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Conventional surgical methods can not completely remove the tumor cells, and an inevitable recurrence always results in death. In this study, we prepared a conformal hydrogel nanocomposite with potential to inhibit the recurrence of glioma. Based on the MRI of a patient's brain tumor cavity (BTC), we 3D-printed a mould for preparing the customized implants that could match the resection cavity. The obtained macroporous hydrogel, containing Paclitaxel (PTX) nanoparticles, could sustained release PTX. From the confocal microscopy image, we could detect that the hydrogel nanocomposite combined with nanoparticles uniformly. The nanoparticles were fabricated through a self-assembled process with PTX. Moreover, the in vitro studies showed that nanoparticles could release PTX slowly and efficiently inhibited the proliferation of tumor cells. This work prepared a conformal hydrogel nanocomposite for local delivery of paclitaxel, which could inspire the development of future protocols for precision therapy of residual glioma after surgical resection.

A facile one-pot synthetic strategy was explored to synthesize carbon/calcium phosphate/Fe3O4 composite nanoparticles (carbon/CaP/Fe3O4 composite NPs). Taking advantage of the unique structure including mesoporous, small CaP and Fe3O4 subunits homogeneously distributed in a carbon matrix, carbon/CaP/Fe3O4 NPs integrate high drug loading, pH/NIR-sensitive, photothermal and magnetic properties into one nanoplatform for cancer theranostics.

Doxorubicin (Dox) is a broad-spectrum antitumor drug used for the treatment of many types of malignant tumors. Although it possesses powerful antitumor activity, its clinical application is seriously encumbered by its unselective distribution and systemic toxicities, particularly myocardial toxicity. Thus, it is imperative to modify Dox to decrease its systemic toxicities and improve its therapeutic index. In the present study, we adopted a novel type of monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to encapsulate Dox to prepare Dox-loaded MPEG-PCL (Dox/MPEG-PCL) nanoparticles by a controllable self-assembly process. The cellular uptake efficiency and cell proliferation inhibition of the Dox/MPEG-PCL nanoparticles were examined. The antitumor activity of the Dox/MPEG-PCL nanoparticles was tested on a multiple pulmonary metastasis model of melanoma on C57BL/6 mice. Systemic toxicities and survival time were compared between the mice treated with the Dox/MPEG-PCL nanoparticles and free Dox. The potential myocardial toxicity of the Dox/MPEG-PCL nanoparticles was investigated using a prolonged observation period. Encapsulation of Dox in MPEG-PCL nanoparticles significantly improved the cellular uptake and cell proliferation inhibition of Dox in vivo. Intravenous injection of Dox/MPEG-PCL nanoparticles obtained significant inhibition of the growth and metastasis of melanoma in the lung and prolonged survival time compared with free Dox (P<0.05). The Dox/MPEG-PCL nanoparticles did not show obvious additional systemic toxicities compared with free Dox during the treatment time. During the prolonged observation period, obvious decreased cardiac toxicity was observed in the Dox/MPEG-PCL nanoparticle-treated mice compared with that observed in the free Dox-treated mice. These results indicated that encapsulating Dox with MPEG-PCL micelles could significantly promote its antitumor activity and reduce its toxicity to the myocardium.

Camptothecin (CPT) exerts very strong antitumor activities by suppressing the activity of DNA topoisomerase I, but its application is greatly limited owing to its low solubility and the instability of the active lactone form. To overcome this bottleneck, we prepared the novel camptothecin nanocolloids based on N-trimethyl chitosan (CPT-TMC) to efficiently administer CPT systemically. In this study, we investigated the antitumor activity of CPT-TMC against both colon cancer and lung cancer. In vitro cell experiments both CPT and CPT-TMC significantly inhibited the growth of CT26 cells and LL/2 cells, but no statistical difference was observed between CPT-TMC and CPT. In vivo studies, CPT-TMC more effectively inhibited tumor growth and prolonged survival time than CPT both in the CT26 colon carcinoma subcutaneous model and in the LL/2 Lewis lung carcinoma subcutaneous model. In addition, results of PCNA and CD31 immunohistochemical staining of tumor tissues also confirmed the improved antitumor effect of CPT-TMC. These findings suggest that N-trimethyl chitosan could increase the antitumor effect of CPT. Consequently, CPT delivery by N-trimethyl chitosan is a potential approach for effective treatment of cancer.

