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Biomedical subjects

A J Domb

Publications and source records attributed to A J Domb.

At least 37 records · Page 2Linked to original sources
PubMed2000

Polymer chemotherapy for head and neck cancer.

OBJECTIVES: To study a new method of delivery of chemotherapy for the treatment of squamous cell carcinomas (SCCs) of the head and neck, to evaluate the pharmacokinetics of four anticancer agents (cisplatin, fluorouracil [5-FU], methotrexate [MTX], and paclitaxel) loaded into the biodegradable polymer, polyanhydride polymer poly(FAD:SA), and to evaluate the effectiveness and toxicity of the drug-polymer combination against human SCCs, both in vitro and in vivo. STUDY DESIGN: Poly(FAD:SA) was loaded with different chemotherapeutic drugs and its in vitro and in vivo drug release and tissue penetration characteristics were studied. The biocompatibility and toxicity of the polymer-drug combination were determined. The effectiveness of the drug-polymer was evaluated against three different human SCCs (larynx O11, pharynx FADU, and floor of mouth UM- SCC1) cultured in vitro and in nude mice carrying human SCC xenografts. METHODS: The in vitro drug release pharmacokinetics of the drugs were performed using atomic absorption spectrometry for cisplatin and high-pressure liquid chromatography for the 5-FU, MTX, and paclitaxel studies. In vitro tumor cytotoxicity was assessed by growth assay. In vivo cytotoxicity was assessed by growth rate inhibition in a nude mouse model. RESULTS: All four chemotherapy drugs demonstrated a continuous release that followed first-order kinetics from the polymer. More than 95% of the MTX and 5-FU, 70% of the cisplatin, and 20% of the paclitaxel was released within the 10 days of the assay. Tumor cytotoxicity revealed that the polymer was very effective against the human SCCs O11, FADU, and UM- SCC1 in vitro. When a small amount of polymer (1-2 g) was added to the cell culture and left for 7 days, 96.6% of the UM-SCC1 cells, 86.9% of the FADU cells, and 94.6% of the O11 cells were killed. When the culture medium was then changed every 2 days to remove the effect of nutrient depletion or chemicals released by the degrading polymer, 74% of the UM-SCC1 cells, 94.5% of the FADU cells, and 66.1% of the O11 cells were killed at 7 days. The tumor animal model was the nude mouse carrying human floor of mouth SCC xenografts. Different amounts of cisplatin were incorporated into the polymers (5% and 7% drug/polymer at a weight/weight [wt/wt] load). Thirty-five days after implantation of the polymer in nude mice, the mean treated tumor size was 65.5% of controls in the 5% group and 31.8% in the 7% group. Seventy days after implantation the mean treated tumor size was 41.4% of controls in the 5% group and 38.1% in the 7% group, indicating a statistically significant delay of tumor growth compared with controls or with intraperitoneally injected cisplatin. The blank polymer was well tolerated by the mouse and had no effect on tumor growth. CONCLUSIONS: The study results indicate that polymer chemotherapy is effective against a variety of SCCs of the head and neck, both in vitro and in vivo, and may become a useful therapeutic option for head and neck cancer.

Animals↗
PubMed1999

Perivascular delivery of heparin for the reduction of smooth muscle cell proliferation after endothelial injury.

Thin flexible sheets composed of poly(lactic acid) (PLA) laminated polyanhydride, poly(erucic acid dimer-sebacic anhydride) (P(EAD-SA)), loaded with heparin were evaluated in vitro and in vivo. PLA was used for coating the polyanhydride to improve the release profile and improve the strength of the films. Heparin was released constantly for 20 days from PLA-coated 2% loaded P(EAD-SA). The uncoated film of P(EAD-SA) released heparin for only 4 days. The localized delivery of heparin around the carotid artery was investigated by implanting polymer loaded with [3H]heparin around the carotid artery of rats and the heparin release and tissue distribution was monitored. The maximum heparin concentration in the artery exposed to the drug was on day 4 for the P(EAD-SA) uncoated device (fast releasing system) and day 11 for the coated devices. The control artery, the uncovered segments of the artery, and the surrounding tissue contained negligible amounts of radioactivity. These data confirm that heparin was delivered locally without systemic exposure. Two independent animal studies were conducted to evaluate the effectiveness of these heparin-releasing devices. In both studies the balloon catheter injury in a rat model was used. After inflicting an injury to the common carotid, a matrix oriented with its long axis along the artery was placed under the injured portion of the vessel. In both studies the treated rats showed a very thin layer of neointima where the control group showed a significant reduction of the artery internal diameter with SMC neointima ratio greater than 1.

