Injectable poly(organophosphazene) hydrogel system for effective paclitaxel and doxorubicin combination therapy

Abstract

Combination therapy is an important option for gastric cancer which is the second leading cause of cancer-related death worldwide. The administration schedule of cell cycle-specific drugs, such as doxorubicin (DOX) and paclitaxel (PTX), is important for therapeutic efficacy. However, to control the schedule is clinically inconvenient. Additionally, in vitro cytotoxicity tests against human gastric cancer cells (SNU-601) showed that the combination indices (CIs) of DOX and PTX were 1.43 (α?=?0) and 1.90 (α?=?1), respectively, indicating that the DOX and PTX interaction was antagonistic. Thus, based on the finding that the release rate of drugs from poly(organophosphazene) (PPZ) hydrogel is dependent on the hydrophobicity of the drugs, we used injectable PPZ hydrogel in combination therapy. In vivo anticancer activity test in human gastric cancer cell-xenografted mice showed that intratumoral injection with aqueous PPZ solution, containing DOX (15?mg/kg) and PTX (30?mg/kg), resulted in the highest tumor inhibition and safety (no mortality for approximately 3 months) in the experimental groups. Consequently, PPZ hydrogel is expected to be a promising drug delivery system for cell cycle-specific drugs, facilitating the control of their administration schedule for effective combination therapy.     

Galactosylated chitosan-g-PEI/DNA complexes-loaded poly(organophosphazene) hydrogel as a hepatocyte targeting gene delivery system

Hydrogels are widely used in drug delivery systems because they can control the release and thereby enhance the efficiency of locally delivered bioactive molecules such as therapeutic drugs, proteins, or genes. For gene delivery, localized release of plasmid DNA or polymer/DNA complexes can transfect cells and produce sustained protein production. We tested the galactosylated chitosan-graft-polyethylenimine (GC-g-PEI)/DNA complexes-loaded poly(organophosphazene) thermosensitive biodegradable hydrogel as a hepatocyte targeting gene delivery system. The poly(organophosphazene) hydrogel loaded with GC-g-PEI/DNA complexes showed low cytotoxicity and higher transfection efficiency than PEI/DNA complexes, as well as good hepatocyte specificity in vitro and in vivo. Our results indicate that poly(organophosphazene) hydrogels loaded with GC-g-PEI/DNA complexes may be a safe and efficient hepatocyte targeting gene delivery system.     

Thermosensitive Micelles–Hydrogel Hybrid System Based on Poloxamer 407 for Localized Delivery of Paclitaxel

A thermosensitive micelles–hydrogel hybrid system based on Poloxamer 407 (P407) was prepared to resolve the fast erosion and low loading capability of lipophilic drug of P407 gels for local chemotherapy. Different amounts of glutaraldehyde (GA) were applied to generate cross-linked networks with carboxymethyl chitosan (CMCS) interpenetrated in P407 gels, in which paclitaxel (PTX)-loaded N-octyl-O-sulfate chitosan micelles (PTX-M) were dispersed uniformly. The in vitro characteristics of CMCS-modified P407 gels (PTX-M-MG) were performed by examining the viscosity, swelling ratio, mechanical property, and drug release, while the in vivo evaluation included tissue distribution and anticancer efficacy through in-tratumoral administration in hepatoma solidity cell (Heps) tumor-bearing mice. The results showed that PTX-M-MG containing 0.05% (w/v) GA possessed lower viscosity, higher swelling ratio, stronger mechanical property, and longer term drug release, in which the loading efficiency of PTX was enlarged by the introduction of PTX-M. Moreover, PTX-M-MG revealed a prolonged retention at tumor sites, lasting for 20 days, and a superior tumor inhibition rate (64.27%) with reduced toxicity compared with Taxol®, PTX-M, and PTX-M loaded unmodified P407 gels (PTX-M-P407). It can be concluded that PTX-M-MG is a promising local delivery system for hydrophobic drug in cancer therapy, providing both improved efficacy and relieved side effects. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2707–2717, 2013     

