Research And Development Of A Novel Paclitaxel Or 5-fluorouracil Loaded Esophageal Stent Combinations

The treatment for oesophageal cancer patients at late stage has been facing up with an awkward dilemma.The chemotherapy that kills the cancer cells was also associated with severe side effects,and the widely used nitinol stents for palliation of dysphagia cannot hinder the tumor growth.In an attempt to combine the advantages of both chemotherapy and stent,we have developed a novel drug/stent combination device for immediate dysphagia relief and localized delivery of chemo-drugs.A novel paclitaxel or 5-fluorouracil/esophageal stent combination(PTX or 5-FU/stent)was designed and prepared.The PTX or 5-FU/stent was prepared by covering a nitinol stent with a bilayered polymer film that consisted of a layer of 50%PTX or 5-FU and a layer of drug-free backing.For the in vitro investigation,the percentages of the drugs that permeated from the backing layer over a period of 95 days were very small(0.61%of 5-FU),and an overwhelming majority of the PTX and the 5-FU was released from the other side of the film(91.96%of 5-FU).Therefore,results demonstrated that this PTX or 5-FU/stent has presented unidirectional,sustained and prolonged drug release profiles.This treatment modality was also evaluated for safty issues in vivo by implantating this device into the esophagus of porcine and New Zealand rabbit.During the follow-up period(120 days for porcine,60 days for rabbit),the drug/stent was always maintained in the esophagus of porcine and rabbits.Althought an extremely high concentration of drugs was analyzed in esophagus tissues(81500.0 ng/g of PTX at 13days in porcine model),no obvious tissue responses have been found in the esophagus wall that contacted with the drug-loaded film after 120 days of PTX/stent or5-FU/stent implantation.However,severe tissue responses included inflammation,ulceration,and granulations have been found in the bared stent and blank film covered stent groups.This indicates that the drug/stent combinations not only cause no damage to the esophageal wall but they also prevent ulceration,inflammation and hyperplasia.Meanwhile,this treatment did not show any obvious systemic toxicity,for example,the drug concentrations were highest in the esophagus compared with in the heart,liver,spleen,lung,kidney and blood(81500.0 ng/g vs.3.9 ng/m L of PTX in the plasma at 13 days in porcine model).Moreover,No obvious histopathological and blood parameter abnormalities and were observed,no matter whether PTX or5-FU/stents or blank film-covered stents were used.These results indicated that the drug/stent combinations might allow for the possible treatment of cancer with maximum efficacy and minimum systemic toxicity.The antitumor capabilities of PTX/stent combination were also evaluated in vivo byimplantating into a rabbit model of oesophageal cancer.A newly developed rabbit model of oesophageal cancer was used for evaluating its efficacy and toxicity.The oesophageal tumor bearing rabbits treated with i.v.injection of paclitaxel experienced a rapid tumor growth from 0.08 cm~3(at day 0)to 14.97 cm~3(at day 21),which was significant different when compared with PTX/stent group(0.09 cm~3 at day 21).This might due to the extremely high drug concentration in tumor tissue(5483.2 ng/g in tumor tissue vs.13.7 ng/ml in plasma,152.9 ng/g in spleen,98.7 ng/g in liver at 21days),and the drug inhibited the cell replication process(PCNA immunohistological analysis).This device was also proved to be well tolerated and resulted in minimal systematic toxicity,as there was no significant pathological change in tissues and blood parameters.These resultes proved that the drug/stent combination could offer a treatment modality with maximum efficacy and minimum systemic toxicity.Results also found that the tumor would gradually grow after 30 days of drug/stent implantation.It is hyposised that introduction of hyperthermia might improve the antitumor capability of this drug/stent combination.The Ni-Ti stent was found to be capable of providing hyperthermia treatment under magnetic field.The temperature rising condition(set at 43?)has been investigated and MTT assay has been used to test the antitumor capability of the therapy that combining the hyperthermia and drug/stent.Results indicated that hyperthermia could improve the antitumor capability after 21 days in VX-2 and ECA-109 cells.In vivo results also show that hyperthermia combining drug/stent would largely inhibit the tumor growth when compared to i.v.PTX injection,blank film/stent and PTX/stent group at 21 days.Overall,the PTX/stent and the 5-FU/stent might provide three treatment therapies altogether,including a stent,a local drug delivery device and a local hyperthermia therapy platform,which would be a potential treatment modality with high efficacy and minimal systematic toxicity for esophageal cancer.