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Micellar nanoparticles have unique advantages as carriers for therapeutic or imaging agents, owing to their smaller size and better penetration of tumors. However, some agents, due to their physical or chemical properties, are difficult to load into micelles. IR780 is one of these agents, and is also a promising near-infrared dye for fluorescence imaging (FI)/photoacoustic imaging (PAI) and cancer photothermal therapy (PTT). Its hydrophobic and high crystallization structure results in limited bioavailability in vivo. It is difficult to load into micelles constructed from an amphiphilic block polymer with relatively low molecular weight. In this study, we use computer simulation and introduce another small biomolecule, α-lipoic acid, into the micelles constructed from a mPEG-PCL copolymer, to lower the energy of molecular interaction between MPEG-PCL and IR780, and expect to enhance the loading capacity of the micelles to IR780. The introduction of α-lipoic acid decreases the energy of molecular interaction between MEPG-PCL and IR780 from -46.18 kJ mol-1 to -196.52 kJ mol-1 and increases the loading capacity and stability of the mPEG-PCL micelles to IR780, which also maintains the loading capacity to DTX. We further construct DTX/IR780 co-loaded mPEG-PCL micelles for FI/PAI dual modal imaging guided PTT/chemotherapy of cancer. By FI and PAI evaluation in vitro and in vivo, we demonstrate that the DTX/IR780 co-loaded micelles can be used as FI and PAI probes. By further evaluating the therapeutic outcome of PTT/chemotherapy co-therapy of breast cancer, we demonstrate that the DTX/IR780 co-loaded mPEG-PCL micelles can serve as promising candidates for FI and PAI guided PTT/chemotherapy of breast cancer.

Polymeric micelles have presented superior delivery properties for poorly water-soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed.

Chemotherapy for breast cancer is significantly restricted by the tumor's physio-pathological complexity. Here we have constructed a targeted nano-system based on PEGylated poly (D, L-lactide) (PEG-PDLLA) using a novel ligand, CLKADKAKC (CK3) peptide, for active targeting to Neuropilin-1-rich breast cancer cells. CK3 increased the cellular uptake of micelles 4.7-fold compared with the free drug and nearly 2.2-fold compared with the unmodified micelles (PM), respectively. Furthermore, in vivo imaging revealed that CK3-modified micelles (CK3-PM) had excellent specific tumor cells targeting and the drug accumulation was also enhanced. When paclitaxel (PTX) was loaded into micelles, CK3-PM-PTX induced the strongest inhibition and apoptosis against MDA-MB-231 cells in vitro and in vivo. These results demonstrated that CK3-modified PEG-PDLLA micelles developed in this study could be a potential targeted vehicle for enhancing the chemotherapy of breast cancers.

