In this study, gold nanorods (GNRs) were incorporated into the hydrogel networks formed by the copolymerization of N-isopropylacrylamide (NIPAm) and methacrylated poly-β-cyclodextrin (MPCD)-based macromer to fabricate an injectable and near-infrared (NIR)/pH-responsive poly(NIPAm-co-MPCD)/GNRs nanocomposite hydrogel, which could serve as a long-acting implant for chemophotothermal synergistic cancer therapy. The nanocomposite hydrogel showed superior mechanical and swelling properties, gelation characteristics, and excellent NIR-responsive property. A hydrophobic acid-labile adamantane-modified doxorubicin (AD-DOX) prodrug was loaded into the hydrogel efficiently by host–guest interaction. The nanocomposite hydrogel exhibited a manner of sustained drug release and could sustain the slow and steady release of DOX for more than 1 month. The pH-responsive release of DOX from the nanocomposite hydrogel was observed owing to the cleavage of acid-labile hydrazone bond between DOX and the adamantyl group in acidic environment. NIR irradiation could accelerate the release of DOX from the networks, which was controlled by the collapse of the hydrogel networks induced by photothermal effect of GNRs. The in vitro cytotoxicity test demonstrated the excellent biocompatibility and photothermal effect of the nanocomposite hydrogel. Moreover, the in situ-forming hydrogel showed promising tissue biocompatibility in the mouse model study. The in vivo antitumor test demonstrated the capacity of the nanocomposite hydrogel for chemophotothermal synergistic therapy with reduced adverse effects owing to the prolonged drug retention in the tumor region and efficient photothermal effect. Therefore, this injectable and NIR/pH-responsive nanocomposite hydrogel exhibited great potential as a long term drug delivery platform for chemophotothermal synergistic cancer therapy.Keywords: chemophotothermal; gold nanorods; host−guest interaction; long-acting implant; nanocomposite hydrogel; NIR/pH-responsive;

In the photodynamic therapy (PDT) of cancer, zinc phthalocyanine (ZnPc) as a photosensitizer possesses superior photosensitive properties. However, the therapeutic effect of ZnPc in PDT is limited due to its aggregation, low solubility and poor selectivity. In this study, charge-reversal phthalocyanine-based coordination polymer nanoparticles (PCPN) are developed for improving the curative effect of ZnPc. Tetra(4-carboxyphenoxy)-phthalocyaninatozinc(II) (TPZnPc) is coordinated with the zinc ion to form the core of PCPN, which is coated with a lipid bilayer by self-assembly (PCPNs@Lip). TPZnPc molecules in the core of PCPN are in the monomeric state and can generate cytotoxic singlet oxygen (1O2) efficiently, which solves the solubility and aggregation problems of ZnPc. Meanwhile, 1,2-dicarboxylic-cyclohexane anhydride modified lysyl-cholesterol (DLC) is functionalized on the surface of PCPN (PCPNs@Lip/DLC), endowing PCPN with a charge-reversal ability which could be triggered by a mildly acidic tumor microenvironment. PCPNs@Lip/DLC is proved to enhance tumor cellular uptake and generate more intracellular 1O2 after irradiation. As confirmed by in vitro and in vivo studies, PCPNs@Lip/DLC remarkably increases the PDT effect. All these results demonstrate that PCPNs@Lip/DLC is a promising nanoplatform for the application of ZnPc in effective PDT.

Bone is the most common organ affected by metastatic breast cancer. Targeting cancers within the bone remains a great challenge due to the inefficient delivery of therapeutic to bone. In this study, a polyethylene glycol (PEG) coated nanoparticles (NPs) made of a Zn2 + coordination polymer was linked with a bone seeking moiety, alendronate (ALN), to deliver cisplatin prodrug (DSP) to the bone. The particle sizes of this novel system, DSP-Zn@PEG-ALN NPs, were regulated by adjusting the volume ratio of water phase to oil phase in microemulsion. It was small enough (about 55 nm) to extravasate through the clefts (80 nm) of the bone's sinusoidal capillaries and localize into metastatic bones. DSP-Zn@PEG-ALN NPs showed much higher affinity for hydroxyapatite in vitro and bone in vivo than non-targeted DSP-Zn@PEG NPs and cisplatin. In addition, the in vivo biodistribution studies demonstrated that about 4-fold of platinum was delivered to the bone metastatic lesions than that in healthy bones by DSP-Zn@PEG-ALN NPs intravenously. Finally, DSP-Zn@PEG-ALN NPs not only inhibited the tumor growth efficiently but also reduced the osteocalastic bone destruction. Besides, DSP-Zn@PEG-ALN NPs showed significantly reduced toxicity of cisplatin. These results indicate that the DSP-Zn@PEG-ALN NPs have a great potential in enhancing chemotherapeutic efficacy for the treatment of bone metastatic breast cancer.Download high-res image (253KB)Download full-size image