Topotecan hydrochloride liposomes incorporated into thermosensitive hydrogel for sustained and efficient in situ therapy of H22 tumor in Kunming mice

Abstract

Topotecan hydrochloride (TPT) has potential for the treatment of ovarian cancer, but the activity of TPT tends to decrease due to the ring-opening at physiological pH. In this study, we proposed to incorporate TPT liposomes into injectable thermosensitive in situ hydrogel, consisting of chitosan (CS) and β-glycerophosphate (β-GP), for sustained release and preservation of active lactone form of TPT. The rheology studies were carried out to investigate the sol–gel temperature, flow behavior and viscosity of these CS/β-GP systems. The optimized formulation exhibited sol–gel transition at 40.2?±?0.4?°C, with pseudoplastic flow behavior. The drug release rate of TPT liposomes loaded CS/β-GP hydrogel in phosphate buffer saline (pH?=?7.4) was found to be slowed down, and the lactone fraction of TPT in the hydrogel matrix was maintaining 40% after 50?h. In addition, the antitumor efficacy in Kunming mice bearing Hepatoma-22 tumor, after intratumoral injection of TPT liposomes loaded CS/β-GP hydrogel, was higher than that of TPT in saline and TPT in CS/β-GP hydrogel. Those results demonstrated that TPT liposomes loaded CS/β-GP hydrogel could become a potential formulation for improving the antitumor efficacy of TPT and suggested an important technology platform for intratumoral administration of derivative of camptothecin-family drugs.     

A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel.

A novel injectable thermosensitive in situ gelling hydrogel has been developed. The system, which falls under the BST-Gel platform technology developed at Biosyntech Inc. (Laval, QC, Canada), consists of a chitosan solution (C) neutralized with beta-glycerophosphate (GP) that is liquid at room temperature but gels when heated to body temperature. We propose to use this thermosensitive hydrogel for the sustained release of paclitaxel at tumor resection sites in order to prevent local tumor recurrence. The in vitro release profiles demonstrated controlled delivery over 1 month. The initial drug loading substantially affected the release. Local delivery of paclitaxel from the formulation injected intratumorally was investigated using EMT-6 tumors implanted subcutaneously on Balb/c mice. These experiments showed that one intratumoral injection of the thermosensitive hydrogel containing paclitaxel was as efficacious as four intravenous injections of Taxol in inhibiting the growth of EMT-6 cancer cells in mice, but in a less toxic manner. Further histological analysis revealed that while the proportion of necrotic areas was similar for the C/GP/paclitaxel and the Taxol-treated tumors, a disparity between tumor-associated inflammatory cell populations may suggest differing anti-tumor mechanisms.     

Vaginal delivery of carboplatin-loaded thermosensitive hydrogel to prevent local cervical cancer recurrence in mice

Local tumor recurrence after cervical cancer surgery remains a clinical problem. Vaginal delivery of thermosensitive hydrogel may be suited to reduce tumor relapse rate with more efficacy and safety. A pilot study was carried out to evaluate the efficacy of carboplatin-loaded poloxamer hydrogel to prevent local recurrence of cervical cancer after surgery. In vivo vaginal retention evaluation of 27% poloxamer hydrogel in mice was proven to be a suitable vaginal drug delivery formulation due to its low gelation temperature. A mimic orthotopic cervical/vaginal cancer recurrence model after surgery was established by injecting murine cervical cancer cell line U14 into the vaginal submucosa to simulate the residual tumor cells infiltrated in the surgical site, followed by drug administration 24?h later to interfere with the formation/recurrence of the tumor. By infusing fluorescein sodium-loaded hydrogel into the vagina of mice, a maximized accumulation of fluorescein sodium (Flu) in the vagina was achieved and few signals were observed in other organs. When used in the prevention of the cervical cancer formation/recurrence in mice, the carboplatin-loaded poloxamer hydrogel exhibited great efficacy and systemic safety. In conclusion, thermosensitive hydrogel presents a simple, practical approach for the local drug delivery via vagina against cervical cancer recurrence.     