In this study, PEG-derivatized octacosanol copolymer was successfully developed to improve the anti-tumor activity and eliminate toxicity of the commercial formulation of paclitaxel (PTX). MPEG2K-C28, the conjugation of monomethoxy Poly(ethylene glycol) 2000 and octacosanol, was readily soluble in aqueous solution and self-assembled to form micelles with small sizes (< 20 nm) that are efficient in encapsulating PTX with a drug loading of 9.38 ± 0.18% and an encapsulation efficiency of 93.90 ± 2.12%. Meanwhile, octacosanol is very safe for humans and amazingly exhibits antitumor activity through inhibition activity of matrix metalloproteinases (MMPs) and translocation of the transcription factor (nuclear factor-kappa B, NF-κB) to the nucleus, which may be able to promote synergistic effects with PTX. A sustained and slower in vitro release behavior was observed in the (PTX micelles) than that of Taxol. PTX micelles exhibited more potent cytotoxicity than Taxol in the 4T1 breast cancer cell line. More interestingly, MPEG2K-C28 selectively inhibited the growth of 4T1 cells rather than the normal cells (HEK293 and L929 cell lines), indicating the antitumor activity of octacosanol remained after conjugation with MPEG. Acute toxicity evaluations indicated that MPEG2K-C28 was a safe drug carrier. Pharmacokinetic study revealed that PTX micelles improved the T1/2 and AUC of PTX (compared with Taxol) from 1.910 ± 0.139 h and 13.999 ± 1.109 mg/l × h to 2.876 ± 0.532 h and 76.462 ± 8.619 mg/l × h in vivo, respectively. The maximal tolerated dose (MTD) for PTX micelles (ca. 120 mg PTX/kg) in mice was significantly higher than that for Taxol (ca. 20mg PTX/kg). PTX micelles exhibited slightly better antitumor activity than Taxol but safer in 4T1 breast cancer model in vivo. The cell apoptosis in the immunofluorescent studies and the cell proliferation in the immunohistochemical studies also proved the results. In conclusion, MPEG2K-C28 is a simple, safe and effective drug delivery carrier for PTX, and has some therapeutic effects in 4T1 cells in vitro. PTX micelles showed significant antitumor activity in vivo with low systemic toxicity in 4T1 breast cancer. MPEG2K-C28 micelles entrapping PTX deserve more studies in the future., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aim: To make delivery improvements via delivery systems for 6-(4-morpholino-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (DZO) - a model compound of hydrophobic antitumor candidate pyridazinone derivatives., Materials & Methods: Methoxy poly(ethylene glycol)-poly(D,L-lactide) (MPEG-PDLLA) micelle was employed as a vector, and DZO was encapsulated in. The DZO-loaded micelles were characterized in detail and its cytotoxicity, maximum tolerated dose (MTD) and pharmacokinetic experiments were done. In vivo anticancer activity was studied through a subcutaneous 4T1 tumor model., Results: Compared with free DZO, the DZO-loaded micelles possessed a sustained release property, an improved MTD, better pharmacokinetic parameters and an enhanced antitumor activity for subcutaneous 4T1 model in vivo., Conclusion: An effective injectable delivery system for DZO was developed successfully.

The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) was discovered to possess antitumor activity, revealing its potential value in future chemotherapy. However, its poor water solubility makes it difficult for intravenous administration. In this study, the monomethyl poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) copolymer was applied to prepare nanoassemblies of fisetin by a self-assembly procedure. The prepared fisetin micelles gained a mean particle size of 22 ± 3 nm, polydisperse index of 0.163 ± 0.032, drug loading of 9.88 ± 0.14%, and encapsulation efficiency of 98.53 ± 0.02%. Compared with free fisetin, fisetin micelles demonstrated a sustained and prolonged in vitro release behavior, as well as enhanced cytotoxicity, cellular uptake, and fisetin-induced apoptosis in CT26 cells. As for in vivo studies, fisetin micelles were more competent for suppressing tumor growth and prolonging survival time than free fisetin in the subcutaneous CT26 tumor model. Furthermore, histological analysis, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, immunohistochemical detection of Ki-67, and microvessel density detection were conducted, demonstrating that fisetin micelles gained increased tumor apoptosis induction, proliferation suppression, and antiangiogenesis activities. In conclusion, we have successfully produced a MPEG-PCL-based nanocarrier encapsulating fisetin with enhanced antitumor activity.

