Green synthesis of chitosan/polyacrylic acid/graphitic carbon nitride nanocarrier as a potential pH-sensitive system for curcumin delivery to MCF-7 breast cancer cells.

A novel pH-sensitive nanocarrier containing chitosan (CS), polyacrylic acid (PAA), and graphitic carbon nitride (g-C3N4) was designed via water/oil/water (W/O/W) emulsification to administer curcumin (CUR) drug. g-C3N4 nanosheets with a high surface area and porous structure were produced via simple one-step pyrolysis process using thiourea as precursor, and incorporated into CS/PAA hydrogel. X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT-IR) were used to assess the crystalline structure of the nanocarrier and the interactions between its components, respectively. Scanning electron microscopy (SEM) images revealed a spherical structure and confirmed the g-C3N4 impregnation into the CS/PAA matrix. Zeta potential and dynamic light scattering (DLS) provided information about the surface charge and average size distribution. High CUR loading and entrapment efficiencies were obtained, which were further improved upon addition of g-C3N4. The release kinetics of drug-loaded CS/PAA/g-C3N4 nanocomposites were investigated at pH = 5.4 and pH = 7.4, and the results showed an excellent controlled pH-sensitive release profile. Cell apoptosis and in vitro cytotoxicity were investigated using flow cytometry and MTT analyses. CS/PAA/g-C3N4/CUR resulted in the highest rate of apoptosis in MCF-7 breast cancer cells, demonstrating the excellent nanocomposite efficacy in eliminating cancerous cells. CS/PAA hydrogel coated with g-C3N4 shows great potential for pH-sensitive controlled drug release.

Conductive conduit based on electrospun poly (l-lactide-co-D, l-lactide) nanofibers containing 4-aminopyridine-loaded molecularly imprinted poly (methacrylic acid) nanoparticles used for peripheral nerve regeneration.

Using biocompatible polymer nanofibrous conduits with a controlled drug delivery have attracted much attention for peripheral nerve regeneration. This work was aimed at preparing electrospun poly (l-lactide-co-D, l-lactide) (PLDLLA) containing multi-walled carbon nanotubes (MWCNTs) and 4-aminopyridine (4-AP)-loaded molecularly imprinted nanoparticles (MIP4-AP) as well as evaluating their performance in in vitro and in vivo assessments. After synthesis of MIP4-AP based on poly (methacrylic acid) with imprinting factor of 1.78, it was incorporated into the PLDLLA/MWCNTs nanofibers to optimize. By adjusting the process variables, the average diameter and electrical conductivity of the nanofibrous sample were 92 nm and 2870 × 10-7 S cm-1, respectively. Afterward, 4-AP release of the optimum sample showed the presence of MIP4-AP leading to initial burst release decrease and plateau level postpone up to 96 h. Moreover, the culture results of PC12 as neuroblastoma cell line on optimal PLDLLA/MWCNTs/MIP4-AP nanofibrous sample revealed the highest cell proliferation without cytotoxicity compared to neat nanofibers. Eventually, the animal model experiment exhibited that the conductive conduit based on the optimum sample was able to repair the rat's sciatic nerve after four weeks in accordance with sciatic function index and histological studies.

Osteogenesis enhancement using poly (l-lactide-co-d, l-lactide)/poly (vinyl alcohol) nanofibrous scaffolds reinforced by phospho-calcified cellulose nanowhiskers.

Electrospun poly (l-lactide-co-d, l-lactide) (PLDLLA)/poly (vinyl alcohol) (PVA) nanofibers were reinforced by various contents (0-1 wt%) of phospho-calcified cellulose nanowhiskers (PCCNWs) as scaffolds in bone applications. The hydrophilicity and rate of hydrolytic degradation of PLDLLA were improved by introducing 10 wt% of PVA. PCCNWs with inherent hydrophilic properties, high aspect ratio, and large elastic modulus enhanced the hydrophilicity, accelerated the rate of degradation, and improved the mechanical properties of the nanofibrous samples. Moreover, calcium phosphate and phosphate functional groups on the surface of PCCNWs possessing act as stimulating agents for cellular activities such as proliferation and differentiation. Besides the physico-chemical properties investigation of PLDLLA/PVA-PCCNWs nanofibrous samples, their cytotoxicity was also studied and they did not show any adverse side effect. Incorporation of PCCNWs (1 wt%) into the PLDLLA/PVA nanofibrous samples showed more enzymatic activities and deposited calcium. The micrograph images of the morphology of human mesenchymal stem cells (hMSCs) cultured on the nanofibrous sample containing 1 wt% of PCCNWs after 14 days of cell differentiation revealed their high potential for bone tissue engineering.

