCT-PEG- b-PGu(DA-TPE) with pH- and redox-triggered drug release and aggregation-induced emission (AIE) active imaging has been developed for active targeting of neuroendocrine neoplasms (NENs), especially neuroendocrine carcinomas (NECs) with poor prognosis. These micelles showed excellent biocompatibility and stability. After the formation of borate ester bonds, core-cross-linked micelles (CCLMs) showed enhanced emission properties. In addition, etoposide (ETO), one of the most important anticancer drugs of NECs, was loaded into the hydrophobic core of micelles by self-assembly with an average diameter of 274.6 nm and spherical morphology. Octreotide (OCT) conjugated onto the micelles enhanced cellular uptake by receptor-mediated endocytosis. ETO-loaded micelles demonstrated the dual-responsive triggered intracellular drug release and great tumor suppression ability in vitro. Compared with free ETO, ETO-loaded CCLMs exhibited a considerable antitumor effect and significantly reduced side effects. Considering the active tumor targeting, dual-responsive drug release and the AIE effect, the polymer micelle system will be a potential candidate for diagnosis and oncotherapy of NENs.

Black Phosphorus-Based Drug Nanocarrier for Targeted and Synergetic Chemophotothermal Therapy of Acute Lymphoblastic Leukemia

As one of the novel two-dimensional nanomaterials, black phosphorus nanosheets (BP NS) have been proven to be excellent carrier materials for drugs, owing to their fine optical properties and biocompatibility. In this work, a composite drug nanocarrier based on BP NS is proposed, which can perform a synergetic and targeted chemophotothermal therapy of acute lymphoblastic leukemia (ALL). First, BP NS were prepared by an improved liquid exfoliation technique. Then, polyethylene glycol (PEG) was modified on the surfaces of BP NS through electrostatic adsorption. Drug molecules can also be loaded onto the BP NS via electrostatic adsorption. The PEG layer can effectively protect the interior BP NS from water and air to enhance their physiological stability. The obtained PEGylated BP NS (BP NS@PEG) not only demonstrated an excellent photothermal conversion efficiency and photothermal stability but also exhibited a good pH and photothermal dual-responsive drug release behavior. In addition, the BP NS@PEG were further modified with Sgc8 aptamers through covalent bonding. The aptamers provided an efficient specificity toward ALL cells (CCRF-CEM) and greatly increased the endocytosis of the nanocarriers through a receptor-mediated manner, which can further improve the therapeutic effect. Hence, the presented BP NS-based multifunctional nanocarrier can achieve a targeted and synergetic chemophotothermal therapy of ALL, which shows a promising potential in improving the curative efficiency.

BSA modified, disulfide-bridged mesoporous silica with low biotoxicity for dual-responsive drug delivery

Abstract Siliceous materials based intelligent drug delivery systems (DDS) have attracted numerous attentions. Unfortunately, their intrinsic biologic inertia and non-degradability are critical issues need to be addressed because it hampers further clinical translation application. Herein, disulfide-bridged mesoporous silica nanoparticles (designed as mSiO2(s-s)) have been synthesized through nucleophilic substitution reaction, which have biodegradability in simulative tumor reducing conditions. Furthermore, folic acid (FA) decorated bull serum albumin (BSA) has been modified onto the surface of mSiO2(s-s) to improve tissue biocompatibility, prevent anticancer drugs leakage and endow effective targeting capacity. Therefore, the nanoparticles present good biodegradability, tissue biocompatibility, tumor cell targeting capacity and pH/glutathione (GSH) dual-responsive drug release capacity. This novel drug nanocarrier possesses biosafety and effective anti-cancer strategy, provides significant promising in future biomedical application.

PEGylated Poly(α-lipoic acid) Loaded with Doxorubicin as a pH and Reduction Dual Responsive Nanomedicine for Breast Cancer Therapy.

Disulfide-containing nanoparticles are promising vehicles for anticancer drug delivery. However, the preparation of disulfide-containing nanoparticles usually relies on complex synthetic procedures. In the present work, a PEGylated poly(α-lipoic acid) (mPEG-PαLA) copolymer was facilely synthesized and used for pH and reduction dual responsive drug delivery. Poly(α-lipoic acid) was prepared by thermal polymerization of α-lipoic acid without any catalyst or solvent and then conjugated with methoxy poly(ethylene glycol) to form the mPEG-PαLA copolymer. The obtained mPEG-PαLA copolymer was amphiphilic, which could self-assemble into nanoparticles (NPs) in aqueous solution. More interestingly, the mPEG-PαLA NPs showed high drug loading efficiency (87.7%) for the cationic drug doxorubicin (DOX). The DOX-loaded NPs (NPs-DOX) exhibited pH and reduction dual responsive drug release behaviors. Moreover, the flow cytometry analysis and confocal laser scanning microscopy confirmed that the drug-loaded nanoparticles could be efficiently internalized and subsequently release DOX in 4T1 cancer cells. As a result, the NPs-DOX displayed favorable antiproliferation efficacy in 4T1 cancer cells (measured by MTT assays). Furthermore, the NPs-DOX showed enhanced antitumor efficacy in a 4T1 tumor-bearing mice model with reduced side toxicities toward normal organs due to the prolonged circulation time and improved biodistribution in vivo. In other words, this work demonstrates that the PEGylated poly(α-lipoic acid) copolymer can be used as a biocompatible and stimuli-responsive nanocarrier for anticancer drug delivery, which may have potential clinical utility.

