Release Of Mitomycin C Research Articles

Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment

Molecularly Engineered Aptamers Targeting Tumor Tissue and Cancer Cells for Efficient in Vivo Recognition and Enrichment

Drug Release Profiles of Mitomycin C Encapsulated Quantum Dots-Chitosan Nanocarrier System for the Possible Treatment of Non-Muscle Invasive Bladder Cancer.

Nanotechnology-based drug delivery systems are an emerging technology for the targeted delivery of chemotherapeutic agents in cancer therapy with low/no toxicity to the non-cancer cells. With that view, the present work reports the synthesis, characterization, and testing of Mn:ZnS quantum dots (QDs) conjugated chitosan (CS)-based nanocarrier system encapsulated with Mitomycin C (MMC) drug. This fabricated nanocarrier, MMC@CS-Mn:ZnS, has been tested thoroughly for the drug loading capacity, drug encapsulation efficiency, and release properties at a fixed wavelength (358 nm) using a UV–Vis spectrophotometer. Followed by the physicochemical characterization, the cumulative drug release profiling data of MMC@CS-Mn:ZnS nanocarrier (at pH of 6.5, 6.8, 7.2, and 7.5) were investigated to have the highest release of 56.48% at pH 6.8, followed by 50.22%, 30.88%, and 10.75% at pH 7.2, 6.5, and 7.5, respectively. Additionally, the drug release studies were fitted to five different pharmacokinetic models including pesudo-first-order, pseudo-second-order, Higuchi, Hixson–Crowell, and Korsmeyers–Peppas models. From the analysis, the cumulative MMC release suits the Higuchi model well, revealing the diffusion-controlled mechanism involving the correlation of cumulative drug release proportional to the function square root of time at equilibrium, with the correlation coefficient values (R2) of 0.9849, 0.9604, 0.9783, and 0.7989 for drug release at pH 6.5, 6.8, 7.2, and 7.5, respectively. Based on the overall results analysis, the formulated nanocarrier system of MMC synergistically envisages the efficient delivery of chemotherapeutic agents to the target cancerous sites, able to sustain it for a longer time, etc. Consequently, the developed nanocarrier system has the capacity to improve the drug loading efficacy in combating the reoccurrence and progression of cancer in non-muscle invasive bladder diseases.

Controlled release of Mitomycin C from modified cellulose based thermo-gel prevents post-operative de novo peritoneal adhesion

The complications from surgery associated peritoneal adhesion can be alleviated by combination of physical isolation and pharmaceutical treatment. This work aims to develop thermo-sensitive hydrogel barrier by combining mitomycin C (MMC) with modified tempo oxidized nanocellulose (cTOCN) through EDC/NHS-chemical conjugation followed by integration with methyl cellulose (MC). The MMC was successfully combined with cTOCN and ensured controlled release of MMC from hydrogel throughout 14 days. Amount of MC (1.5, 2.5, 3.5% w/v) was proportional to gelation time and inversely proportional to degradation of hydrogel. The optimized hydrogel (C2.5T1M0.2) needed only 30 s for thermoreversible sol-gel (4℃-37℃) phenomenon and did not show in vitro fibroblast cells toxicity as well as ensured complete adhesion prevention efficacy, reperitonealization in rat side wall-cecal abrasion model. Overall, the developed C2.5T1M0.2 thermo-gel advances state-of-the-art in view of cytocompatibility, mechanical stability, optimum degradation, good injectability, sustain drug release from surgical sites, and satisfactory de novo anti-adhesion capacity.

Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study

To evaluate the safety and feasibility of single and serial instillations of MitoGel into the upper urinary tract using a preclinical swine animal model. MitoGel is a novel sustained release formulation of mitomycin C (MMC) based on RTGel, a proprietary thermosensitive hydrogel technology. MitoGel is liquid at cold temperatures and solidifies to gel state at body temperature. It is intended as a treatment for upper tract urothelial carcinoma, given its ability to provide sustained release of MMC in the upper urinary tract. We utilized 23 pigs in a 3-phase design. All animals underwent bilateral nephrostomy tube placement. During phase 1, 3 animals underwent antegrade RTGel instillation, imaging, and euthanasia within 12 hours. In phase 2, 10 pigs underwent single antegrade instillation, unilateral nephrectomy 3 days following instillation, and contralateral nephrectomy and euthanasia 30 days following instillation. During phase 3, 10 animals underwent 6 instillations over 3 weeks, followed by bilateral nephrectomy and necropsy 30 days postinstillation. MitoGel (2 mg/mL and 4 mg/mL), aqueous MMC (2 mg/mL and 4 mg/mL), and RTGel alone were evaluated. MitoGel remained visible within the pelvicalyceal system on fluoroscopic and computed tomography imaging for 4-6 hours. MMC plasma levels were well within acceptable safety thresholds. There was no evidence of urinary obstruction, acute kidney injury, sepsis, or myelosuppression. Histologic changes in the urinary system were mild and transient. Antegrade MitoGel delivery to the pelvicalyceal system of Yorkshire swine is feasible and safe. Further evaluation of MitoGel in human clinical trials is warranted.

A new drug delivery system for Mitomycin C to improve intravesical instillation

The conventional administration of Mitomycin C (MMC) in intravesical instillations has its limitations. In this study, MMC was loaded onto an in situ forming depot consisting of chitosan (CS), β-glycerophosphate (GP) and Fe3O4 magnetic nanoparticles (Fe3O4-MNPs) to improve its effects. The features and effects of this new drug delivery mode were investigated. The new drug delivery system (Fe3O4-MMC-CS/GP) exhibited superior sol-gel transformation and magnetism. Sustained release of MMC was observed both in vitro and in vivo, and the retention, which lasted for 72h in the rat bladder, was further examined using frozen sections. The Cell-Counting Kit-8 (CCK-8) and flow cytometry assays revealed better anti-tumor activity of Fe3O4-MMC-CS/GP compared with the free MMC solution. Animal experiments showed that Fe3O4-MMC-CS/GP provided a favorable survival rate and inhibited the growth of bladder tumors. Moreover, this drug delivery system enhanced tumor cell apoptosis compared with the conventional route of MMC administration in rats.

A swellable drug eluting stent to target fibrosis-induced ureteral stricture

Event Abstract Back to Event A swellable drug eluting stent to target fibrosis-induced ureteral stricture Huang Yingying1, Lim Wei Shan1, Chong Tsung Wen2, Kenneth Chen2* and Subbu Venkatraman1* 1 Nanyang Technological University, School of Materials Science and Engineering, Singapore 2 Singapore General Hospital, Urology Centre, Singapore Ureteral stricture is a serious urological disease which results in the difficulty for urine to pass through the ureter space from kidney to bladder. Consequently, this can result in hydronephrosis, morbidity and loss of a functioning kidney. Ureteral stricture may result from a variety of causes, including stone passage, endoscopic urologic procedures, radiation therapy, open or laparoscopic surgery, and penetrating traumatic injuries[1]. Standard of care comprising endoscopic incision and stenting is not always successful, nor able to produce durable favourable outcomes, and normally associated with recurrent obstruction. This study reports on a swellable bilayer drug-eluting stent to be placed in the ureter post-operatively to enhance the localized delivery of an anti-fibrotic drug into the proximate disease area with sustained delivery over the period of time when the stent is left in-situ. The swellable bilayer stents were prepared by spray coating the bare polyurethane stent with a biodegradable polymer loaded with Mitomycin C (MMC), and the hydrogel is coated via in-situ crosslinking onto the biodegradable polymer that was pre-treated with oxygen plasma. Firstly, the adhesion of the hydrogel to the polymer as well as its swelling properties was evaluated. Next, the in vitro release studies of MMC from both polymer coated stent with different coating thickness and swellable coated stent were evaluated. Lastly, the effect of the released MMC from the swellable coated stent on human bladder stroma fibroblast cells was studied. The results show the adhesion of hydrogel onto the polymeric stent coating remained firm for 28 days and the bilayer coated stent can swell up to comparable ureteric diameters of 4-5 mm, as shown in Figure 1 (A – D). Moreover, the release profile may be manipulated by thickness of PLC and the drug loading, to achieve about 10% to 50% of cumulative MMC release over 28 days (Figure 2A and 2B); the hydrogel itself does not have any effect on this release profile, Figure 2C. Finally, the release of MMC from selected coated stent is able to inhibit human bladder stroma fibroblast cells in vitro as shown in Figure 3. In conclusion, a swellable coated stent developed in our work, has the ability to adhere onto the bare PU stent for 28 days, and swell up to 4-5 mm. The release of MMC from selected coated stent is able to inhibit human bladder stroma fibroblast cells in in vitro. Therefore, a swellable coated stent can have significant benefit for managing fibrosis-induced ureteral strictures.