pH triggered injectable amphiphilic hydrogel containing doxorubicin and paclitaxel

Injectable hydrogel with hydrophobic microdomains for incorporating both hydrophilic and hydrophobic drugs, herein doxorubicin hydrochloride (DOX) and paclitaxel (PTX), was synthesized through dynamic bonding of glycol chitosan and benzaldehyde capped poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) via Schiff's reaction triggered by environmental pH. Rheology tests show that the inclusion of hydrophilic drug decreases the gelation time and gains more robust gel, while the addition of hydrophobic drug has opposite influences. Dual-drug release from the DOX+PTX loaded gels was observed and the release rate can be accelerated by decreasing the environmental pH from physiological (7.4) to weak acidic pH (6.8). In vivo investigation proved that the gels were able to diminish the amount of DOX in blood circulation and limit the DOX-induced cardiotoxicity. By intratumoral administration, the hydrogel-drug formulations resulted in efficient growth inhibition of subcutaneous tumor (B16F10) on C57LB/6 mouse model. The advantage of the current system for DOX+PTX combination therapy was demonstrated by a prolongation of survival time in comparison with the single drug therapy.     

Injectable and biodegradable poly(organophosphazene) gel containing silibinin: its physicochemical properties and anticancer activity

The biodegradable poly(organophosphazene) hydrogels were developed as a locally injectable drug carrier for a hydrophobic silibinin to overcome its limited bioavailability. The aqueous solution of poly(organophosphazene) enhanced the solubility of silibinin up to 2000 times compared with that of phosphate buffered saline (0.0415 vs. 84.55 mg/mL). Both aqueous polymer solutions with and without silibinin showed a sol-gel transition as a function of temperature. A faster in vitro degradation rate of the gel and drug release rate from the gel at pH 6.8 than those at pH 7.4 were observed when the degradation and release study on hydrogels were conducted at 37 °C. Silibinin was sustainedly released from the hydrogel mainly by a diffusion-controlled mechanism. The silibinin released from the hydrogel was shown to be effective considering the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In the HT-29 xenografted mice model, the intratumorally injected hydrogel containing silibinin exhibited a good antitumor effect in comparison with the control groups. The Western blotting indicated that one of the reasons for the enhanced antitumor effect of the hydrogel system was the sustained antiangiogenic effect of silibinin. The poly(organophosphazene) gels are expected to be an effective candidate of the locally injectable drug carrier for silibinin.     

醋酸曲安奈德温敏凝胶药效学及滞留性

目的：制备关节腔注射用醋酸曲安奈德TAA温敏凝胶,考察其药效学和滞留性。方法：采用物理混合法制得TAA温敏凝胶,建立老鼠皮下气囊炎症模型,给予不同组分药物治疗后,通过对比皮下囊物理特征、组织切片的相关评价以及elisa试剂盒检测炎性因子TNF-α水平等来考察所制备的TAA温敏凝胶药效学及缓释性能,并通过小动物活体成像实验评价其滞留性。结果：药效学结果显示制备的TAA温敏凝胶相比于市售TAA混悬液对于气囊滑膜炎模型的炎症抑制作用更强、作用时间更持久。小动物活体成像实验结果显示制备的TAA温敏凝胶在体内滞留时间能达到9 d以上,能够达到缓释药物的目的,适用于关节腔局部用药的要求。结论：所制备的TAA温敏凝胶的炎症抑制作用强且持久,缓释效果及滞留性良好,有望成为新的关节腔给药传递系统。     

Anti-tumor activity of heptaplatin in combination with 5-fluorouracil or paclitaxel against human head and neck cancer cells in vitro