Microfluidic-Assisted Preparation of 5-Fluorouracil-Loaded PLGA Nanoparticles as a Potential System for Colorectal Cancer Therapy.

This work aims at fabricating 5-fluorouracil (5-FU)-loaded poly (lactic-co-glycolic) acid nanoparticles (PLGA NPs) using a microfluidic (MF) technique, with potential for use in colorectal cancer therapy. In order to achieve 5-FU-loaded NPs with an average diameter of approximately 119 nm, the parameters of MF process with fork-shaped patterns were adjusted as follows: the ratio of polymer to drug solutions flow rates was equal to 10 and the solution concentrations of PLGA as carrier, 5-FU as anti-cancer drug and poly (vinyl alcohol) (PVA) as surfactant were 0.2 (% w/v), 0.01 (% w/v) and 0.15 (% w/v), respectively. In this way, a drug encapsulation efficiency of approximately 95% into the PLGA NPs was obtained, due to the formation of a hydrodynamic flow focusing phenomenon through the MF chip. A performance evaluation of the NP samples in terms of the drug release, cytotoxicity and cell death was carried out. Finally, by analyzing the results after induction of cell death and 4', 6-diamidino-2-phenylin-dole (DAPI) staining, MF-fabricated NPs containing 5-FU [0.2 (% w/v) of PLGA] revealed the dead cell amounts of 10 and 1.5-fold higher than the control sample for Caco2 and SW-480, respectively.

Microfluidics combined with ionic gelation method for production of nanoparticles based on thiol-functionalized chitosan to adsorb Hg (II) from aqueous solutions.

This work aimed at producing nanoparticles (NPs) based on thiol-functionalized chitosan (CS) using capillary microfluidic (MF) device combined with ionic gelation method to adsorb mercury ion [Hg (II)] from aqueous solutions. In this line, CS was functionalized with epichlorohydrin/cysteaminium chloride (2.73 M ratio) followed by fabricating NPs via MF and bulk mixing (BM) methods. To characterize the morphology, zeta potential, functionality, structure, and magnetic property of the samples, a series of tests such as SEM, TEM, DLS, FTIR, XRD, and VSM were carried out, respectively. The obtained results showed that MF technique was able to produce NPs with a diameter as small as 18 ±â€¯3 nm, and a uniform shape compared to BM method. Thiol groups (-SH) functionalization on CS surface was confirmed by appearing a characteristic peak at 2579 cm-1. Also, the XRD patterns indicated the appropriate synthesis of Fe3O4 (magnetite), and no change in the structure of CS NPs in the presence of magnetite. Moreover, adding the magnetite to thiol-functionalized CS NPs led to suitable saturation magnetization about 26 emu/g to facilitate their separation using a magnetic field. To evaluate the performance of the nanoadsorbent, it has been exposed to Hg (II) in an aqueous solution which in turn the parameters optimization for the adsorption was done via Box-Behnken design (BBD) method, exhibiting the effect of adsorbent dose and the initial concentration of Hg (II) was much more significant than that of pH. Different concentrations of total dissolved solids up to 1000 mg/L had no adverse impact on the adsorption process confirmed by EDAX spectra. The least value of RMSE (5.023) and χ2 (0.3) were observed for Redlich-Peterson, Radke-Prausnitz, and UT isotherms. Maximum adsorption capacities calculated using Langmuir and UT models were 1192 mg/g and 1126 mg/g, respectively. Thermodynamic studies demonstrated that the nature of the adsorption process was spontaneous and endothermic. Recovery of nanoadsorbent was successfully carried out using HCl 0.5 mol/L. The adsorption studies revealed that the prepared nanoadsorbent is promising candidate used in mercury removal from a real wastewater potentially.

Fabrication and characterization of electrospun laminin-functionalized silk fibroin/poly(ethylene oxide) nanofibrous scaffolds for peripheral nerve regeneration.