Sustained Release of Mitomycin C from Its Conjugate with Single-Walled Carbon Nanotubes Associated by Pegylated Peptide.

A novel sustained release formulation of mitomycin C (MMC) was developed by employing single-walled carbon nanotubes (SWCNTs) wrapped by designed peptide with polyethylene glycol (PEG) modification (pegylation) as a nano-scale molecular platform. The amino groups of polycationic and amphiphilic H-(-Cys-Trp-Lys-Gly-)(-Lys-Trp-Lys-Gly-)6-OH [CWKG(KWKG)6] peptide associated with SWCNTs were modified using PEG with 12 units (PEG12) to improve the dispersion stability of the composite. Then thiol groups of peptide were conjugated with MMC using N-ε-maleimidocaproic acid (EMCA) as a linker via transformation of aziridine group of MMC. The obtained SWCNTs-CWKG(KWKG)6-(PEG)12-C6-MMC composites particularly that with 13.6% PEG modification extent of amino groups, showed good dispersion stability both in water and in a cell culture medium for 24 h. The release of MMC from SWCNTs-CWKG(KWKG)6-(PEG)12-C6-MMC was confirmed to follow first-order kinetics being accelerated by the pH increase in good agreement with the results observed for MMC-dextran conjugate with the same conjugation structure. The SWCNTs-CWKG(KWKG)6-(PEG)12 composite exhibited a considerably low cytotoxicity against cultured human lung adenocarcinoma epithelial cell line (A549). In contrast, SWCNTs-CWKG(KWKG)6-(PEG)12-C6-MMC demonstrated delayed but relatively corresponding antitumor activity with free MMC at the same concentration. The results suggested the potential role of SWCNTs-CWKG(KWKG)6-(PEG)12 as a carrier for a controlled release drug delivery system (DDS).

The fabrication and characterization of stable core-shell superparamagnetic nanocomposites for potential application in drug delivery

Two systems of core-shell superparamagnetic nanoparticles in the size range of 45–80 nm have been fabricated by the coating of bare magnetite particles with either mesoporous silica or liposomes and the loading/release of the anti-cancer drug Mitomycin C (MMC) from their surfaces has been investigated. The magnetic cores of size ∼10 nm were produced by a co-precipitation method in aqueous solution, with the silica coating containing an unstructured network of pores of size around 6 nm carried out using a surfactant-templating approach and the liposome coating achieved by an evaporation-immersion technique of the particles in a lipid solution. Stability measurements using a scanning column magnetometry technique indicated that the lipid-coating of the particles halts the sedimentation otherwise apparent in <1 h for the bare magnetite to produce an ultra-stable system and thereby overcome one of the main barriers to potential in-vivo applications. Whilst an increase in stability was also observed in the silica-coated system, it was still unstable over a few hours and will require further investigation. Magnetization curves of the coated systems were indicative of superparamagnetic behavior whilst the in vitro loading and release of MMC resulted in two distinctly different outcomes for the two systems: (i) the silica-coated particles saturated in <4 h to a loading of around 7 μg/mg of material, releasing about 6% at a near constant rate over 48 h whilst (ii) the lipid-coated particles saturated to around only 4 μg/mg over the same time period but with a subsequent rapid release rate over the first 3 h to 27% then rising near-linearly to a value of about 45% at the 48 h mark. This gives scope for systems' to be tuned to the appropriate rate and load delivery as required by clinical need with further investigations underway.

Single-step assembly of polymer-lipid hybrid nanoparticles for mitomycin C delivery.