PH and Ultrasound Dual-Responsive Polydopamine-Coated Mesoporous Silica Nanoparticles for Controlled Drug Delivery.

A pH- and ultrasound dual-responsive drug release pattern was successfully achieved using mesoporous silica nanoparticles (MSNs) coated with polydopamine (PDA). In this paper, the PDA shell on the MSN surface was obtained through oxidative self-polymerization under the alkaline condition. The morphology and structure of this composite nanoparticle were fully characterized by a series of analyses, such as infrared (IR), transmission electron microscopy, and thermogravimetric analysis. Doxorubicin hydrochloride (DOX)-loaded composite nanoparticles were used to study the performances of responsive drug storage/release behavior, and this kind of hybrid material displayed an apparent pH response in DOX releasing under the acidic condition. Beyond that, upon high-intensity focused ultrasound exposure, loaded DOX in composite nanoparticles was successfully triggered to release from pores because of the ultrasonic cavitation effect, and the DOX-releasing pattern could be optimized into a unique pulsatile fashion by switching the on/off status. From the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, it was observed that our blank nanoparticles showed no toxicity to HeLa cells, but DOX-loaded nanoparticles could inhibit the growth of tumor cells. Furthermore, these composite nanoparticles displayed an effective near-IR photothermal conversion capability with a relatively high conversion efficiency (∼37%). These as-desired drug delivery carriers might have a great potential for future cancer treatment that combine the chemotherapy and photothermal therapy.

Green Reduced Graphene Oxide Toughened Semi-IPN Monolith Hydrogel as Dual Responsive Drug Release System: Rheological, Physicomechanical, and Electrical Evaluations.

Macroporous hydrogel monoliths having tailor-made features, conductivity, superstretchability, excellent biocompatibility, and biodegradability, have become the most nurtured field of interest in soft biomaterials. Green method assisted reduced graphene oxide has been inserted by in situ free radical gelation into semi-IPN hydrogel matrix to fabricate conducting hydrogel. Mechanical toughness has been implemented for the graphene-polymer physisorption interactions with graphene basal planes. Moreover, the as-prepared 3D scaffold type monolith hydrogel has been rheologically superior regarding their high elastic modulus and delayed gel rupturing. κ-Carragenaan, one of the components of the hydrogel, has biodegradable nature. The most significant outcome is their low electrical percolation threshold and reversibly ductile nature. Reversible ductility provides them with rubber-like consistency in flow conditions. Surprising, the hydrogels showed dual stimuli-responsiveness, that is, environmental pH and external electrical stimulation. Electro-stimulation has been adopted here for the first time in semi-IPN systems, which could be an ideal alternative for iontopheretic devices and pulsatile drug release through skin. Regarding this, the hydrogel also has been passed to biocompatibility assay; they are noncytotoxic and show cell proliferation without negligible cell death in live-dead assay. The porosity of the nanocomposite scaffold-like gels was also analyzed by microcomputed tomography (μ-CT), which exhibited their connectivity in cell/voids inside the matrix. Thus, the experimentations are on the support of biocompatible soft material for dual-responsive tunable drug delivery.

Redox and pH Dual-Responsive Polymeric Micelles with Aggregation-Induced Emission Feature for Cellular Imaging and Chemotherapy.

Intelligent polymeric micelles for antitumor drug delivery and tumor bioimaging have drawn a broad attention because of their reduced systemic toxicity, enhanced efficacy of drugs, and potential application of tumor diagnosis. Herein, we developed a multifunctional polymeric micelle system based on a pH and redox dual-responsive mPEG-P(TPE- co-AEMA) copolymer for stimuli-triggered drug release and aggregation-induced emission (AIE) active imaging. These mPEG-P(TPE- co-AEMA)-based micelles showed excellent biocompatibility and emission property, exhibiting great potential application for cellular imaging. Furthermore, the antitumor drug doxorubicin (DOX) could be encapsulated during self-assembly process with high loading efficiency, and a DOX-loaded micelle system with a size of 68.2 nm and narrow size distribution could be obtained. DOX-loaded micelles demonstrated great tumor suppression ability in vitro, and the dual-responsive triggered intracellular drug release could be further traced. Moreover, DOX-loaded micelles could efficiently accumulate at the tumor site because of enhanced permeability and retention effect and long circulation of micelles. Compared with free DOX, DOX-loaded micelles exhibited better antitumor effect and significantly reduced adverse effects. Given the efficient accumulation targeting to tumor tissue, dual-responsive drug release, and excellent AIE property, this polymeric micelle would be a potential candidate for cancer therapy and diagnosis.