Docetaxel (DOC) produces anti-tumor effects by inducing apoptosis and inhibiting cell growth. However, its clinical application is limited by its hydrophobicity and low biocompatibility. Therefore, improving DOC's water solubility, biocompatibility, and anti-tumor effects are important goals that will improve its clinical utility. In this work, DOC and methoxy poly(ethylene glycol) (MPEG)/polycaprolactone (PCL) (MPEG-PCL) showed good compatibility through computer simulations. We prepared DOC-loaded polymeric micelles (DOC/MPEG-PCL micelles) with drug loading of 6.82% and encapsulation efficiency of 98.36%; these were monodispersed and approximately 30 nm in diameter, and released DOC over an extended period in vitro and in vivo. In addition, DOC/MPEG-PCL micelles inhibited cell growth and induced apoptosis more effectively than free DOC in vitro. Furthermore, DOC/MPEG-PCL micelles inhibited ovarian tumor growth more significantly than free DOC. Immunohistochemical analysis indicated that DOC/MPEG-PCL micelles improved DOC's anti-tumor effect by enhancing tumor cell apoptosis and suppressing tumor cell proliferation. Moreover, in bio-imaging analysis, DOC/MPEG-PCL micelles showed a higher concentration and a longer retention time in ovarian tumor tissue than did free DOC, indicating that the DOC/MPEG-PCL micelles delivered more anti-tumor drug to the tumor. Our data suggest that DOC/MPEG-PCL micelles have the potential to be applied clinically in ovarian cancer therapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In this study, a composite drug delivery system was developed and evaluated for oral delivery of docetaxel: docetaxel-loaded micelles in pH-responsive hydrogel (DTX-micelle-hydrogel). Docetaxel was successfully loaded in micelles with small particle size of 20 nm and high drug loading of 7.76%, which contributed to the drug absorption in the intestinal tract. The experiments of cytotoxicity on 4T1 cells demonstrated the effective antitumor activity of DTX micelles. Meanwhile, a pH-responsive hydrogel was synthesized and optimized for incorporating the docetaxel micelles. The pH-responsiveness and reversibility of the hydrogel were investigated under the pH conditions of the gastrointestinal tract. Furthermore, the DTX-micelle-hydrogel system showed much quicker diffusion of micelles in simulated intestinal fluid than in simulated gastric fluid, which was mainly caused by the change of pH value. The docetaxel released from the micelle-hydrogel system quite slowly, so it had little influence on the absorption of DTX micelles in small intestine. More important, the pharmacokinetic study revealed that the DTX-micelle-hydrogel significantly improved the oral bioavailability of docetaxel (75.6%) about 10 times compared to DTX micelles, and this increase in bioavailability was probably due to the small intestine targeting release of the pH-responsive hydrogel. Consequently, the oral DTX-micelle-hydrogel system was effective in inhibiting tumor growth in subcutaneous 4T1 breast cancer model, and decreased systemic toxicity compared with intravenous treatment. The apoptosis cells in the immunofluorescent studies and the proliferation-positive cells in the immunohistochemical studies were also consistent with the results. Therefore, the DTX-micelle-hydrogel system might be a promising candidate oral drug for breast cancer therapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Quercetin (Que) loaded polymeric micelles were prepared to obtain an aqueous formulation of Que with enhanced anti-tumor and anti-metastasis activities. A simple solid dispersion method was used, and the obtained Que micelles had a small particle size (about 31 nm), high drug loading, and high encapsulation efficiency. Que micelles showed improved cellular uptake, an enhanced apoptosis induction effect, and stronger inhibitory effects on proliferation, migration, and invasion of 4T1 cells than free Que. The enhanced in vitro antiangiogenesis effects of Que micelles were proved by the results that Que micelles significantly suppressed proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). Subsequently, transgenic zebrafish models were employed to investigate anti-tumor and anti-metastasis effects of Que micelles, in which stronger inhibitory effects of Que micelles were observed on embryonic angiogenesis, tumor-induced angiogenesis, tumor growth, and tumor metastasis. Furthermore, in a subcutaneous 4T1 tumor model, Que micelles were more effective in suppressing tumor growth and spontaneous pulmonary metastasis, and prolonging the survival of tumor-bearing mice. Besides, immunohistochemical and immunofluorescent assays suggested that tumors in the Que micelle-treated group showed more apoptosis, fewer microvessels, and fewer proliferation-positive cells. In conclusion, Que micelles, which are synthesized as an aqueous formulation of Que, possess enhanced anti-tumor and anti-metastasis activity, which can serve as potential candidates for cancer therapy.