Cisplatin (CDDP) is a potent anti-carcinogen that is widely used for various solid tumors; however, its clinical application is limited by its severe nephrotoxicity. Novel platinum–bisphosphonate polymer–metal complex nanoparticles (Pt–bp NPs), based on platinum–bisphosphonate coordination, have been established. Three polymer carriers bearing alendronate (ALN) ligands, while containing different lengths of alkyl hydrophobic chains, were synthesized. Their structures were characterized by 1H NMR, 31P NMR and FTIR. The ALN was used to coordinate to the CDDP precursor [Pt(NH3)2(OSO3)(OH2)], and the Pt–bp NPs were formed spontaneously. The Pt–bp NPs formed by the polymer carrier, ALN-PEG2k-ASAC18, which contained the poly(ethylene glycol) chain with ALN on one side and the octadecyl hydrophobic chain on the other side, was denoted as ALN-ASAC18-CDDP; its diameter was within 200 nm. CDDP was released in a Cl− or pH-dependent manner. The cytotoxic effects to the HeLa, A549 and MCF-7 cell lines were relatively weak, compared to CDDP. However, ALN-ASAC18-CDDP showed significantly prolonged blood circulation time and tumor accumulation of platinum of 2.5-fold, compared to CDDP at 8 h. Besides, ALN-ASAC18-CDDP was demonstrated to remarkably reduce systemic toxicity without compromising in vivo antitumor activity. These results indicate that the facilely prepared ALN-ASAC18-CDDP has great utilization potential for CDDP delivery in a clinical setting.

Emodin, a potential anti-diabetic nephropathy agent, is limited by its oral use due to the poor water solubility. The present study aimed to enhance the absorption and the suppressive effects of emodin on renal fibrosis by developing a self-microemulsifying drug delivery system (SMEDDS). Solubility studies, compatibility tests, pseudo-ternary phase diagrams analysis and central composite design were carried out to obtain the optimized formulation. The average droplet size of emodin-loaded SMEDDS was about 18.31 ± 0.12 nm, and the droplet size and zeta potential remained stable at different dilution ratios of water and different values of pH varying from 1.2 to 7.2. Enhanced cellular uptake in both the Caco-2 cells and glomerular mesangial cells (GMCs) is great advantageous for the formulation. The AUC0–24 h of emodin-loaded SMEDDS was 1.87-fold greater than that of emodin suspension, which may be attributed to enhanced uptake in Caco-2 cells. Moreover, emodin-loaded SMEDDS showed better suppressive effects on the protein level of fibronectin (FN), transforming growth factor-beta 1 (TGF-β1) and intercellular adhesion molecule 1 (ICAM-1) than the crude emodin in advanced glycation-end products (AGEs)-induced GMCs and renal tubular epithelial cells (NRK-52E). Our study illustrated that developed SMEDDS improved the oral absorption of emodin, and attained better suppressive effects on the protein level of renal fibrosis compositions in AGEs-induced GMCs and NRK-52E cells.Download high-res image (299KB)Download full-size image