Animals↗
PubMed1999

Ricinoleic acid-based biopolymers.

Polyanhydrides synthesized from pure ricinoleic acid half-esters with maleic and succinic anhydrides possess desired physicochemical and mechanical properties for use as drug carriers. Ricinoleic acid maleate or succinate diacid half-esters were prepared from the reaction of crude ricinoleic acid (85% content) with succinic or maleic anhydride. The pure diacid monomers were obtained by chromatography purification through silica gel using petroleum ether/ethyl acetate/acetic acid (80/30/1 v/v/v) mixture as eluent. The pure diacid monomers (>99%) were polymerized by melt condensation to yield film-forming polymers with molecular weights exceeding 40,000 with a polydispersity of 2. Extensive biocompatibility study demonstrated their toxicological inertness and biodegradability. Their rate of elimination from rats in the course of about 4-6 weeks was faster than that found for similar fatty acid-based polyanhydrides previously tested. In vitro studies showed that these polymers underwent rapid hydrolytic degradation in 10 days. Methotrexate release from the polymers was not affected by the initial polymer molecular weight in the range of 10,000-35,000. The in vitro drug release correlated with the degradation of the polymers. The fatty acid ester monomers were further degraded to its counterparts, ricinoleic acid and succinic or maleic acid.

Animals↗
PubMed1999

A novel injectable water-soluble amphotericin B-arabinogalactan conjugate.

New, stable, highly water-soluble, nontoxic polysaccharide conjugates of amphotericin B (AmB) are described. AmB was conjugated by a Schiff-base reaction with oxidized arabinogalactan (AG). AG is a highly branched natural polysaccharide with unusual water solubility (70% in water). A high yield of active AmB was obtained with the conjugates which were similarly highly water soluble and which could be appropriately formulated for injection. They showed comparable MICs for Candida albicans and Cryptococcus neoformans (MICs, 0.1 to 0.2 microg/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37 degrees C, was nonhemolytic and was much safer than conventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjugate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. This conjugate, similarly to the liposomal formulation (AmBisome), was more effective than AmB-deoxycholate in prolonging survival. It was more effective than both the liposomal and the deoxycholate formulations in eradicating yeast cells from target organs. The overall results suggest that after further development of the AmB-AG conjugate, it may be a potent agent in the treatment of fungal infections.

Amphotericin B↗
PubMed1999

Efficacious treatment of experimental leishmaniasis with amphotericin B-arabinogalactan water-soluble derivatives.

In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED(50)s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 microg/ml, respectively, for Leishmania major promastigotes and 0.17 and 0.31 microg/ml, respectively, for amastigotes. The effect on Leishmania infantum-infected macrophages was more marked, with ED(50)s of 0.035 microg/ml for rAmB-AG and 0.027 microg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.

Amphotericin B↗
PubMed1998

Prolonged seizure suppression by a single implantable polymeric-TRH microdisk preparation.

Thyrotropin-releasing hormone (TRH; Protirelin) is an endogenous neuropeptide known to have anticonvulsant effects in several seizure models and in intractable epileptic patients. Like most neuropeptides, its duration of action may be limited by a lack of sustained site-specific bioavailability. To attempt to provide long-term delivery, we attached TRH to a biodegradable polyanhydride copolymer as a sustained-release carrier. Utilizing the rat kindling model of temporal lobe epilepsy, a single TRH microdisk implanted stereotaxically into the seizure focus (amygdala) significantly suppressed kindling expression when assessed by the number of stimulations required to reach each behavioral stage and to become fully kindled (8.63 +/- 0.92 vs. 16.17 +/- 1.37; Mean +/- S.E.M.). Two indices of seizure severity, afterdischarge duration (Mean +/- S.E.M., sec.) (stimulated amygdala [87.40 +/- 5.47 vs. 51.80 +/- 15.65] and unstimulated amygdala [89.60 +/- 5.55 vs. 48.67 +/- 15.8] and clonus duration (71.2 +/- 5.94 vs. 29.40 +/- 8.87; Mean +/- S.E.M., sec.), were also significantly reduced by a single polymeric-TRH implant. Fifty days after initiation of the study a significant reduction in clonus duration (53.90 +/- 3.27 vs. 40.09 +/- 4.14) still remained in the TRH-implanted groups. This report is the first to provide evidence in support of in situ microdisk pharmacotherapy for potential neuropeptide delivery in intractable epilepsy and possibly other neurological disorders.