A biodegradable in situ gel-forming controlled drug delivery system composed of curcumin loaded micelles and thermosensitive hydrogel was prepared and applied for cutaneous wound repair. Curcumin is believed to be a potent antioxidant and anti-inflammatory agent. Due to its high hydrophobicity, curcumin was encapsulated in polymeric micelles (Cur-M) with high drug loading and encapsulation efficiency. Cur-M loaded thermosensitive hydrogel (Cur-M-H) was prepared and applied as wound dressing to enhance the cutaneous wound healing. Cur-M-H was a free-flowing sol at ambient temperature and instantly converted into a non-flowing gel at body temperature. In vitro studies suggested that Cur-M-H exhibited well tissue adhesiveness and could release curcumin in an extended period. Furthermore, linear incision and full-thickness excision wound models were employed to evaluate the in vivo wound healing activity of Cur-M-H. In incision model, Cur-M-H-treated group showed higher tensile strength and thicker epidermis. In excision model, Cur-M-H group exhibited enhancement of wound closure. Besides, in both models, Cur-M-H-treated groups showed higher collagen content, better granulation, higher wound maturity, dramatic decrease in superoxide dismutase, and slight increase in catalase. Histopathologic examination also implied that Cur-M-H could enhance cutaneous wound repair. In conclusion, biodegradable Cur-M-H composite might have great application for wound healing., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In this paper, two nanoscale preparations were described for docetaxel encapsulation using poly(epsilon-caprolactone)poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) copolymer as carrier for treating malignant tumor. The first formulation was docetaxel-loaded PCEC micelle (D-M), which was characterized by XRD, TEM and Malvern laser particle size and drug release studies. The highest drug-loading of docetaxel in micelle was about 22.1 +/- 1.9%, optimized average diameter and polydispersity index was 25.2 +/- 1.1 nm, 0.13 +/- 0.12, respectively. Another formulation was docetaxel-loaded PCEC thermosensitive hydrogel (D-H), which displayed special gel-sol transition behavior with body temperature. We studied the cytotoxicity and in vitro hemolytic test of blank PCEC copolymer, the result was superiority. The data of relative body weight (RW), relative tumor volume (RV) and micrographs of hematoxylin and eosin (H&E)-stained histological sections showed D-M and D-H had significant antitumor effect and exhibited different characteristics of antitumor activity. Thus, the experiments signified that the combination therapy of intravenous (i.v.) and intratumoral administration using the two formulations maybe an effective way to treat malignant tumor.

As a traditional immunosuppressive drug, tacrolimus showed the potency in treating ulcerative colitis. In this study, a novel drug delivery vehicle achieved by self-assembly was applied to tacrolimus. During the preparation, amphiphilic copolymer MPEG-PCL was chosen to form the unique core-shell structure, and tacrolimus was loaded into the hydrophobic core due to its great hydrophobicity. After several relevant tests, MPEG-PCL (2000-2000) was selected to be the most suitable and safest copolymer for drug carrier. For the tacrolimus loaded MPEG-PCL (2000-2000) micelles, the mean particle size and drug entrapment efficiency were ca. 25 +/- 5 nm and 98.47 +/- 0.43% respectively. The micelles could be stored for quite a long time even at room temperature after freeze-drying, and the freeze-drying process didn't affect the monodispersity of micelles. Transmission electron microscope (TEM) image emerged the spherical shape of micelles. Both Differential Scanning Calorimetric (DSC) and X-ray Diffractometer (XRD) assays demonstrated that tacrolimus was relatively completely incorporated into the core-shell structure. In vitro release profiles showed the apparent sustained release behavior compared with tacrolimus solution. Above all, animal treatment showed the most satisfactory therapeutic effect of tacrolimus loaded micelles, which means the micelles possess the ability to treat ulcerative colitis induced by dextran sulfate sodium (DSS) in mice. Therefore, micelles of MPEG-PCL could be a very promising novel vehicle for tacrolimus.