Because of the peculiarity of the bone microstructure, the uptake of chemotherapeutics often happens at non-targeted sites, which induces side effects. In order to solve this problem, we designed a bone-targeting drug delivery system that can release drug exclusively in the nidus of the bone. Alendronate (ALN), which has a high ability to target to hydroxyapatite, was used to fabricate double ALN-conjugated poly (ethylene glycol) 2000 material (ALN-PEG2k-ALN). The ALN-PEG2k-ALN was characterized using 1H NMR and 31P NMR and FTIR. ALN-PEG2k-ALN-modified calcium phosphate nanoparticles (APA-CPNPs) with an ALN targeting moiety and hydrophilic poly (ethylene glycol) arms tiled on the surface was prepared for bone-targeted drug delivery. The distribution of ALN-PEG2k-ALN was tested by X-ray photoelectron spectroscopy. Isothermal titration calorimetry data indicated that similar to free ALN, both ALN-PEG2k-ALN and APA-CPNPs can bind to calcium ions. The bone-binding ability of APA-CPNPs was verified via ex vivo imaging of bone fragments. An in vitro release experiment demonstrated that APA-CPNPs can release drug faster in an acid environment than a neutral environment. Cell viability experiments indicated that blank APA-CPNPs possessed excellent biocompatibility with normal cells. Methotrexate (MTX) loaded APA-CPNPs have the same ability to inhibit cancer cells as free drug at high concentrations, while they are slightly weaker at low concentrations. All of these experiments verified the prospective application of APA-CPNPs as a bone-targeting drug delivery system.Download high-res image (103KB)Download full-size image

•AGM/HPβ-CD inclusion complexes was prepared successfully by freeze-drying.•The inclusion mechanism was evaluated by variety of methods including 1H NMR and molecular modeling.•The oral bioavailability of AGM was significantly enhanced by inclusion technology.Agomelatine (AGM), is efficacious in both the acute phase and the continuation phase of depression. However, its poor water-solubility, low bioavailability and polymorphism limit its pharmacological effects. To address these problems, agomelatine-hydroxypropyl-β-cyclodextrin inclusion complex (AGM/HPβ-CD) was prepared successfully by freeze-drying. The products was evaluated by structural characterization, solubilization test, in-situ absorption of rat intestinal tract and pharmacokinetic study. In addition, thermodynamic studies were performed, the results indicated that the inclusion process was enthalpy-determined and exothermic nature of complexation, signifying the role of steric interactions in complex formation. Molecular docking of AGM with HPβ-CD has been conducted as well to verify the experimental findings and predict the stable molecular structure of the inclusion complex. The in vivo data showed that, AGM was mainly absorbed in duodenum and jejunum by passive diffusion. AGM/HPβ-CD inclusion complex displayed earlier Tmax and higher Cmax, and the AUC0-12h was approximately twice larger than its physical mixture. These results suggested that AGM/HPβ-CD inclusion complex was established with 1:1 stoichiometry through the naphthalene group of AGM and it was deeply inserted into the cavity of HPβ-CD, and the inclusion complex could significantly enhance the oral bioavailability of AGM.

Lymphatic metastasis plays an important role in tumour recurrence. The applications of nanoparticles in the treatment of lymphatic metastatic tumours have been limited by targeting inefficiency and nonselective toxicity. Hence, in this report, we have developed lipid-coated ZnO nanoparticles (LZnO NPs) in an attempt to solve these issues. Using the microreactor method, we have fabricated ultrasmall (∼30 nm) core–shell-structured nanoparticles loaded with 6-mercaptopurine (6-MP). In vivo results show that the lipid shell induces a remarkable improvement in lymphotropism and biocompatibility compared to ZnO nanoparticles. Furthermore, the ZnO core exhibits not only pH-responsive behaviour to guarantee effective drug delivery, but also a strong preferential ability to kill cancerous cells, as a consequence of the generation of higher inducible levels of reactive oxygen species in rapidly dividing cells. Furthermore, LZnO NPs enhance the cytotoxicity of 6-MP, resulting from the improved internalization of nanoparticles through endocytosis. These findings indicate that LZnO NPs are a promising candidate for use as lymphatic-targeted drug carriers.

One of the most important and challenging goals in pharmaceutical prevention for posterior capsule opacification is to preserve an effective drug concentration in capsular bag for a long period without affecting the patients' vision. Here, a novel kind of composite, which was prepared by 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) via a two-step process, was applied for capsular tension ring (CTR) as an implant that could deliver docetaxel (DTX) over a long period of time. The drug release rate of the composite could be controlled by the ethyleneglycol dimethacrylate (EGDMA) content and the ratio of HEMA/MMA as well as the structure of porous PMMA framework. The CTR could continuously release DTX for up to 6 weeks in vitro and maintain DTX in effective concentration in the aqueous humor after 42 days. Docetaxel-load capsular tension ring (DTX–CTR) presented strong inhibition on the lens epithelial cells in-vivo without obvious damage to normal tissues. These results indicate that the drug sustained-release CTR can provide a promising application in posterior capsule opacification prevention.