The peripheral nerve regeneration is still one of the major clinical problems, which has received a great deal of attention. In this study, the electrospun silk fibroin (SF)/poly(ethylene oxide) (PEO) nanofibrous scaffolds were fabricated and functionalized their surfaces with laminin (LN) without chemical linkers for potential use in the peripheral nerve tissue engineering. The morphology, surface chemistry, thermal behavior and wettability of the scaffolds were examined to evaluate their performance by means of scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and water contact angle (WCA) measurements, respectively. The proliferation and viability of Schwann cells onto the surfaces of SF/PEO nanofibrous scaffolds were investigated using SEM and thiazolyl blue (MTT) assay. The results showed an improvement of SF conformation and surface hydrophilicity of SF/PEO nanofibers after methanol and O2 plasma treatments. The immunostaining observation indicated a continuous coating of LN on the scaffolds. Improving the surface hydrophilicity and LN functionalization significantly increased the cell proliferation and this was more prominent after 5 days of culture time. In conclusion, the obtained results revealed that the electrospun LN-functionalized SF/PEO nanofibrous scaffold could be a promising candidate for peripheral nerve tissue regeneration. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1595-1604, 2018.

Optimizing computed tomography simulation wait times in a busy radiation medicine program.

PURPOSE: An audit was conducted of patient schedules for computed tomography simulation (CT-Sim) scans within the Radiation Medicine Program at the Princess Margaret Cancer Centre to investigate opportunities for improved efficiencies, enhancing process, reducing rescanning rates, and decreasing wait times. METHODS AND MATERIALS: A 3-phased approach was undertaken to evaluate the current practice in the CT-Sim facility with a view toward implementing improvements. The first phase involved a review and assessment of the validity of current guidelines and protocols associated with 16 different disease sites. The second phase incorporated the use of a patient record and verification program MOSAIQ to capture the duration of each appointment. The last phase allocated additional time for patient-centered care and staff engagement. RESULTS: The audit revealed that efficiency could be achieved through staff training, updating protocols, and improving process coordination. With the exception of sarcoma, pediatric, and palliative patients who require unique management approaches, the duration for each CT-Sim appointment was successfully shortened for all disease sites by 22% to 33%, corresponding to a reduction of 10 to 15 minutes per appointment. Rescanning rates for patients requiring self-administered preparations before CT-Sim procedures were also significantly reduced by enhancing processes to increase patient compliance. Implementation of procedural changes resulted in an overall net gain of 3060 minutes, equivalent to 102 additional 30-minute CT-Sim appointment slots available for each month. CONCLUSIONS: This retrospective evaluation, review, and optimization of CT-Sim guidelines and practices identified opportunities to shorten appointment timeslots, and reduce rescanning rates for CT-Sim procedures, thereby significantly shortening wait times and improving access to service for our patients.

The microRNA-218~Survivin axis regulates migration, invasion, and lymph node metastasis in cervical cancer.

Cervical cancer is the third most common cancer in women worldwide. In the present study, global microRNA profiling for 79 cervical cancer patient samples led to the identification of miR-218 down-regulation in cervical cancer tissues compared to normal cervical tissues. Lower miR-218 expression was associated significantly with worse overall survival (OS), disease-free survival (DFS), and pelvic/aortic lymph node recurrence. In vitro, miR-218 over-expression decreased clonogenicity, migration, and invasion. Survivin (BIRC5) was subsequently identified as an important cervical cancer target of miR-218 using in silico prediction, mRNA profiling, and quantitative real-time PCR (qRT-PCR). Concordant with miR-218 over-expression, survivin knockdown by siRNA decreased clonogenicity, migration, and invasion. YM155, a small molecule survivin inhibitor, significantly suppressed tumor growth and lymph node metastasis in vivo. Our findings demonstrate that the miR-218~survivin axis inhibits cervical cancer progression by regulating clonogenicity, migration, and invasion, and suggest that the inhibition of survivin could be a potential therapeutic strategy to improve outcome in this disease.

Hypoxia and cellular localization influence the radiosensitizing effect of gold nanoparticles (AuNPs) in breast cancer cells.