Encapsulation of hydrophobic agents in polymer micelles can improve the water solubility of cargos, contributing to develop novel drugs. Quercetin (QU) is a hydrophobic agent with potential anticancer activity. In this work, we encapsulated QU into biodegradable monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles and tried to provide proof-of-principle for treating ovarian cancer with this nano-formulation of quercetin. These QU loaded MPEG-PCL (QU/MPEG-PCL) micelles with drug loading of 6.9% had a mean particle size of 36 nm, rendering the complete dispersion of quercetin in water. QU inhibited the growth of A2780S ovarian cancer cells on a dose dependent manner in vitro. Intravenous administration of QU/MPEG-PCL micelles significantly suppressed the growth of established xenograft A2780S ovarian tumors through causing cancer cell apoptosis and inhibiting angiogenesis in vivo. Furthermore, the anticancer activity of quercetin on ovarian cancer cells was studied in vitro. Quercetin treatment induced the apoptosis of A2780S cells associated with activating caspase-3 and caspase-9. MCL-1 downregulation, Bcl-2 downregulation, Bax upregulation and mitochondrial transmembrane potential change were observed, suggesting that quercetin may induce apoptosis of A2780S cells through the mitochondrial apoptotic pathway. Otherwise, quercetin treatment decreased phosphorylated p44/42 mitogen-activated protein kinase and phosphorylated Akt, contributing to inhibition of A2780S cell proliferation. Our data suggested that QU/MPEG-PCL micelles were a novel nano-formulation of quercetin with a potential clinical application in ovarian cancer therapy.

Nanoscale polymeric micelles have promising applications as drug delivery systems (DDS). In this work, to improve the anti-tumor activity and eliminate toxicity of the commercial formulation (cremophor EL and ethanol) of paclitaxel (PTX), we developed biodegradable poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles entrapping PTX by a simple one-step solid dispersion method, which is without any surfactants or additives and is easy to scale up. In addition, the PTX micelles could be lyophilized into powder without any adjuvant and the re-dissolved PTX micelles are stable and homogeneous. The prepared PTX micelles have a mean particle size of 38.06 ± 2.30 nm, a polydispersity index of 0.168 ± 0.014, a drug loading of 14.89 ± 0.06% and an encapsulation efficiency of 99.25 ± 0.38%. A molecular modeling study implied that PTX interacted with PCL as a core, which was embraced by PEG as a shell. The encapsulation of PTX in polymeric micelles enhanced its cytotoxicity by increasing the uptake by LL/2 cells. A sustained in vitro release behavior and slow extravasation behavior from blood vessels in a transgenic zebrafish model were observed in the PTX micelles. Furthermore, compared with Taxol®, the PTX micelles were more effective in suppressing tumor growth in the subcutaneous LL/2 tumor model. The PTX micelles also inhibited metastases in the pulmonary metastatic LL/2 tumor model and prolonged survival in both mouse models. Pharmacokinetic and tissue distribution studies showed that after PTX was encapsulated in polymeric micelles, the biodistribution pattern of PTX was altered and the PTX concentration in tumors was increased compared with Taxol® after intravenous injection. In conclusion, we have developed a polymeric micelles entrapping PTX that enhanced cytotoxicity in vitro and improved anti-tumor activity in vivo with low systemic toxicity on pulmonary carcinoma. The biodegradable MPEG-PCL micelles entrapping PTX may have promising applications in pulmonary carcinoma therapy.

In this work, we aim to develop a dual drug delivery system (DDDS) of self-assembled micelles in thermosensitive hydrogel composite to deliver hydrophilic and hydrophobic drugs simultaneously for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administered to form micelles or thermosensitive hydrogels, respectively. Therefore, the DDDS was constructed from paclitaxel (PTX) encapsulated PCEC micelles (PTX-micelles) and a fluorouracil (Fu) loaded thermosensitive PCEC hydrogel (Fu-hydrogel). PTX-micelles were prepared by self-assembly of biodegradable PCEC copolymer (M(n) = 3700) and PTX without using any surfactants or excipients. Meanwhile, biodegradable and injectable thermosensitive Fu-hydrogel (M(n) = 3000) with a lower sol-gel transition temperature at around physiological temperature was also prepared. The obtained PTX-micelles in thermosensitive Fu-hydrogel (PTX-micelles-Fu-hydrogel) composite is a free-flowing sol at ambient temperature and rapidly turned into a non-flowing gel at physiological temperature. In addition, the results of cytotoxicity, hemolytic study, and acute toxicity evaluation suggested that the PTX-micelles-Fu-hydrogel was non-toxic and biocompatible. In vitro release behaviors of PTX-micelles-Fu-hydrogel indicated that both PTX and Fu have a sustained release behavior. Furthermore, intraperitoneal application of PTX-micelles-Fu-hydrogel effectively inhibited growth and metastasis of CT26 peritoneal carcinomatosis in vivo (p < 0.001), and induced a stronger antitumor effect than that of Taxol® plus Fu (p < 0.001). The pharmacokinetic study indicated that PTX-micelles-Fu-hydrogel significantly increased PTX and Fu concentration and residence time in peritoneal fluids compared with Taxol® plus Fu group. Thus, the results suggested the micelles-hydrogel DDDS may have great potential clinical applications.