Mitomycin C is one of the most effective chemotherapeutic agents for a wide spectrum of cancers, but its clinical use is still hindered by the mitomycin C (MMC) delivery systems. In this study, the MMC-loaded polymer-lipid hybrid nanoparticles (NPs) were prepared by a single-step assembly (ACS Nano 2012, 6:4955 to 4965) of MMC-soybean phosphatidyhlcholine (SPC) complex (Mol. Pharmaceutics 2013, 10:90 to 101) and biodegradable polylactic acid (PLA) polymers for intravenous MMC delivery. The advantage of the MMC-SPC complex on the polymer-lipid hybrid NPs was that MMC-SPC was used as a structural element to offer the integrity of the hybrid NPs, served as a drug preparation to increase the effectiveness and safety and control the release of MMC, and acted as an emulsifier to facilitate and stabilize the formation. Compared to the PLA NPs/MMC, the PLA NPs/MMC-SPC showed a significant accumulation of MMC in the nuclei as the action site of MMC. The PLA NPs/MMC-SPC also exhibited a significantly higher anticancer effect compared to the PLA NPs/MMC or free MMC injection in vitro and in vivo. These results suggested that the MMC-loaded polymer-lipid hybrid NPs might be useful and efficient drug delivery systems for widening the therapeutic window of MMC and bringing the clinical use of MMC one step closer to reality.

Adjustable release of mitomycin C for inhibition of scar tissue formation after filtration surgery

The aim of this study is to demonstrate a drug delivery system with the capacity to adjust the release of mitomycin C (MMC), based on polymer composition, and inhibit fibroblast proliferation to a better effect than is currently used in glaucoma filtration surgery. The polymer used in this work is made from the oligosaccharide cyclodextrin, from which others and we have demonstrated adjustable release of small molecule drugs due to specific molecular interactions or “affinity” between drug and the cyclodextrin polymer. To adjust release rate, cyclodextrin polymers were synthesized in either dimethylformamide (DMF) or dimethyl sulfoxide, (DMSO) at a crosslinking ratio of 1:0.16 or 1:0:32 (molecule of glucose: molecule of crosslinker). The polymers were then loaded with mitomycin C, dried, and release evaluated in a physiological environment. Drug release was determined by visible spectroscopy. Released aliquots of mitomycin C were incubated with 3T3 fibroblast cells to determine cytotoxic or inhibitory effect through a cell proliferation assay. We show that by using affinity between drug and polymer, we can adjust MMC release rates to be slower and more sustained than from conventional, diffusion-only polymers, for both the DMF polymers (p = 0.00526) and the DMSO polymers (p = 0.0113). The incorporated and released MMC maintains inhibition of fibroblast proliferation much longer than is possible with a one-time application. Affinity polymers with 1:0.16 and 1:0.32 crosslink ratio showed significant inhibition of proliferation for up to 100 h (p = 0.018 and p = 0.014 respectively). The use of our controlled drug delivery technology applied after surgery could have a greater therapeutic impact than the current one-time applications of MMC.

477P - Liposomal Prodrug of Mitomycin C with Thiolytic Activation: Improved Therapeutic Index Over Mitomycin C in Preclinical Studies

ABSTRACT Disclosure A.A. Gabizon: I am the founder and Chief Scientist of Lipomedix Inc., a company with a vested interest in the product discussed in this presentation. Y. Amitay: Paid employee of Lipomedix, a product of which is discussed here. All other authors have declared no conflicts of interest. We have developed a formulation of a mitomycin-C lipid-based prodrug (MLP) in pegylated liposomes (PL) in which MLP is activated by thiolytic cleavage to mitomycin C (MMC). PL-MLP (PROMITIL™) was previously reported to have reduced toxicity and an improved therapeutic index as compared to MMC in human and mouse tumor models. In the following studies, we examined the pharmacokinetics, toxicity, and therapeutic activity of scaled-up batches of PL-MLP (prepared under the same protocol design as for clinical batches) in rodent and miniswine species. PL-MLP is a liquid suspension of vesicles of ∼100 nm diameter with MLP entrapped in the lipid bilayer at 10% molar ratio. Pharmacokinetic studies revealed major (>100-fold) differences in Cmax, AUC, plasma clearance and volume of distribution between MMC (i.v. 3 mg/kg) and PL-MLP (i.v. 6 mg/kg in MMC-equivalents). While MMC is cleared from blood within minutes and extensively distributed to peripheral tissues, PL-MLP is cleared very slowly with a mono-exponential half-life of ∼15 hours in rats and has a limited volume distribution roughly equivalent to the blood volume. In rat toxicity studies in rats, the MTD of PL-MLP was two to three-fold higher than that of MMC in mg-equivalent doses. Therapeutic studies in BALB/c mice inoculated i.p. with C26 tumor cells show a clear survival advantage for treatment with PL-MLP over free MMC at all dose levels tested, whether treatment was administered by the i.v. or by the i.p. route. In the porcine model, no acute infusion reaction to i.v. administration of PL-MLP was observed. PL-MLP appears to be a stable formulation with minimal prodrug activation and release of MMC in circulation, yet significant antitumor activity, indicating in vivo prodrug activation in tumors. PL-MLP may represent an effective therapeutic tool in a broad spectrum of malignancies, including multi-drug resistant tumors, with improved safety over free MMC, and is due to be tested in a human phase I study in 2012.