Nanocarriers with positive surface charges are known for their toxicity which has limited their clinical applications. The mechanism underlying their toxicity, such as the induction of inflammatory response, remains largely unknown. In the present study we found that injection of cationic nanocarriers, including cationic liposomes, PEI, and chitosan, led to the rapid appearance of necrotic cells. Cell necrosis induced by cationic nanocarriers is dependent on their positive surface charges, but does not require RIP1 and Mlkl. Instead, intracellular Na(+) overload was found to accompany the cell death. Depletion of Na(+) in culture medium or pretreatment of cells with the Na(+)/K(+)-ATPase cation-binding site inhibitor ouabain, protected cells from cell necrosis. Moreover, treatment with cationic nanocarriers inhibited Na(+)/K(+)-ATPase activity both in vitro and in vivo. The computational simulation showed that cationic carriers could interact with cation-binding site of Na(+)/K(+)-ATPase. Mice pretreated with a small dose of ouabain showed improved survival after injection of a lethal dose of cationic nanocarriers. Further analyses suggest that cell necrosis induced by cationic nanocarriers and the resulting leakage of mitochondrial DNA could trigger severe inflammation in vivo, which is mediated by a pathway involving TLR9 and MyD88 signaling. Taken together, our results reveal a novel mechanism whereby cationic nanocarriers induce acute cell necrosis through the interaction with Na(+)/K(+)-ATPase, with the subsequent exposure of mitochondrial damage-associated molecular patterns as a key event that mediates the inflammatory responses. Our study has important implications for evaluating the biocompatibility of nanocarriers and designing better and safer ones for drug delivery.

Star-shaped polymer micelles have good stability against dilution with water, showing promising application in drug delivery. In this work, biodegradable micelles made from star-shaped poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) copolymer were prepared and used to deliver doxorubicin (Dox) in vitro and in vivo. First, an acrylated monomethoxy poly (ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) diblock copolymer was synthesized, which then self-assembled into micelles, with a core-shell structure, in water. Then, the double bonds at the end of the PCL blocks were conjugated together by radical polymerization, forming star-shaped MPEG-PCL (SSMPEG-PCL) micelles. These SSMPEG-PCL micelles were monodispersed (polydispersity index = 0.11), with mean diameter of ≈25 nm, in water. Blank SSMPEG-PCL micelles had little cytotoxicity and did not induce obvious hemolysis in vitro. The critical micelle concentration of the SSMPEG-PCL micelles was five times lower than that of the MPEG-PCL micelles. Dox was directly loaded into SSMPEG-PCL micelles by a pH-induced self-assembly method. Dox loading did not significantly affect the particle size of SSMPEG-PCL micelles. Dox-loaded SSMPEG-PCL (Dox/SSMPEG-PCL) micelles slowly released Dox in vitro, and the Dox release at pH 5.5 was faster than that at pH 7.0. Also, encapsulation of Dox in SSMPEG-PCL micelles enhanced the anticancer activity of Dox in vitro. Furthermore, the therapeutic efficiency of Dox/SSMPEG-PCL on colon cancer mouse model was evaluated. Dox/SSMPEG-PCL caused a more significant inhibitory effect on tumor growth than did free Dox or controls (P < 0.05), which indicated that Dox/SSMPEG-PCL had enhanced anticolon cancer activity in vivo. Analysis with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) showed that Dox/SSMPEG-PCL induced more tumor cell apoptosis than free Dox or controls. These results suggested that SSMPEG-PCL micelles have promising application in doxorubicin delivery for the enhancement of anticancer effect.

Some bladder disease therapies can benefit from intravesical drug delivery, which involves direct instillation of drug into the bladder via a catheter, to attain high local concentrations of the drug with minimal systemic effects. Deguelin is a potential anticancer agent, however, its poor water solubility and neurotoxicity restrict its clinical application. To address these challenges, we investigated the promising application of deguelin in the intravesical therapy of bladder cancer by designing a novel intravesical drug delivery system for deguelin. It was found that deguelin could efficiently kill bladder cancer cells and inhibit angiogenesis. Intravesically administrated deguelin had better tolerance than systemically applied deguelin. Encapsulation of deguelin in cationic DOTAP and monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) hybrid nanoparticles (DMP) created the deguelin loaded DMP nanoparticles (D/DMP). They had a mean particle size of 35 nm and zeta potential of 21 mV, rendering deguelin completely dispersible in aqueous media. Encapsulation of deguelin in cationic DMP nanoparticles enhanced the anticancer activity of deguelin in vitro. In addition, D/DMP nanoparticles were incorporated into a thermo-sensitive Pluronic F127 hydrogel, forming a novel D/DMP-F system, which remained in a flowing liquid state at lower than 25 °C, but underwent gelation at higher temperatures. The DMP nanoparticles in the F127 hydrogel system (DMP-F) could significantly extend the hydrophobic drug residence time and increase the drug concentration within the bladder. These results suggested that DMP-F was a good intravesical drug delivery system and D/DMP-F may have promising applications in intravesical therapy of bladder cancer.