The aim of the present study was to develop layered double hydroxide (LDH) nanoparticles coated with PEGylated phospholipid membrane. By comparing the size distribution and zeta potential, the weight ratio of LDH to lipid materials which constitute the outside membrane was identified as 2:1. Transmission electron microscopy photographs confirmed the core-shell structure of PEGylated phospholipid membrane coated LDH (PEG-PLDH) nanoparticles, and cell cytotoxicity assay showed their good cell viability on Hela and BALB/C-3T3 cells over the concentration range from 0.5 to 50 μg/mL.

In the present study, Form I, Form II and Form III of agomelatine were prepared to investigate the variability of polymorphs, then the in-vitro in-vivo correlation were established. The presence of three polymorphs of agomelatine was corroborated through studies by XRPD, TGA and DSC. All the forms obtained were then subjected to the powder and intrinsic dissolution tests. The IDR ranked in the order of Form III > Form I > Form II. Form I and Form III both underwent solvent-mediated phase transformation (SMPT) to Form II during dissolution and the transition points were 62 and 45 min, respectively. Pharmacokinetic profiles were acquired after oral administration of tablets, showing that the ka and AUC0–12 h of Form I, Form II, Form III were 0.58 ± 0.11, 0.34 ± 0.05, 0.74 ± 0.07 h−1 and 296.25 ± 49.39, 186.05 ± 45.93, 331.16 ± 54.74 ng*h/ml, respectively. Good linearities between IDR and ka, IDR and AUC were established, suggesting that the agomelatine polymorphic forms with faster dissolution rates in-vitro would increase the rate and extent of oral absorption in-vivo. These results demonstrated that IDR was predictive in estimating the relative bioavailability of agomelatine polymorphic forms.

Docetaxel-loaded sustained-release preparation based on 2-Hydroxyethyl methacrylate (HEMA) and Methyl methacrylate (MMA) cross-linked copolymer (P(HEMA-co-MMA)) was prepared to examine the potential use for preventing posterior capsule opacification (PCO). The preparations were prepared by polymerizing the mixture of HEMA, MMA, cross-linking agent (EGDMA), initiator (AIBN) and docetaxel. The influence factors and mechanism of drug release were studied in the experiments. FT-IR, X-RD and SEM methods were used to characterize the polymer (P(HEMA-co-MMA)) and docetaxel-loaded sustained-release preparations. Biocompatibility of P(HEMA-co-MMA) and in-vitro effect of docetaxel-loaded sustained-release preparations were also evaluated. The results showed that docetaxel could release sustainedly from these preparations prepared by cross-linking polymerization. And the release rate could be accelerated by increasing the MMA ratio or EGDMA ratio of the polymer. Release mechanism of docetaxel fitted the Higuchi model well. The results of IR and X-RD showed that only a hydrogen bond was formed between docetaxel and P(HEMA-co-MMA). Docetaxel dispersed in P(HEMA-co-MMA) in amorphous form. The elution test showed that P(HEMA-co-MMA) had good biocompatibility and the in-vitro pharmacodynamics study proved that docetaxel could release stably from the preparations and inhibit HLECs' proliferation. The docetaxel-loaded sustained-release preparations proved to be a promising therapy for preventing PCO. These results also lay a theoretical and experimental foundation for the future.

Lymphatic metastasis plays an important role in tumour recurrence. The applications of nanoparticles in the treatment of lymphatic metastatic tumours have been limited by targeting inefficiency and nonselective toxicity. Hence, in this report, we have developed lipid-coated ZnO nanoparticles (LZnO NPs) in an attempt to solve these issues. Using the microreactor method, we have fabricated ultrasmall (∼30 nm) core–shell-structured nanoparticles loaded with 6-mercaptopurine (6-MP). In vivo results show that the lipid shell induces a remarkable improvement in lymphotropism and biocompatibility compared to ZnO nanoparticles. Furthermore, the ZnO core exhibits not only pH-responsive behaviour to guarantee effective drug delivery, but also a strong preferential ability to kill cancerous cells, as a consequence of the generation of higher inducible levels of reactive oxygen species in rapidly dividing cells. Furthermore, LZnO NPs enhance the cytotoxicity of 6-MP, resulting from the improved internalization of nanoparticles through endocytosis. These findings indicate that LZnO NPs are a promising candidate for use as lymphatic-targeted drug carriers.