Hypoxia exists in all solid tumors and leads to clinical radioresistance and adverse prognosis. We hypothesized that hypoxia and cellular localization of gold nanoparticles (AuNPs) could be modifiers of AuNP-mediated radiosensitization. The possible mechanistic effect of AuNPs on cell cycle distribution and DNA double-strand break (DSB) repair postirradiation were also studied. Clonogenic survival data revealed that internalized and extracellular AuNPs at 0.5 mg/mL resulted in dose enhancement factors of 1.39 ± 0.07 and 1.09 ± 0.01, respectively. Radiosensitization by AuNPs was greatest in cells under oxia, followed by chronic and then acute hypoxia. The presence of AuNPs inhibited postirradiation DNA DSB repair, but did not lead to cell cycle synchronization. The relative radiosensitivity of chronic hypoxic cells is attributed to defective DSB repair (homologous recombination) due to decreased (RAD51)-associated protein expression. Our results support the need for further study of AuNPs for clinical development in cancer therapy since their efficacy is not limited in chronic hypoxic cells.

A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase.

Uroporphyrinogen decarboxylase (UROD) catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16), was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM), but did not affect porphobilinogen deaminase (at 62.5 µM), thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE) cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1). This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.

Thermosensitive depot-forming injectable phosphatidylcholine blends tailored for localized drug delivery.

A thermosensitive depot-forming system was developed for sustained and localized delivery of the anticancer drug, paclitaxel. The formulation is injectable as a melt slightly above the body temperature and forms a solid depot upon cooling to 37°C. The thermosensitive system was prepared by blending various combinations of phosphatidylcholines at specific weight ratios solubilized in laurinaldehyde. Of the blends investigated, distearoyl-phosphatidylcholine (DSPC) and egg-phosphatidylcholine (ePC) were found to be most miscible. A liquid-to-gel phase transition temperature (TC ) of 39°C was observed for the 70:30 (w/w) DSPC-ePC blend and a TC of 38.4°C with the addition of paclitaxel. Blends containing higher concentrations of ePC had a greater degree of swelling and weight loss. Furthermore, microscopy revealed an increase in porosity and erosion as the amount of ePC was increased in blends incubated in biologically relevant media. DSPC-ePC blends provided sustained release of paclitaxel over a 30-day period and the rate of drug release increased as the amount of ePC increased. Overall, the relationships established between the composition and properties of the blend may be employed to tailor the thermosensitive injectable formulation for localized chemotherapy of solid tumors.

Neoplastic cell response to tiopronin-coated gold nanoparticles.

The present study characterized the in vitro biological response of a comprehensive set of cancer cell lines to gold nanoparticles (2.7 nm) coated with tiopronin (AuNPs-TP). Our findings suggest that upon entering cells, the AuNPs-TP are sequestered in vacuoles such as endosomes and lysosomes, and mostly localize in perinuclear areas. Peak cell accumulation was achieved at 8 hours after incubation. L929 and H520 cells showed more than 75% surviving fraction when treated with 0.5 mg/mL of AuNPs-TP for 24 hours, whereas the surviving fractions were 60% in MCF-7 and 20% in HeLa cells. Reactive oxygen species (ROS) production by the AuNPs-TP was dependent on cell line and exposure time. Antioxidants inhibited ROS generation to various extents, with glutathione and tiopronin being most effective. Overall, exposure time, concentration of the AuNPs-TP, and cell line influenced neoplastic cell response. Furthermore, the mechanism of cytotoxicity of the AuNPs-TP was found to be ROS generation. FROM THE CLINICAL EDITOR: This study describes the basic intracellular characteristics of Tiopronin-Au nanoparticles from the standpoint of their anti-cancer activity in different cancer cell cultures.

Recent advances in drug delivery strategies for treatment of ovarian cancer.

INTRODUCTION: Ovarian cancer is associated with the highest mortality rate of all gynecological malignancies, due in part to inadequate treatment strategies and the asymptomatic nature of the disease. Current standard of care includes surgery and systemic chemotherapy. However, this approach can result in toxicities and eventual disease relapse, due to the emergence of multidrug resistance. Drug delivery systems (DDS) have shown promise in overcoming many of the limitations facing conventional treatment regimens. AREAS COVERED: This review provides an overview of recent advances in DDS strategies for the treatment ovarian cancers. Nano-sized systems, including nanoparticles, micelles, liposomes and drug conjugates; microspheres; implants and injectable depots are discussed. The advantages, limitations and clinical potential of these strategies are also outlined. EXPERT OPINION: Nano-sized DDS enable passive targeting to tumors due to their size, and further improvements in tumor localization can be made using targeting moieties. Microspheres, implants and injectable depots have been investigated for peritoneal localized and sustained therapy. Overall, the benefits of using DDS for ovarian cancer therapy include higher drug levels at the diseased site, circumvention of drug resistance mechanisms, minimization of non-specific toxicities, improvements in solubility of poorly soluble drugs and elimination of toxicities associated with conventionally used pharmaceutical excipients.