For cancer therapy, optimization of carrier features is necessary to effectively deliver the targeting agents to tumor sites. Biodegradable poly(ether-anhydrides) micelles with filamentous, rod-like, and spherical shapes are fabricated. Their size and morphology are characterized by AFM and TEM. The encapsulation of doxorubicin hydrochloride (DOX) into the micelles does not impact their shape. The effect of micellar shape on the drug loading capacity and encapsulation efficiency, as well as in vitro drug release, is investigated. The cellular uptakes are evaluated using fluorescence microscopy, confocal laser scanning microscopy and flow cytometry on co-cultures of human hepatoblastoma cell line (HepG2), lung epithelial cancer cell line (A549), and human nasopharyngeal epidermoid carcinoma cells (KB) and fibroblast normal cells mixed with the different shapes of DOX-loaded micelles. The results show that the spherical DOX-loaded micelles are more readily taken up by all types of cells. The impact of micellar shape on in vivo antitumor function is also assessed from changes of tumor volume, body weight loss, and survival rate of 4T1-bearing mice and the immunostaining of tumor sections for analysis of tumor cell proliferation. The results reveal that the filamentous DOX-loaded micelles possess the highest safety to body and the best therapeutic effects to artificial solid tumors. Therefore, the filamentous shape is deemed the most suitable morphology for design and engineering of drug vehicles for cancer therapy., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The great potential of oridonin (ORI) for clinical application in cancer therapy is greatly limited due to its poor water-solubility. The purpose of this study was to increase the water solubility of oridonin using monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone) (MPEG-PCL) as drug carrier. The ORI-loaded MPEG-PCL micelles were prepared by thin film hydration method. The obtained ORI-micelles could be lyophilized into powder form, which could be re-dissolved in water to form homogeneous solution. This study showed that ORI was successfully incorporated in the core-shell structure of MPEG-PCL micelles and maintained its anticancer activity. The average particle size was 25.55 +/- 0.10 nm and the mean zeta potential was -4.71 +/- 0.05 mV. The actual drug loading and encapsulation efficiency were 7.99 +/- 0.03% and 99.51 +/- 0.34%, respectively. ORI could be released from MPEG-PCL micelles in a sustained manner in vitro. The permeation profiles of ORI from ORI-micelles and ORI water saturated solution through excised mouse skin demonstrated that ORI-micelles showed much better transdermal penetration performance than ORI water saturated solution. The prepared ORI-micelles have great potential for both direct intravascular administration and being further developed as a transdermal drug delivery system in cancer chemotherapy.

Doxorubicin has been widely used in cancer treatment, but its severe side-effects restrict its clinical application greatly. So, we hope to design a novel delivery system to decrease its side-effects. In this paper, we prepared core cross-linked micelle based on poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (CCPCEC) at about 30 nm in diameter with a narrow distribution. The prepared core cross-linked PCL-PEG-PCL micelles were employed to load doxorubicin by pH-induced self-assembly method. Doxorubicin-loading did not obviously affect the micelle size or size distribution. Furthermore, these micelles exhibited a significantly enhanced thermodynamic stability against dilution with aqueous solvents and showed CMC in the range of 1 x 10(-3) to 2 x 10(-3) mg/mL. Cytotoxicity study confirmed great biocompatibility of the micelles and showed that the encapsulated doxorubicin in CCPCEC micelles enhanced the cytotoxicity of doxorubicin on C26 cell line in vitro. Moreover, in vitro release profile demonstrated a significant difference between rapid release of free doxorubicin and much slower and sustained release of doxorubicin-loaded core cross-linked micelles. In addition, a faster DOX-release from micelles at pH 5.5 than that at pH 7.4 was also observed. These results suggested that this new biodegradable Core Cross-linked PCL-PEG-PCL Micelles might be potential carriers for drug delivery in cancer chemotherapy.