Animals↗
PubMed1998

Liposphere local anesthetic timed-release for perineural site application.

PURPOSE: This investigation determines the drug delivery capacity of Lipospheres, which are drug-containing solid-filled vesicles made of triglyceride with a phospholipid outer covering, to release local anesthetic in vitro and to produce sustained peripheral nerve block in vivo. METHODS: The local anesthetic, bupivacaine, was loaded into Lipospheres in several dosage forms, characterized, and measured for in vitro release. In rats, Lipospheres were administered into a large space between muscle layers surrounding the sciatic nerve to assess sensory and motor block in vivo. RESULTS: The particle size of Lipospheres was determined to be between 5 and 15 microm, with over 90% surface phospholopid. Lipospheres released bupivacaine over two days under ideal sink conditions. Liposphere nerve application produced dose-dependent and reversible block. Indeed, sustained local anesthetic block (SLAB) was observed for 1-3 days in various in vivo tests: a) Hind paw withdrawal latency to noxious heat was increased over 50% for 96 hr period after application of 3.6% or 5.6% bupivacaine-Lipospheres. The 3.6% and 5.6% doses were estimated to release bupivacaine at 200 and 311 microg drug/ hr, respectively, based on release spanning 72 hr. Application of 1.6% bupivacaine-Lipospheres increased withdraw latency 25-250% but for only a 24 hr duration; b) Similarly, vocalization threshold to hind paw stimulation was increased 25-50% for 72 hr following application of 3.6% bupivacaine-Lipospheres; c) Finally, sensory blockade outlasted or equaled corresponding motor block duration for all Liposphere drug dosages. CONCLUSIONS: Liposphere delivery of local anesthetic drugs may be well suited for site-specific pharmacotherapy of neural tissue to produce SLAB. Dose-dependent effects in duration of action may include lipophilic tissue storage.

Anesthetics, Local↗
PubMed1997

In vitro/in vivo comparison of drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides--a noninvasive approach by the combined use of electron paramagnetic resonance spectroscopy and nuclear magnetic resonance imaging.

PURPOSE: The purpose of this study was to compare drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides in vitro and in vivo in real time and with minimal disturbance of the investigated system. METHODS: P(FAD-SA) 20:80 and P(FAD-SA) 50:50 polymer tablets were loaded with the spin probe 3-carboxy-2,2,5,5-tetramethyl-pyrrollidine-1-oxyl (PCA) and implanted subcutaneously in the neck of rats or placed in 0.1 M phosphate buffer. 1.1 GHz EPR spectroscopy experiments and 7T MRI studies (T1 and T2 weighted) were performed. RESULTS: A front of water penetration was visible by MRI in vitro in the case of P(FAD-SA) 20:80, but not for P(FAD-SA) 50:50. For both polymers, the thickness of the tablets decreased with time and a insoluble, easy deformable residue remained. Important processes such as edema, deformation of the implant, encapsulation and bioresorption were observable by MRI in vivo. P(FAD-SA) 50:50 was almost entirely absorbed by day 44, whereas an encapsulated residue was found for P(FAD-SA) 20:80 after 65 days. The EPR studies gave direct evidence of a water penetration induced changes of the microenvironment inside the tablet. EPR signals were still detectable in P(FAD-SA) 20:80 implants after 65 days, while the nitroxide was released in vitro within 16 days. CONCLUSIONS: Important parameters and processes such as edema, deformation of the tablet, microviscosity inside the tablet and encapsulation can be monitored in real time by the combined use of the noninvasive techniques MRI and EPR leading to better understanding of the differences between the in vitro and in vivo situation.