Micelles assembled from amphiphilic poly(ethylene glycol)/poly(-caprolactone) (PEG/PCL) copolymers are promised as safe and effective drug delivery systems. They offer the potential to achieve high solubility of hydrophobic drugs, long blood circulation time and effective delivery to target organs. These advantages contribute to their application as vehicles of a broad variation of therapeutic compounds. In this review, we discussed the safety of the copolymers, release behavior of PEG/PCL micelles in vitro, and pharmacokinetic profiles referring to the optimized fate in vascular system and targeting biodistribution.

Nanotechnology provides researchers with new tools for cancer treatment. Biodegradable polymeric nanoparticles, as an advanced drug delivery system, have promising applications in cancer treatment. Poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) copolymers are biodegradable and amphiphilic, and show potential application in drug delivery. In recent years, PCL/PEG copolymeric nanoparticles, as a potential nanoplatform for anticancer agent delivery, received increasing attention. This paper reviews PCL/PEG copolymer nanoparticles for anticancer agent delivery, including overcoming water insolubility of hydrophobic drug, targeting chemotherapeutic drug to tumor, and delivering genes, vaccines, and diagnostic agents.

In an attempt to improve anticancer activity and reduce systemic toxicity of doxorubicin (Dox), we encapsulated Dox in monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles by a novel self-assembly procedure without using surfactants, organic solvents or vigorous stirring. These Dox encapsulated MPEG-PCL (Dox/MPEG-PCL) micelles with drug loading of 4.2% were monodisperse and ∼ 20 nm in diameter. The Dox can be released from the Dox/MPEG-PCL micelles; the Dox-release at pH 5.5 was faster than that at pH 7.0. Encapsulation of Dox in MPEG-PCL micelles enhanced the cellular uptake and cytotoxicity of Dox on the C-26 colon carcinoma cell in vitro, and slowed the extravasation of Dox in the transgenic zebrafish model. Compared to free Dox, Dox/MPEG-PCL micelles were more effective in inhibiting tumor growth in the subcutaneous C-26 colon carcinoma and Lewis lung carcinoma models, and prolonging survival of mice bearing these tumors. Dox/MPEG-PCL micelles also induced lower systemic toxicity than free Dox. In conclusion, incorporation of Dox in MPEG-PCL micelles enhanced the anticancer activity and decreased the systemic toxicity of Dox; these Dox/MPEG-PCL micelles are an interesting formulation of Dox and may have potential clinical applications in cancer therapy.

Honokiol (HK) shows potential application in cancer treatment, but its poor water solubility restricts clinical application greatly. In this paper, monomethoxy poly(ethylene glycol)-poly(lactic acid) (MPEG-PLA) was synthesized by ring-opening polymerization and processed into nanoparticle for honokiol delivery. Chemical structure of the synthesized polymer was confirmed by (1)H NMR, and its molecular weight was determined by gel permeation chromatography (GPC). Honokiol loaded MPEG-PLA nanoparticles were prepared by solvent extract method. And particle size distribution, morphology, drug loading, drug release profile and anticancer activity in vitro were studied in detail. The described honokiol loaded MPEG-PLA nanoparticles in this paper might be a novel formulation for honokiol delivery., (Copyright 2009 Elsevier B.V. All rights reserved.)