Heptaplatin (HTP), a newly developed platinum analog, has been approved for the treatment of gastric cancers in South Korea. In this study we explored the potential of HTP for the treatment of head and neck squamous cell cancers (HNSCC). The anti-proliferative activity of HTP was evaluated in FaDu, a human HNSCC cell line. Combinations of HTP with 5-fluorouracil (5-FU) or paclitaxel (PTX) were determined using combination indexes, and were compared with combinations of cisplatin and 5-FU or PTX. In order to evaluate the transport of HTP into tumor tissue, its penetration through multicell layers (MCLs) of cancer cells was measured. Cisplatin+5-FU and HTP+5-FU showed additive to antagonistic interactions. In terms of the HTP+paclitaxel combination, HTP showed antagonism and additivity at the 50 and 80% growth inhibition levels, respectively. An additive interaction was obtained and apoptosis was increased by 2-fold at both inhibition levels when the combinatorial PTX dose was reduced to 1/10. HTP, but not cisplatin or oxaliplatin (L-OHP), maintained its anti-proliferative activity after MCL penetration at clinically relevant concentrations, which can be attributed to lower protein binding of HTP. In conclusion, the present study suggests that low-dose PTX may sensitize tumor cells to HTP. HTP also showed greater penetration through multilayers of tumor cells compared to cisplatin and L-OHP, which may be an important characteristic for solid tumor treatment. Overall, the present study supports the clinical development of HTP in combination with low-dose PTX against HNSCC.     

Formulation and evaluation of pH sensitive hydrogel of camptothecin with enhanced solubility by using β-cyclodextrin

The use of a novel injectable biocompatible and biodegradable camptothecin (CPT) formulation for controlled intra-tumoral release of CPT is described. The drug delivery vehicle is an autogelling pH sensitive formulation, which is based on the natural biopolymer chitosan. The formulation was prepared by Crosslinking methods. The formulations were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, gelation time and viscosities were investigated for controlled release hydrogel formulation. The formulation, containing homogeneously dispersed CPT, was studied by MTT assay on tumor cell MCF-7. The effectiveness of treatment was measured in terms of percentage control tumor growth inhibition (TGI). The hydrogel formulation of CPT showed good release profile with polymer [chitosan (C)/glyceryl monooleate (GMO)/β-cyclodextrin (β-CD)] compare to without polymer. The gelation pH of the formulation PF, PF4, PF6, PF10 and PF12 were found to be 6.58, 7.42, 7.20, 6.98 and 7.30 respectively and calculated values of viscosity in centipoises of the formulation PF, PF4, PF6, PF10 and PF12 were 3,413.3, 5,843.1, 6,948.8, 5,212.6 and 6,972.6 respectively at 25 °C. It was found that cumulative percentage drug release for formulations prepared PF, PF4, PF6, PF10 and PF12 were released 48.48, 76.92, 83.72, 78.97 and 59.23 % respectively. The formulation PF6 showed maximum cumulative percentage drug release which has 3 % w/v chitosan, 3 % w/v GMO and 1.5 % w/v β-CD. The TGI was found that for formulations CPT, PF, PF4, PF6, PF10 and PF12 were 10.2 ± 1.22, 10.4 ± 0.85, 14.92 ± 1.06, 16.42 ± 1.11, 13.58 ± 1.21 and 11.71 ± 1.14 % respectively. The formulation PF6 showed maximum TGI in comparison to other formulation. The system formulated with CPT was found to be stable and the release profiles of a formulation with chitosan, GMO and β-CD showed all most effective release kinetics. These findings show chitosan/GMO/β-CD hydrogel to be a safe, effective, homogeneous, injectable and stable formulation for delivery of CPT and this approach represents an attractive technology platform for the delivery of other clinically important hydrophobic drugs.     

Development, characterization and anti-tumor effect of a sequential sustained-release preparation containing ricin and cobra venom cytotoxin

Cobra venom cytotoxin (CVC) loaded in poly (lactide-co-glycolide) (PLGA) microspheres was mixed with ricin and encapsulated in a thermosensitive PLGA-PEG-PLGA hydrogel for this study. This sequential sustained-release preparation (SSRP) containing ricin and CVC could avoid burst release effect of CVC from microspheres. In addition, in SSRP, the two biotoxins have different drug release rates and antitumor mechanisms, which can be complementary to each other. Ricin has a faster release rate than CVC. It can combine with the tumor cell membrane and enter the cell, inhibiting protein synthesis within 2 weeks. Whereas CVC releases slowly in 5 weeks directly dissolving the tumor cell membrane and killing the cells which are less-sensitive to ricin. The in vivo experiments showed that intratumoral injection of SSRP could inhibit hepatocellular carcinoma growth significantly, and the tumor growth inhibition rate reached 73.5%. It appears that a new medicine preparation for cancer local treatment should be further studied for clinical applications.     