Animals↗
PubMed1997

Craniofacial and TMJ effects after glutamate and TRH microsphere implantation in proximity to trigeminal motoneurons of growing rats.

The sequelae of sustained, in vivo delivery of two important neurotransmitter substances, glutamate and thyrotropin-releasing hormone (TRH), upon craniofacial growth and development have previously not been investigated. Our purpose was to document and compare the relative effects of glutamate and TRH microspheres stereotactically placed in proximity to trigeminal motoneurons within the trigeminal motor nucleus. The following null hypotheses were tested: (1) TRH microspheres in proximity to trigeminal motoneurons have no significant effect upon the craniofacial skeleton, and (2) there are no significant differences between the relative effects of chronic, long-term delivery of glutamate and TRH upon the neuromusculoskeletal system of growing rats. Forty male Sprague-Dawley rats were divided into 4 experimental groups (glutamate microspheres, TRH microspheres, blank microspheres, sham surgeries) and underwent stereotactic neurosurgery at 35 days; 5 rats of each group were killed at 14 and 21 days for data collection. Histology revealed that implants were clustered in the pontine reticular formation, close to the ventrolateral tegmental nucleus. Both glutamate and TRH rats had implant-side deviation of their facial skeleton and snout regions; 4 x 2 ANOVA and post hoc t-tests revealed significant (P < or = 0.05, 0.01) differences between groups and sides for motoneuron count, muscle weight, and osteometric data. TRH rats also demonstrated larger implant-side TMJ discs and mandibular fossae in comparison with the other groups. The stated null hypotheses were therefore rejected.

Analysis of Variance↗
PubMed1996

Interstitial delivery of carboplatin via biodegradable polymers is effective against experimental glioma in the rat.

PURPOSE: Carboplatin has shown promise experimentally as an antineoplastic agent against both primary central nervous system (CNS) tumors and several solid tumors that frequently metastasize to the brain. Unfortunately, carboplatin is limited in its clinical use for tumors in the CNS by systemic toxicity and poor penetration through the blood brain barrier. Recent advances in polymer technology have made feasible the intracranial implantation of a biodegradable polymer capable of local sustained delivery of chemotherapy for brain neoplasms. This study assessed the toxicity and efficacy of carboplatin delivered from intracranial sustained release polymers in the treatment of experimental gliomas in rodents. METHODS: Two biodegradable anhydride polymer systems were tested: a copolymer of 1,3-bis-(p-carboxyphenoxy propane) and sebacic acid, and a copolymer of fatty acid dimer and sebacic acid. The polymers were loaded with carboplatin and dose escalation studies evaluating toxicity were performed by implanting carboplatin-loaded polymers into the brains of rats. Next, efficacy was tested. F-98 glioma cells were injected intracranially into rats, and 5 days later polymers containing the highest tolerated doses were implanted at the site of tumor growth. The survival of animals receiving carboplatin-loaded polymer was compared with that of animals receiving intraperitoneal doses of the same agent. RESULTS: Carboplatin-polymer was well tolerated at doses up to 5% loading in both polymer systems. Locally delivered carboplatin effectively prolonged survival of rats with F98 gliomas. Maximal treatment effect was seen with 5% loading of either polymer, with median survival increased threefold over control (P < 0.004). Systemic carboplatin also significantly prolonged survival, but the best intracranial polymer dose was significantly more effective than the best systemic dose tested. CONCLUSIONS: Carboplatin can be safely delivered intracranially by biodegradable sustained- release polymers. This treatment improves survival in rodents with experimental gliomas, with locally delivered carboplatin being more effective than systemic carboplatin.

Animals↗
PubMed1996

Biodegradable bone cement compositions based on acrylate and epoxide terminated poly(propylene fumarate) oligomers and calcium salt compositions.