Synthesis of a novel CS-g-MMCs conjugate and the inhabitation on the proliferation of Tenon’s capsule fibroblasts in vitro

A novel anti-proliferative macromolecular conjugate, CS-g-MMCs, was synthesized in order to decrease the cytotoxicity of Mitomycin C (MMC) which was a traditional anti-proliferative agent of fibroblast in trabeculectomy. The structure of CS-g-MMCs was characterized by 1H NMR, FT-IR spectroscopy and GPC analysis. The grafting degree (dg) of MMC onto chitosan (CS) was determined to be in the range of 2.8–11.3%, which could be controlled by variation of the molar ratios of MMC to oxidized chitosan (CS-CHO). In the drug release profiles of CS-g-MMCs in vitro, an initial burst followed by slow leakage was observed, and addition of acid or lysozyme obviously accelerated the MMC release. The MTS assay indicated that CS-CHO of 8mg/ml has no cytotoxicity against human Tenon’s capsule fibroblasts (HTCFs). The inhibition of HTCFs proliferation by CS-g-MMCs increased along with increasing the dg of conjugate. The CS-g-MMCs also caused the apoptosis of HTCFs and interfered in the active DNA synthesis in HTCFs. Furthermore, the expression of a-SMA at gene and protein levels were obviously lower when HTCFs were treated with CS-g-MMCs, as compared to MMC or blend of MMC/CS-CHO (p<0.05). Our results primarily demonstrated that the CS-g-MMCs conjugates have low cytotoxicity and have the effect to inhibit fibroblast proliferation.

New Method to Prepare Mitomycin C Loaded PLA-Nanoparticles with High Drug Entrapment Efficiency.

The classical utilized double emulsion solvent diffusion technique for encapsulating water soluble Mitomycin C (MMC) in PLA nanoparticles suffers from low encapsulation efficiency because of the drug rapid partitioning to the external aqueous phase. In this paper, MMC loaded PLA nanoparticles were prepared by a new single emulsion solvent evaporation method, in which soybean phosphatidylcholine (SPC) was employed to improve the liposolubility of MMC by formation of MMC–SPC complex. Four main influential factors based on the results of a single-factor test, namely, PLA molecular weight, ratio of PLA to SPC (wt/wt) and MMC to SPC (wt/wt), volume ratio of oil phase to water phase, were evaluated using an orthogonal design with respect to drug entrapment efficiency. The drug release study was performed in pH 7.2 PBS at 37 °C with drug analysis using UV/vis spectrometer at 365 nm. MMC–PLA particles prepared by classical method were used as comparison. The formulated MMC–SPC–PLA nanoparticles under optimized condition are found to be relatively uniform in size (594 nm) with up to 94.8% of drug entrapment efficiency compared to 6.44 μm of PLA–MMC microparticles with 34.5% of drug entrapment efficiency. The release of MMC shows biphasic with an initial burst effect, followed by a cumulated drug release over 30 days is 50.17% for PLA–MMC–SPC nanoparticles, and 74.1% for PLA–MMC particles. The IR analysis of MMC–SPC complex shows that their high liposolubility may be attributed to some weak physical interaction between MMC and SPC during the formation of the complex. It is concluded that the new method is advantageous in terms of smaller size, lower size distribution, higher encapsulation yield, and longer sustained drug release in comparison to classical method.