Stability of paclitaxel-loaded solid lipid nanoparticles in the presence of 2-hydoxypropyl-β-cyclodextrin

Paclitaxel (PTX)-loaded solid lipid nanoparticles without hydroxyl-β-cyclodextrin (PS) or with hydroxypropyl-β-cyclodextrin (PSC) were prepared by hot-melted sonication. Biocompatible and biodegradable stearic acid was used to produce the solid matrix. The stability of PS and PSC was assessed at different temperatures. Drug stability, as assessed by encapsulation efficiency (EE; %), particle size, and the polydispersity index (PDI), was examined and in vitro release of PTX from PS or PSC for up to 180 days was assessed. After 180 days of storage at 25 °C, no significant change in particle size, PDI, or EE of PS or PSC was observed. PS and PSC displayed similar sustained PTX release patterns. The particle size, PDI, EE, PTX release profile, and cytotoxicity of PS changed significantly with increasing incubation time, whereas those of PSC showed no significant change, when samples were stored at 40 ± 2 °C. PSC was more stable than PS in plasma with regard to particle size and PDI. These results demonstrate that PSC could be a promising formulation to increase drug stability.     

The <Emphasis Type="BoldItalic">In vitro</Emphasis> Sub-cellular Localization and <Emphasis Type="BoldItalic">In vivo</Emphasis> Efficacy of Novel Chitosan/GMO Nanostructures containing Paclitaxel

Purpose

To determine the in vitro sub-cellular localization and in vivo efficacy of chitosan/GMO nanostructures containing paclitaxel (PTX) compared to a conventional PTX treatment (Taxol^®).

Methods

The sub-cellular localization of coumarin-6 labeled chitosan/GMO nanostructures was determined by confocal microscopy in MDA-MB-231 cells. The antitumor efficacy was evaluated in two separate studies using FOX-Chase (CB17) SCID Female-Mice MDA-MB-231 xenograph model. Treatments consisted of intravenous Taxol^® or chitosan/GMO nanostructures with or without PTX, local intra-tumor bolus of Taxol^® or chitosan/GMO nanostructures with or without PTX. The tumor diameter and animal weight was monitored at various intervals. Histopathological changes were evaluated in end-point tumors.

Results

The tumor diameter increased at a constant rate for all the groups between days 7-14. After a single intratumoral bolus dose of chitosan/GMO containing PTX showed significant reduction in tumor diameter on day 15 when compared to control, placebo and intravenous PTX administration. The tumor diameter reached a maximal decrease (4-fold) by day 18, and the difference was reduced to approximately 2-fold by day 21. Qualitatively similar results were observed in a separate study containing PTX when administered intravenously.

Conclusion

Chitosan/GMO nanostructures containing PTX are safe and effective administered locally or intravenously. Partially supported by DOD Award BC045664

     

Multicompartimental Nanoparticles for Co-Encapsulation and Multimodal Drug Delivery to Tumor Cells and Neovasculature

Purpose

The purpose of this work was the development of a multicompartimental nanocarrier for the simultaneous encapsulation of paclitaxel (PTX) and genistein (GEN), associating antiangiogenic and cytotoxic properties in order to potentiate antitumoral activity.

Method

Polymeric nanocapsules containing PTX were obtained by interfacial deposition of preformed polymer and coated with a phospholipid bilayer entrapping GEN. Physical-chemical and morphological characteristics were characterized, including size and size distribution, drug entrapment efficiency and drug release profile. In vivo studies were performed in EAT bearing Swiss mice.