An injectable depot system for sustained intraperitoneal chemotherapy of ovarian cancer results in favorable drug distribution at the whole body, peritoneal and intratumoral levels.

The current study characterizes the impact of docetaxel (DTX) distribution on efficacy following sustained intraperitoneal (IP) chemotherapy in murine models of ovarian cancer. A polymer-lipid biodegradable depot (PoLigel) was used to deliver DTX in a sustained manner over 21-days following IP administration. Distribution and efficacy studies were carried out in SCID mice bearing SKOV3 IP solid tumors or C57BL/6 mice with ID8 IP ascites fluid. In addition, a subcutaneous (SC) SKOV3 model was used to determine whether systemic drug levels that result from IP administration of the PoLigel influence antitumor efficacy. Immunostained IP and SC SKOV3 tumor sections were used to study cell death, intratumoral drug distribution and tumor penetration. Sustained concentrations of DTX were observed in plasma, tissue, tumor and ascites over the entire study period. Drug accumulation was several fold greater in tumors and ascites when compared to plasma levels. Sustained chemotherapy resulted in significant reduction in tumor burden and ascites volume. IP tumors showed greater cell death compared to the SC tumors as seen by higher TUNEL and caspase-3 expression. At the intratumoral level, DTX distributed more towards the core of IP tumors compared to the SC tumors. Tumor penetration of drug from nearest blood vessel was 1.5 fold greater in the IP tumors than the SC tumors. Overall, favorable drug distribution at the whole-body, peritoneal and intratumoral levels in combination with local and systemic sustained drug exposure contribute to the high efficacy observed. These results encourage the clinical use of IP sustained chemotherapy for ovarian cancer.

Chemotherapy dosing schedule influences drug resistance development in ovarian cancer.

Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1×/wk or 3×/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including ß-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1×/wk or 3×/wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance-related genes, especially in chemoresistant xenografts. More frequent, 3×/wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, docetaxel induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory ovarian cancer.

Docetaxel distribution following intraperitoneal administration in mice.

PURPOSE: Intraperitoneal (IP) chemotherapy with high molecular weight lipophilic antineoplastic agents such as the taxanes has shown promise in clinical trial evaluation for treatment of localized peritoneal cancers. We have previously developed an IP injectable hydrogel formulation (PoLigel) for sustained peritoneal delivery of docetaxel (DTX), and observed significant efficacy in murine models of ovarian cancer when compared to Taxotere®, the FDA approved formulation of DTX. In order to understand the relationship between drug distribution and efficacy, the current study compares the tissue distribution and pharmacokinetics of DTX administered IP in the PoLigel or Taxotere® formulations. METHODS: The PoLigel was prepared by blending a water-soluble chitosan derivative, egg phosphatidylcholine and lauric aldehyde with DTX (drug to material ratio 1:8 w/w). DTX concentrations in plasma, heart, liver, spleen, stomach, intestine, kidney and peritoneal muscle were measured over a five day period following IP administration of the PoLigel and Taxotere® formulations in CD-1 female mice. RESULTS: Three days after Taxotere® administration, no detectable levels of DTX were seen in plasma, while sustained DTX plasma levels of 0.06 ug/ml ± 0.01 per day were observed with PoLigel. At five days post Taxotere® administration, only intestine, stomach and peritoneal muscle showed detectable DTX concentrations whereas all tissues and plasma showed sustained DTX levels in mice that received PoLigel. DTX concentrations that resulted from PoLigel administration were significantly higher in the peritoneal cavity and 200 fold higher than concentrations found in plasma. CONCLUSIONS: Overall, the PoLigel formulation increases tissue and plasma drug retention and provides sustained DTX levels compared to the clinically used Taxotere® formulation. The sustained DTX levels seen in the peritoneal cavity following IP administration of the PoLigel may be responsible for the improvement in efficacy that has been observed in our previous studies.

Combination drug delivery strategy for the treatment of multidrug resistant ovarian cancer.