Corneal Light Shield as a Delivery System for Standardized Application of Mitomycin C in Excimer Surface Ablation

To develop a simple, reproducible method of applying intraoperative mitomycin C (MMC) in excimer surface ablation surgery. A two-part protocol was developed to study several properties of corneal light shields. Part A tested the amount of MMC (0.2 mg/mL) absorbed, expansion dimension attained, and amount released to filter paper. Part B examined in vitro release of MMC to a photorefractive keratectomy (PRK)-treated enucleated pig eye. Mean MMC absorbed by corneal light shields was 63.7 +/- 5.0 mg (range: 57.4 to 72.8 mg); coefficient of variability was 7.8%. Expansion diameter and thickness were constant at 9.0 mm and 1.1 mm, respectively. Mean solution released to filter paper was 55.4 +/- 3.9 mg (range: 51.3 to 63.5 mg); coefficient of variability was 7.1%. Mean solution transferred to the PRK-treated pig eye was 2.3 +/- 0.7 mg (range: 1.1 to 3.5 mg); coefficient of variability was 33%. Mitomycin C contact surface area, amount absorbed, and amount released by each corneal light shield were reproducible. Uniform dimensions theoretically provide uniform distribution of MMC. This method may allow standardization of intraoperative MMC application in excimer surface ablation.

Dosage et cinétique de libération de mitomycine C d’un implant de collagène utilisé comme moyen d’administration lors d’une chirurgie filtrante chez le lapin

To determine the absorption and the release of mitomycin-C from a collagen implant and tissue impregnation in the anterior structures of the rabbit eye. Determining the quantity of mitomycin-C that a collagen implant can absorb with the difference between dry and soaked weight. Mitomycin-C release was measured in vitro using spectrophotometry. The measurement was repeated using a bioassay. Ocular tissue impregnation was determined in 12 eyes of six rabbits. Sclera, implant, aqueous, and ciliary body specimens were collected for concentration measurement using HPLC from 1 to 6 h after surgery. The mean mitomycin-C quantity absorbed in the implant was 3.22+/-0.2 microg. In vitro release was 0.13 mg/ml after 10 min and 0.05 microg/ml at 6 h. The bioassay showed almost no antifibrotic activity in sclera. In vivo release of mitomycin-C was high from the first to the sixth hour. After filtering surgery, mitomycin-C in the collagen implant is clearly released and ocular tissues are effectively impregnated.

Generation of tolerogenic dendritic cells by treatment with mitomycin C: inhibition of allogeneic T-cell response is mediated by downregulation of ICAM-1, CD80, and CD86.

Deliberately generated tolerogenic dendritic cells (DC) might be a useful tool for induction of donor-specific tolerance in transplantation. In this article, the authors study the effect of mitomycin C (MMC)-treated DC on rat T cells and delineate the mechanism of their conversion into tolerogenic cells. The influence of MMC treatment on the capacity of DC to activate allogeneic T cells was tested in vitro, and the expression of cell surface molecules was studied by flow cytometry. MMC-treated DC lose their allostimulatory capacity, and this cannot be attributed to cell death or release of MMC. Interestingly, suppressed T cells cannot be restimulated, indicating that MMC-treated DC induce tolerance. MMC treatment selectively decreases adhesion (intercellular adhesion molecule [ICAM]-1) and co-stimulatory (CD80, CD86) molecules. Functional blocking of these molecules with specific antibodies confers to DC the same T-cell-suppressive properties as treatment with MMC. MMC treatment converts rat DC into tolerogenic cells. This mechanism is mediated by decrease of ICAM-1, CD80, and CD86.

Phase I bioequivalency study of MitoExtra and mitomycin C in patients with solid tumors