In the present study, we prepared poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) nanomaterials by solvent-extraction method. The obtained PCEC nanomaterials were studied extensively for acute toxicity and genotoxicity using bacterial reverse mutation test (Ames test), chromosomal aberration test and mouse micronucleus test. All of the Sprague-Dawley rats did not show any mortality and clinical signs of toxicity after intravenous injection at the level of 2.4g/kg body weight. Thus, the LD(50) of PCEC nanomaterials was determined to be greater than 2.4g/kg. In Ames test, PCEC nanomaterials were negative in Salmonellatyphimurium strains TA97, TA98, TA100, TA102, and TA1535 with or without metabolic activation. PCEC nanomaterials did not induce chromosomal aberrations in cultured Chinese hamster lung cells up to 5000mug/mL with or without metabolic activation. Micronucleus assay demonstrated that PCEC nanomaterials did not significantly increase micronucleated polychromatic erythrocytes (MNPCE) in the bone marrow of ICR mice or suppress bone marrow, indicating they did not cause chromosome aberrations. In conclusion, our results indicated that PCEC nanomaterials did not cause any acute toxicity and genotoxicity in our experimental conditions. Its potential to be a candidate of drug carrier is worth being further investigated., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Honokiol (HK) can efficiently inhibit the growth of tumors. However, its clinical applications have been restricted by its extreme hydrophobicity. We hope to improve its water solubility by nanotechnology. And we wonder whether a novel honokiol nanoparticles-loaded thermosensitive poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) hydrogel (HK-hydrogel) could improve the therapeutic efficacy on malignant pleural effusion (MPE). To evaluate the therapeutic effects of HK-hydrogel on MPE, MPE-bearing mice were administered intrapleurally with HK-hydrogel, HK nanoparticles (HK-NP), blank hydrogel, or normal saline (NS) at days 4 and 11 after Lewis lung carcinoma (LLC) cells inoculation, respectively. Pleural tumor foci and survival time were observed, and antiangiogenesis of HK-hydrogel was determined by CD31. Histological analysis and assessment of apoptotic cells were also conducted in tumor tissues. HK-hydrogel reduced the number of pleural tumor foci, while prolonging the survival time of MPE-bearing mice, more effectively, as compared with control groups. In addition, HK-hydrogel successfully inhibited angiogenesis as assessed by CD31 (P < 0.05). Histological analysis of pleural tumors exhibited that HK-hydrogel led to the increased rate of apoptosis. This work is important for the further application of HK-hydrogel in the treatment of MPE.

In this work, a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) hydrogel was studied. The prepared PCEC hydrogel undergoes temperature-dependent sol-gel-sol transition, which is a flowing sol at ambient temperature and turns into a non-flowing gel at around physiological body temperature. Furthermore, the sol-gel phase transition mechanism was investigated using (13)C-nuclear magnetic resonance imaging and a laser diffraction particle size analyzer. The in vitro release behaviors of several model drugs, including a hydrophilic small-molecule drug, a hydrophobic small-molecule drug and a macromolecular protein drug, from PCEC hydrogel were also investigated in detail. The results showed that the model drugs could be released from the PCEC hydrogel system over a sustained period. In addition, an anaesthesia assay was conducted using the tail flick latency (TFL) test to evaluate the in vivo controlled drug delivery effect of the PCEC hydrogel system. In the TFL assay, a lidocaine-loaded PCEC hydrogel produced significantly longer-lasting local anaesthetic effects compared with lidocaine aqueous solution at the same dose. Therefore, PCEC hydrogel is promising for use as an injectable local drug delivery system.

Rapid local transdermal anaesthetic is desirable in clinic. In this paper, lidocaine loaded poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL) nanoparticles were prepared, and a novel transdermal lidocaine formulation: lidocaine loaded PCL-PEG-PCL nanoparticles in F127 hydrogel (Nano-Lido Gel), was demonstrated. These lidocaine loaded PCL-PEG-PCL nanoparticles with mean particle size of ca. 200 nm had drug loading of about 40%. The efficiency of transdermal anaesthesia of four treatments: EMLA cream (E), Nano-Lido Gel (N), EMLA cream with brief focal ultrasound pretreatment (EU), and Nano-Lidocaine Gel with brief focal ultrasound pretreatment (NU), was evaluated by tail-flick latency test assay in rats. Results indicated that the topical anaesthesia onset time in NU was 5 times and 2.5 times shorter than that in E and EU. The efficiency of anaesthesia in NU, expressed as maximum possible effects (MPE) value, was significantly higher than that in other treatments. It provided a novel path to develop rapid transdermal anaesthesia by combination of ultrasound pretreatment and lidocaine nano-formulation based on polymeric nanoparticles.

Poly(epsilon-caprolactone)-poly(ethylene glycol) (PCL-PEG) copolymers are important synthetic biomedical materials with amphiphilicity, controlled biodegradability, and great biocompatibility. They have great potential application in the fields of nanotechnology, tissue engineering, pharmaceutics, and medicinal chemistry. This review introduced several aspects of PCL-PEG copolymers, including synthetic chemistry, PCL-PEG micro/nanoparticles, PCL-PEG hydrogels, and physicochemical and toxicological properties.