Results

Entrapment efficiency for both drugs in the nanoparticles was approximately 98%. Average particle diameter was 150 nm with a monomodal distribution. In vitro assays showed distinct temporal drug release profiles for each drug. The dose of 0.2 mg/kg/day of PTX resulted in 11% tumor inhibition, however the association of 12 mg/kg/day of GEN promoted 44% tumor inhibition and a 58% decrease in VEGF levels.

Conclusions

Nanoparticles containing GEN and PTX with a temporal pattern of drug release indicated that the combined effect of cytotoxic and antiangiogenic drugs present in the formulation contributed to the overall enhanced antitumor activity of the nanomedicine.     

A novel thermo-responsive drug delivery system with positive controlled release

The model drug, 5-fluorouracil (5-FU) was loaded into the poly(N-isopropylacrylamide) (PNIPA) hydrogel at 25 degrees C, then the drug-loaded, swollen hydrogel sample was carefully enveloped in the dialysis bag to form a novel thermo-responsive drug delivery system (DDS). The concentration of released 5-FU was monitored at 266 nm on the UV spectrophotometer. We found that this novel DDS provides a positive drug release pattern and the drug, 5-FU, was released faster at the increased temperature (37 degrees C, >25 degrees C) than the one at the decreased temperature (10 degrees C, <25 degrees C). This was attributed to the double control of the thermo-sensitivity of the hydrogel matrix and the dialysis membrane. By employing the fast response PNIPA hydrogel instead of the conventional hydrogel in this novel DDS, we can further control the drug release rate and/or drug release amount etc., without changing the positive, thermo-responsive drug release pattern.     

Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy

Breast cancer is one of the most common types of cancer in female patients with high morbidity and mortality. Multi-drug chemotherapy has significant advantages in the treatment of malignant tumors, especially in reducing drug toxicity, increasing drug sensitivity and reducing drug resistance. The objective of this research is to fabricate lipid nanoemulsions (LNs) for the co-delivery of PTX and docosahexaenoic acid (DHA) with folic acid (FA) decorating (PTX/DHA-FA-LNs), and investigate the anti-tumor activity of the PTX/DHA-FA-LNs against breast cancer both in vitro and in vivo. PTX/DHA-FA-LNs showed a steady release of PTX and DHA from the drug delivery system (DDS) without any burst effect. Furthermore, the PTX/DHA-FA-LNs exhibited a dose-dependent cytotoxicity and a higher rate of apoptosis as compared with the other groups in MCF-7 cells. The cellular uptake study revealed that this LNs were more readily uptaken by MCF-7 cells and M2 macrophages in vitro. Additionally, the targeted effect of PTX/DHA-FA-LNs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. The anti-tumor efficiency results showed that PTX/DHA-FA-LNs significant inhibited tumor volume growth, prolonged survival time, and reduced toxicity when compared with the other groups. These results indicated that DHA increases the sensitivity of tumor cells and tumor-associated macrophages (ATM2) to PTX, and synergistic effects of folate modification in breast cancer treatment, thus PTX/DHA-FA-LNs may be a promising nanocarrier for breast cancer treatment.     

Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue

Surface-modified poly(d,l-lactic-co-glycolic acid) PLGA nanoparticles (NPs) were fabricated via nanoprecipitation for obtaining therapeutic concentration of paclitaxel (PTX) in brain tumor. The cellular uptake and cytotoxicity of NPs were evaluated on C6 glioma cells in vitro, and BALB/c mice were used to study the brain penetration and biodistribution upon intravenous administration. Results showed that by finely tuning nanoprecipitation parameters, PLGA NPs coated with surfactants with a size around 150 nm could provide a sustained release of PTX for >2 weeks. Surface coatings could increase cellular uptake efficiency when compared with noncoated NPs, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) showed the most significant enhancement. The in vivo evaluation of TPGS-PLGA NPs showed amplified accumulation (>800% after 96 h) of PTX in the brain tissue when compared with bare NPs and Taxol^®. Therefore, PLGA-NPs with PLGA-TPGS coating demonstrate a promising approach to efficiently transport PTX across blood-brain barrier in a safer manner, with the advantages of easy formulation, lower production cost, and higher encapsulation efficiency.     