The synthesis of biodegradable bone cement compositions is presented. These bone cement compositions can be applied as a putty-like mixture and harden to a strong material in a bone fracture. They degrade from the site of application to allow the ingrowth of new bone for complete healing of the bone fracture. The bone cement is composed of a solid particulate phase dispersed in an initially liquid polymeric phase, which can be hardened by cross-linking. The polymeric phase is a low-molecular-weight liquid poly(propylene fumarate) (PPF) containing double bonds available for cross-linking. The solid particulate phase consists of calcium carbonate and tricalcium phosphate. PPF oligomers of Mw = 1800 and Mn = 750 were prepared from the condensation of non-volatile bis(2-hydroxypropyl fumarate) and propylene-bis(hydrogen maleate) trimers. PPF terminated divinyl and diepoxide derivatives were obtained from the reactions between PPF diol and acryloyl chloride or epichlorhydrin, respectively. Putty-like cement compositions were prepared from a mixture of 30 wt% polymer phase containing benzoyl peroxide-dimethyl toluidine as polymerization catalyst and 70 wt% calcium salts. The divinyl and diepoxide terminated PPF oligomers provided a high strength composition of between 30 and 129 MPa which is suitable for bone cement applications. In vitro hydrolysis of the composites showed little weight loss with the compressive strength remaining above 20 MPa after 4 weeks in buffer solution. Compositions of the PPF oligomers cross-linked without calcium salts showed a gradual weight loss (10-65 wt% after 4 weeks) when placed in buffer solution followed by high water absorption (18-200 wt% after 4 weeks), with the epoxide terminated PPF being the least to degrade or absorb water.

Acrylates↗
PubMed1995

In vivo and in vitro elimination of aliphatic polyanhydrides.

The hydrolysis and elimination processes of biopolyanhydrides has been studied using a polymer series of linear aliphatic diacids. This polymer series degrade into their monomer counterparts at about the same rate but differ in the water solubility of their degradation products. Polymers based on natural diacids of the general structure -[OOC-(CH2)x-CO]n- where x is between 4 and 12 were implanted subcutaneously in rats and the elimination of the polymers from the implantation site was observed. The in vitro hydrolysis of this polymer series was studied by monitoring the weight loss, release of monomer degradation products and the content of anhydride bonds in the polymer as a function of time. A dependence was found between the monomer solubility and the rate of polymer elimination in both in vivo and in vitro. The elimination time for polymers based on soluble monomers (x = 4-8) was 7-14 days, while the polymers based on low monomer solubility (x = 10-12) were eliminated only after 8 weeks. The in vitro degradation of polyanhydrides in the presence of several common hydrolytic enzymes found around implants did not affect polymer degradation. All polymers were biocompatible and found to be useful as carriers for drug delivery.

Anhydrides↗
PubMed1995

Excretion of a radiolabelled anticancer biodegradable polymeric implant from the rabbit brain.

The elimination of a clinically used anticancer biodegradable polymer implant (Gliadel) in the rabbit brain was studied. The implant is composed of N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU) (1.6 wt%) dispersed in a copolyanhydride matrix of 1,3-bis(p-carboxyphenoxypropane) (CPP) and sebacic acid (SA) in a 20:80 molar ratio. Four groups of rabbits were implanted with wafers loaded with BCNU, one in a 14C-SA-labelled polymer, another in a 14C-CPP-labelled polymer and two groups with 14C-BCNU in a non-labelled polymer, one for BCNU disposition study and one for residual drug study. In the rabbits implanted with the 14C-SA-labelled polymer, approximately 10% of the radioactivity was found in the urine and 2% in the faeces, and about 10% remained in the device 7 d after implantation. In contrast, only 4% of the radioactivity of the 14C-CPP-labelled polymer was found in urine and faeces during this period. However, a drastic increase in the CPP excretion was found after 9 d, and at 21 d, 64% of the implanted 14C-CPP was found in the urine and faeces, and 29% was still in the recovered wafers. Approximately 50% of the BCNU in the wafers was released in 3 d, and over 95% was released after 6 d in the rabbit brain. This study demonstrates that BCNU-loaded polyanhydride is biodegradable and is excreted from the body primarily through the renal system. The water-soluble components SA and BCNU were rapidly excreted, while the insoluble CPP was gradually eliminated after a lag time of 9 d.

Animals↗
PubMed1995

Prevention of venous thrombosis in microvascular surgery by transmural release of heparin from a polyanhydride polymer.