This study compares serum pharmacokinetics, urinary excretion patterns, and relative bioequivalencies of single doses of MitoExtra (ME; SuperGen, San Ramon, CA) and mitomycin C (MMC). Thirty-five patients were entered into this open-label, single-institution, crossover study with 2 treatment arms. Each patient received alternating courses of ME and MMC as 15 mg/m(2) single intravenous doses via a short intravenous infusion. Patients were sequentially assigned to receive either ME or MMC as their first treatment course. The courses were given in 6-week intervals and could be repeated up to 4 times in patients with responding disease. Pharmacokinetic parameters were analyzed during the first two courses of therapy. The noncompartmental pharmacokinetic analysis conducted on serum and urine data obtained from patients who received both ME and MMC indicates that the kinetic disposition of these two formulations is similar. This is evident when the mean (+/- standard deviation) values of the various pharmacokinetic parameters are compared. There were no significant differences in any of the kinetic parameters obtained between treatments in all patients examined. The statistical evaluation conducted on the 25 patients that completed both arms of the 2-way pharmacokinetic crossover demonstrates that ME is bioequivalent to MMC. Hematologic and nonhematologic toxicities were similar between the two treatments. There were three clinically significant infusion-related complications associated with MMC administration and none associated with ME. The similar pharmacokinetics of MMC and ME suggest complete release of MMC from the hydroxypropyl-Beta-cyclodextrin carrier contained in the ME formulation. Further studies are needed to define the pharmacodynamics, toxicity, and efficacy of this drug-carrier complex.

Sustained release of mitomycin-C from poly(DL-lactide)/poly(DL-lactide-co-glycolide) films

Mitomycin-C (MMC)-loaded poly(DL-lactide) (PLA)/poly(DL-lactideco-glycolide) (PLGA) films which have different drug loading capacities and thicknesses were prepared by a solvent-evaporation technique. Degradation and release studies were conducted at 37°C in pH 7.4 phosphate buffered saline. The results showed that both the rate and the percentage of released MMC increased as the glycolide content in the copolymer increased from 10 to 30% (w/w) and the drug load increased from 0.5 to 2 mg MMC per 300 mg of polymer. In contrast, they decreased depending upon increasing film thickness from 80 to 300 μm and polymer molecular weight. It was found that the drug release mechanism is diffusion-controlled according to a non-Fickian diffusion mechanism.

Quantification of Intraoperative Administration of Mitomycin-C in Filtering Surgery with Surgical Sponge Material

To determine the absorption and release of mitomycin-C 0.4 and 0.2 mg/mL from sponge-like specimens of Spongostan film (Ferrosan, Copenhagen, Denmark) and the scleral and conjunctival impregnation in an experimental model of filtering surgery. The maximum amount of mitomycin per volume unit that Spongostan is able to absorb was determined physically as the difference between dry weight and soaked weight. Mitomycin-C activity in known volumes of Spongostan after mitomycin-C release in vitro also was determined at 0, 1, 10, and 30 seconds and 1, 3, 5, 10, 15, and 30 minutes. Antibiotic activity of the specimens was evaluated by means of bioassay. Millimeters of inhibition of bacterial growth were related to microg of mitomycin activity according to a reference curve obtained from known amounts of mitomycin-C. Finally, 10 eyes of 10 rabbits underwent filtering surgery with intraoperative application of mitomycin by means of the Spongostan film. The Spongostan implants then were removed and tested for mitomycin activity. Scleral and conjunctival specimens were obtained for bioassay. The maximum capacity of 25 mm2 x 0.5 mm thick Spongostan films saturated in 0.4 and 0.2 mg/mL solutions of mitomycin-C were 8.49 microg and 4.23 microg, respectively. Biologic activity (bioassay determination) was 8.24 microg and 4.19 microg of mitomycin-C, respectively. In vitro release of mitomycin was gradual until 30 minutes. In vivo mitomycin release from Spongostan after 5 minutes was 6.91 microg. Impregnation with the antimitotic was better in conjunctiva than sclera. Bioassay permits quantification of mitomycin-C activity. The release from sponge specimens is gradual, and impregnation was better in conjunctiva than sclera.

Xyloglucan gels as sustained release vehicles for the intraperitoneal administration of mitomycin C

Thermoreversible gels formed by a xyloglucan polysaccharide derived from tamarind seed were evaluated as a sustained-release vehicle for the intraperitoneal administration of mitomycin C (MMC). The in vitro release of MMC from gels prepared from galactoxyloglucan that had been partially degraded by β-galactosidase to eliminate 44% of galactose residues followed root-time kinetics over 5 h. Intraperitoneal administration of MMC in a 1.5% (w/w) xyloglucan gel to rats resulted in a broad concentration–time profile for this drug in both the ascites and the plasma over a 3-h time period, compared with a narrow peak and rapid disappearance from both sites when this drug was given i.p. as a solution.