In our previous work, we had prepared a biodegradable amphiphilic three-armed star-shaped copolymers (SPCE) based on poly(epsilon-caprolactone) (PCL) and poly(ethylene glycol) (PEG), which could form micelles by self-assembly method and it was a potential carrier for hydrophobic drug. For further application, the safety of SPCE micelles was evaluated in vitro and in vivo here. (13)C-NMR was used to confirm the formation of the micelles in aqueous solution, and the morphology was observed on transmission electron microscope (TEM). Also, thermostability of blank SPCE micelles was determined by Malvern Nano-ZS 90 laser particle size analyzer. In vitro toxicity evaluation included hemolytic test and cytotoxicity. In vivo acute toxicity tests and histopathological study of SPCE micelles were carried out on BALB/C mice which were administrated SPCE micelles (1 g/kg b.w.) intravenously. In acute toxicity test, the mice were observed continuously for 7 days, obtained their body weight every day, at last the mice was sacrificed for the following study: the blood of the mice was assigned for blood chemistry and routine analysis, the heart, liver, spleen, lung, and kidneys were used for histopathological study. All results indicated that the biodegradable self-assembled SPCE micelles were nontoxic; therefore, it might be used as a safe candidate for drug delivery system., ((c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association 2010.)

This study aims to develop self-assembled poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) micelles to encapsulate hydrophobic honokiol (HK) in order to overcome its poor water solubility and to meet the requirement of intravenous administration. Honokiol loaded micelles (HK-micelles) were prepared by self-assembly of PECE copolymer in aqueous solution, triggered by its amphiphilic characteristic assisted by ultrasonication without any organic solvents, surfactants and vigorous stirring. The particle size of the prepared HK-micelles measured by Malvern laser particle size analyzer were 58 nm, which is small enough to be a candidate for an intravenous drug delivery system. Furthermore, the HK-micelles could be lyophilized into powder without any adjuvant, and the re-dissolved HK-micelles are stable and homogeneous with particle size about 61 nm. Furthermore, the in vitro release profile showed a significant difference between the rapid release of free HK and the much slower and sustained release of HK-micelles. Moreover, the cytotoxicity results of blank micelles and HK-micelles showed that the PECE micelle was a safe carrier and the encapsulated HK retained its potent antitumor effect. In short, the HK-micelles were successfully prepared by an improved method and might be promising carriers for intravenous delivery of HK in cancer chemotherapy, being effective, stable, safe (organic solvent and surfactant free), and easy to produce and scale up.

Purpose: Honokiol showed potential application in cancer treatment, but its poor water solubility restricts its clinical application greatly. So, we designed a self-assembled monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone) (MPEG-PCL) micelle to load honokiol to overcome its poor water solubility., Methods: We synthesized MPEG-PCL diblock copolymer that could self-assemble into monodisperse micelles at the particle size of ca.18 nm in water. Honokiol was loaded into MPEG-PCL micelle by direct dissolution method assisted by ultrasound, without any surfactants, organic solvents, and vigorous stirring., Results: The blank MPEG-PCL micelles (100 mg/mL) did not induce any hemolysis in vitro and showed very low toxicity ex vivo and in vivo. Honokiol could be molecularly incorporated into MPEG-PCL micelles at the drug loading of about 20% by direct dissolution method assisted by ultrasound. After loaded into MPEG-PCL micelles, honokiol maintained its molecular structure and anticancer activity in vitro. Honokiol could be sustained released from MPEG-PCL micelles in vitro. The honokiol loaded MPEG-PCL micelles could be lyophilized without any adjuvant., Conclusion: The prepared honokiol formulation based on self-assembled MPEG-PCL micelle was stable, safe, effective, easy to produce and scale up, and showed potential clinical application.