BACKGROUND: The effects of transmurally released heparin on the patency of microvenous anastomoses were studied by using a bioerodible polymer delivery system in a rat microvascular thrombosis model. METHODS: A polyanhydride carrier with heparin was wrapped around the outside of a highly thrombogenic venous inversion graft in 14 animals, and patency rates were compared with those of 17 control animals. RESULTS: Anastomotic patency was significantly greater in the groups treated with transmurally released heparin, measured both at 24 hours (86% versus 16%; p < 0.02) and at 7 days (86% versus 36%; p < 0.05) after operation. No significant complications occurred. CONCLUSIONS: Controlled release of heparin by transmural delivery is an effective and safe form of local antithrombotic therapy and may have applications both in microvascular and large vessel surgery.

Anhydrides↗
PubMed1995

Polymeric carriers for regional drug therapy.

The limitations of currently available drug therapies, particularly for the treatment of diseases localized in a specific organ or tissue, have encouraged scientists to consider alternative methods of drug administration to increase their specificity. This is particularly relevant in the treatment of solid tumors and localized infections, where a high rate of recurrence remains a major clinical problem, associated with inadequate drug supply to the diseased site. An alternative treatment is the local administration of the agent from a degradable polymeric delivery system implanted at the site of the disease. In this fashion, the drug depot can maintain a high local concentration at the site for extended time periods with minimal systemic distribution of the drug. The polymer carrier is degraded and eliminated from the body shortly after the drug has been released.

Bone Diseases, Infectious↗
PubMed1995

Insect repellent formulations of N,N-diethyl-m-toluamide (deet) in a liposphere system: efficacy and skin uptake.

Novel formulations for a deet in liposphere microdispersion in the form of lotion were prepared from natural solid triglycerides and phospholipids dispersed in buffer solution. The formulations containing 6.5, 10, and 20% deet were effective as a repellent against the common aggressive biting mosquitoes, Aedes aegypti and Anopheles stephensi, for up to 6 h. The acute dermal absorption of the 10% loaded formulation was conducted in rabbits using 14C-labeled deet. 14C-labeled deet, 10% in alcohol solution or in liposphere microdispersion was applied to the intact rabbit skin under a porous nonirritating cover for 7 days. Plasma levels of radioactivity were determined for 24 h, and daily for a total of 7 days. The 14C-deet blood levels following intravenous bolus administration were also measured. The bioavailability of deet from 10% ethanol solution was 45%, whereas the bioavailability of deet from lipospheres was 16%, a 3-fold reduction in the amount of deet absorbed. Examination of the rabbits during the experiment and after necropsy showed no evidence of toxicity or irritation. The 10% deet-liposphere formulation was stable at room temperature for at least 1 year.

Aedes↗
PubMed1994

Polymer delivery of chemotherapy for squamous cell carcinoma of the head and neck.

BACKGROUND: The role of chemotherapy for the treatment of squamous cell carcinoma of the head and neck is limited by the systemic toxicity of chemotherapeutic agents. An attractive alternative is the controlled and sustained release of anticancer agents from a resorbable polymer delivery system that is implanted next to the tumor. The advantages are a high locoregional drug concentration with low systemic levels and a delivery system that is not limited by poor blood supply caused by previous radiation therapy or surgery. METHODS/SUBJECTS: The polymer used in this study was a biodegradable polyanhydride made up of fatty acid dimer and sebacic acid, Poly (FAD-SA), loaded with cisplatin. The tumor animal model was the nude mouse carrying human floor of mouth squamous cell carcinoma xenografts. Polymer-cisplatin pharmacokinetics and the effect of polymer delivery of cisplatin (5% and 7% drug/polymer at a weight/weight load) on tumor growth rates were evaluated. MAIN RESULT: Thirty-five days after implantation of the polymer, the mean treated tumor size was 65.5% of controls in the 5% group and 31.8% in the 7% group. Seventy days after implantation, the mean treated tumor size was 41.4% of controls in the 5% group and 38.1% in the 7% group, indicating a statistically significant delay of tumor growth compared with controls or with intraperitoneally injected cisplatin. CONCLUSION: This study demonstrates that continuous release of cisplatin directly at the tumor site, using an implantable polymer, is effective against human head and neck squamous cell carcinoma xenografts in nude mice.

Animals↗