Sustained Intravesical Drug Delivery Using Thermosensitive Hydrogel

PURPOSE: Direct instillation of drug solutions into the bladder through a urethral catheter (i.e., intravesical therapy) evades systemic adverse effects of drugs used for bladder diseases. However, conventional vehicles for these drugs fail to extend duration of drug exposure in the bladder beyond the first voiding of urine postinstillation. The current study seeks to overcome the aforementioned inherent limitation of intravesical drug administration by using thermosensitive hydrogel as a matrix for sustained intravesical drug delivery. METHODS: Under halothane anesthesia, normal adult female Sprague-Dawley rats were catheterized with PE-50 tubing to instill either 0.02% w/v solution of fluorescein isothiocyanate (FITC) or the same amount of FITC in a 30% w/v dispersion of thermosensitive [Poly(ethylene glycol)-Poly[lactic acid-co-glycolic acid]-Poly(ethylene glycol)) (PEG-PLGA-PEG) polymer in a 0.1 M phosphate buffer. After instillations, rats were kept in metabolic cages for urine collection. Fluorescence emanating from FITC was measured in the urine at various time points up to 24 h after instillation. A rat model of cyclophosphamide-induced cystitis was chosen for the efficacy study using misoprostol as a model drug entrapped in the thermosensitive hydrogel in place of FITC. Efficacy of hydrogel containing misoprostol was compared against rat groups instilled with saline, hydrogel, and misoprostol independently. RESULTS: Prolonged drug exposure to the bladder afforded by hydrogel was evident from the time course of FITC elimination in the urine and by the green fluorescence of FITC seen at the bladder surface when isolated 24 h after instillation. Rats instilled with free FITC voided almost all of the fluorescence in the urine within the first 8 h, whereas rats instilled with hydrogel encapsulated FITC showed sustained release up to 24 h after instillation. Using a cyclophosphamide-induced cystitis model, rats instilled with misoprostol, a synthetic PGE1 analog, showed significantly reduced frequency of urine voiding (p < 0.05) as compared to the rats instilled with saline. Histological examination of the urothelium showed near normal morphology in rats instilled with misoprostol in hydrogel, whereas extensive tissue damage was observed in rats instilled with saline. CONCLUSION: Our study showed that PEG-PLGA-PEG polymer could be used as a viable sustained drug delivery system for intravesical therapy of diseases of the bladder such as cystitis using misoprostol.     

Paclitaxel targeting to lungs by way of liposomes prepared by the effervescent dispersion technique

In order to develop a novel lung targeting drug delivery system (LTDDS) with large-sized liposomes containing paclitaxel (PTX), the liposomes composed of PTX, phosopholipon 90H and tween-80 were prepared by the effervescent dispersion technique with optimal formulation composition. The liposomes were found to be relatively uniform in particle size (8.166 ± 0.459 μm) with a negative zeta-potential (?12.45 ± 1.34 mv), and high entrapment efficiency (92.20 ± 2.56 %). They kept stable for at least 3 months and exhibited a slow release behavior without any hemolysis reaction. Via intravenous administration in rabbits, the PTX liposomes presented a longer mean residence time and elimination half-life, and a much larger area under the plasma drug concentration–time curve compared with its injection; meanwhile, the liposomes altered its biodistribution and exhibited a significant lung targeting characteristic. For example, the relative intake rate (Re) and the ratio of peak concentration (Ce) of lung were 14.87 and 26.44, respectively. Compared with heart, liver, spleen and kidney, the ratios of targeting efficacy (Te)_liposomes to (Te)_injection of lung were increased by a factor of 20.08, 11.10, 6.97 and 14.41, respectively. To sum up, the liposome could be a promising drug carrier for PTX as LTDDS for lung cancer treatment.