The onset of multidrug resistance (MDR) in ovarian cancer is one of the main causes of treatment failure and low survival rates. Inadequate drug exposure and treatment-free periods due to intermittent chemotherapy select for cancer cells overexpressing drug efflux transporters, resulting in resistant disease. The present study examines the sustained administration of the chemotherapeutic agent docetaxel (DTX) alone and in combination with cepharanthine (CEP), a potent drug efflux transporter inhibitor. DTX and CEP were delivered via the intraperitoneal route in a sustained manner using an injectable polymer-lipid formulation. In vitro, the combination strategy resulted in significantly (p < 0.05) more apoptosis, greater intracellular accumulation of DTX, and lower DTX efflux in ovarian cancer cells showing the MDR phenotype. In vivo, sustained treatment with DTX and CEP showed significantly greater (p < 0.05) tumor inhibition (91 ± 4%) in a murine model of multidrug resistant ovarian cancer compared to sustained DTX treatment (76 ± 6%) and was more than twice as efficacious as intermittent DTX treatment. Overall findings from these studies highlight the impact of sustained delivery of monotherapy and combination therapy in the management of refractory ovarian cancer displaying the MDR phenotype.

Continuous docetaxel chemotherapy improves therapeutic efficacy in murine models of ovarian cancer.

Ovarian cancer is known as the silent killer for being asymptomatic until late stages. Current first-line treatment consists of debulking surgery followed by i.v. chemotherapeutics administered intermittently, which leads to insufficient drug concentrations at tumor sites, accelerated tumor proliferation rates, and drug resistance, resulting in an overall median survival of only 2 to 4 years. For these reasons, more effective treatment strategies must be developed. We have investigated a localized, continuous chemotherapy approach in tumor models of human and murine ovarian cancers using the antineoplastic agent docetaxel. We show here that continuous docetaxel therapy is considerably more efficacious than intermittent therapy, resulting in a greater decrease in tumor burden and ascites fluid accumulation. Immunohistochemical analyses show that continuous chemotherapy abrogates tumor cell proliferation and angiogenesis to the tumor microenvironment, leading to greater tumor cell death than intermittent docetaxel therapy. Overall, our results show greater therapeutic advantages of continuous over intermittent chemotherapy in the treatment of ovarian cancer.

Polymeric drug delivery systems for localized cancer chemotherapy.

Cancer has become one of the most difficult health challenges of our time, accounting for millions of deaths yearly. Systemic chemotherapy is the most common therapeutic approach; however, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. More than 85% of human cancers are solid tumors, which can greatly benefit from localized delivery. This approach allows for high drug concentrations at the target site, lower systemic toxicity, and extended drug exposure which may be beneficial for cell cycle-specific drugs. Polymers have been widely considered in the development of localized delivery systems. This review focuses on both natural and synthetic biodegradable polymers that have been explored for localized chemotherapy, exploring their advantages, disadvantages, and clinical potential while citing examples of their use in pre-clinical development.

Chitosan-phospholipid blend for sustained and localized delivery of docetaxel to the peritoneal cavity.

Localized and sustained delivery of chemotherapeutics presents a "magic bullet" effect by providing high drug concentrations at the target site, extended drug exposure and reduced systemic toxicity. In the present study, an injectable chitosan-phospholipid (PoLi(gel)) blend is put forth as a strategy to achieve sustained and localized delivery of docetaxel (DTX) following intraperitoneal (IP) administration. The stability of the blend was confirmed in vitro, by turbidity measurements and attributed to specific molecular interactions and the organization of the materials within the blend, as evidenced by FTIR analysis and confocal laser scanning microscopy, respectively. The chitosan and phospholipid were found to colocalize in regions surrounding a mean object area of 11.2mum(2) with colocalization coefficients of 43% and 46% for the chitosan and phospholipid, respectively. The PoLi(gel) blend afforded sustained drug release as seen both in vitro (2.4+/-0.7% DTX per day) and in vivo (4.4+/-0.7% DTX per day). Constant concentrations of DTX were observed over a 2-week period in plasma and relevant peritoneal tissues, with no signs of toxicity or inflammation, following IP administration of the blend in healthy CD-1 mice. At DTX doses of 28.8 and 19.2mg/kg, the blend showed significant tumor inhibition of 87.3+/-9.3% and 74.1+/-25.9%, respectively, in a murine xenograft model of human ovarian adenocarcinoma. This localized delivery system has shown excellent potential for sustained IP treatment of cancers, such as ovarian, that reside in the peritoneal cavity.