Disulfide Bond-Driven Oxidation- and Reduction-Responsive Prodrug Nanoassemblies for Cancer Therapy

Disulfide bonds have been widely used to develop reduction-responsive drug-delivery systems (DDS) for cancer therapy. We propose that disulfide bonds might be also used as an oxidation-responsive linkage just like thioether bonds, which can be oxidized to hydrophilic sulfoxide or sulphone in the presence of oxidation stimuli. To test our hypothesis, we design three novel paclitaxel-citronellol conjugates linked via different lengths of disulfide-bond-containing carbon chain. The prodrugs can self-assemble into uniform-size nanoparticles with impressively high drug loading (>55%). As expected, the disulfide-bond-bridged prodrug nanoparticles show redox dual-responsive drug release. More interestingly, the position of disulfide bonds in the carbon chain linkage has profound impacts on the redox dual responsiveness, thereby affecting the drug release, cytotoxicity, pharmacokinetics, biodistribution, and in vivo antitumor efficacy of prodrug nanoassemblies. The redox dual-responsive mechanism is elucidated, and how the position of disulfide bonds in the carbon chain affects the redox dual responsiveness and antitumor efficiency of prodrug nanoassemblies is also clarified. Our findings give new insight into the stimuli responsiveness of disulfide bonds and provide a good foundation for the development of novel redox dual-responsive DDS for cancer therapy.

A novel redox/pH dual-responsive and hyaluronic acid-decorated multifunctional magnetic complex micelle for targeted gambogic acid delivery for the treatment of triple negative breast cancer

Gambogic acid (GA) is a naturally derived potent anticancer agent with extremely poor biocompatibility. In the present study, a novel of redox/pH dual-responsive multifunctional magnetic complex micelle (sPEG/HA/CSO-SS-Hex/Fe3O4/GA), which consisted of a reducible hexadecanol-modified chitosan oligosaccharide polymer micelle (CSO-SS-Hex) coated with hyaluronic acid (HA) and DCA grafted sheddable PEG-PLL (sPEG) copolymers and loaded with gambogic acid (GA) and Fe3O4 nanoparticles were developed for parenteral delivery for the treatment of triple negative breast cancer (TNBC). The ex vivo study showed that the sPEG shielded cationic HA/CSO-SS-Hex/Fe3O4/GA core at physiological pH but quickly shed off to re-expose the core due to its charge reversible property. The sPEG/HA/CSO-SS-Hex/Fe3O4/GA micelles effectively facilitated tumor-targeted GA delivery by HA, which is a targeting ligand for CD44 receptor of TNBC cells, meanwhile increase GA uptake at the acidic condition but diminished the drug uptake at neutral pH. The in vitro cellular uptake study and in vivo biodistribution and antitumor activity of the formulations were determined, all results showed that the complex micelle enhanced TNBC tumor cellular uptake and fast drug release due to the combined effect of magnet targeting, CD44 receptor-mediated internalization and redox/pH dual-responsive drug release. Hence, tumor-targeted delivery of GA with redox/pH dual-responsive multifunctional magnetic complex micelle sPEG/HA/CSO-SS-Hex/Fe3O4/GA might have potential implications for the chemotherapy of TNBC.

Hyaluronic Acid-Functionalized Gold Nanorods with pH/NIR Dual-Responsive Drug Release for Synergetic Targeted Photothermal Chemotherapy of Breast Cancer.

Tumor-targeted delivery of photothermal agent and controlled release of concomitant chemotherapeutic drug are two key factors for combined photothermal chemotherapy. Herein, we developed a pH/near-infrared (NIR) dual-triggered drug release nanoplatform based on hyaluronic acid (HA)-functionalized gold nanorods (GNRs) for actively targeted synergetic photothermal chemotherapy of breast cancer. Targeting folate (FA), dopamine, and adipic acid dihydrazide triconjugated HA was first synthesized and used to decorate GNRs via Au-catechol bonds, and then an anticarcinogen doxorubicin (DOX) was conjugated onto HA moieties via an acid-labile hydrazone linkage, resulting in multifunctional nanoparticles GNRs-HA-FA-DOX. The nanoparticles exhibited excellent stability and had a pH and NIR dual-responsive drug release behavior. In vitro studies showed that the nanoparticles could be efficiently internalized into breast cancer MCF-7 cells and kill them under NIR irradiation in a synergistic fashion via inducing cell apoptosis. Pharmacokinetics and biodistribution studies in tumor-bearing mice indicated that the nanoparticles had a long blood circulation with a half-life of 2.4 h and exhibited a high accumulation of 11.3% in tumor site. The tumors of mice treated with combined chemotherapy and photothermal therapy were completely suppressed without obvious systemic toxicity after 20 d of treatment. These results demonstrated a great potential of GNRs-HA-FA-DOX nanoparticles for targeted synergistic therapy of breast cancer.