A decade of only minor success with liposomes for large-moleculedrug delivery has some researchers turning to microencapsulation todeliver genes, peptides, proteins and conventional drugs.
An international group of researchers relayed their successes ingiving a host of compounds or solutions _ vaccines, antibiotics,interferons, proteins, peptides and genes _ to animals and humans atthe 23rd International Symposium on Controlled Release ofBioactive Materials. Using microscopic balls _ dubbedmicrospheres, nanospheres, or nanoparticles _ researchers havecreated novel combinations and arrangements of biopolymers fordrug delivery.
Leslie Benet, a professor at the University of California, at SanFrancisco, said many drug company executives are becomingincreasingly aware that drug administration should begin with acontrolled release form.
Positive results using microspheres of biocompatible lipids andpolymers to inject active genes should quicken the pace of somaticgene research. Previous successful gene experiments in humans haveused retroviruses or adenoviruses to administer the genes, but thesecarriers now are viewed with some skepticism. Recent experienceswith AIDS and the U.K.'s mad cow disease have some researchersand companies tilting away from using viral vectors for geneadministration.
Highlights from the conference held earlier this month in Kyoto,Japan, featuring the newer drug delivery systems, include:
* Scott Walsh and colleagues at the Johns Hopkins UniversitySchool of Medicine, in Baltimore, successfully delivered the cysticfibrosis gene (the cystic fibrosis transmembrane conductanceregulator or CFTR cDNA) into rabbit lungs using gelatin-DNAmicrospheres.
The researchers sprayed a 1 mL dose of the gelatin-CFTR genemicrospheres into the lungs of New Zealand white rabbits via abronchoscope. Seven days later, PCR studies of the animals' lungsshowed the microsphere-CFTR cDNA genetic material within thelung cells. Walsh said the in vivo transfection of the rabbit lungdemonstrates the safety and effectiveness of this type of gene deliveryvehicle.
Further dose studies in animals now are in progress to see if theCFTR gene microspheres can be given as effective therapy to peoplewith cystic fibrosis. With the correct gene in place in the lungs, acystic fibrosis patient would not produce the defective DNA thatleads to thick mucus that chokes the airways.
* Another group at Johns Hopkins reported positive outcomes with acancer vaccine using the potent cytokine granulocyte macrophagecolony stimulating factor (GM-CSF) formulated in microspheres ascancer immunotherapy. Zhong Zhao and co-workers administeredcross-linked gelatin/chondroitin sulfate (G/CS) mixed microspherescontaining about one million irradiated B16 melanoma cells to conferanti-tumor immunity in mice. They injected the melanoma cell-microsphere vehicle under the skin of one flank of the animals andchallenged them with wild type B16 tumor cells in the opposite flank24 hours later.
Zhao told BioWorld Today the results showed these microspherevaccines protected the mice from developing tumors. The GM-CSFG/CS hybrid microspheres kept the concentration of GM-CSF above1 ng/mg tissue at the vaccine site for more than 10 days. ImmunexCorp., of Seattle, provided the murine GM-CSF for the studies.
* Michael Lysaght, of Brown University, in Providence, R.I.,reported promising results for treating chronic pain usingtransplantation of animal cells from bovine adrenal glands intohuman patients. Researchers from Brown University, the Universityof Lausanne, in Switzerland, and Cytotherapeutics Inc., ofProvidence, tested the analgesic properties of encapsulated bovinechromaffin cells in terminal cancer patients.
Adrenal chromaffin cells release a "cocktail of compounds," Lysaghtsaid, including catecholamines, enkephalins, neurotensin, andsomatostatin. Reports in the journals have indicated these cells showpromise as potent pain relievers. A natural blend of analgesics offerseveral treatment advantages including a low chance for addictionand reduction of side effects.
The researchers placed cultured bovine chromaffin cells in aretrievable thin tubular device of acrylic polymer membranemeasuring about 3 mL long and 1 cm wide. The polymer membranesecreted about 2 to 3 micrograms of catecholamines over 24 hours.Researchers then implanted this device into the base of the spine insix terminal cancer patients who had severe chronic pain related totheir disease. Results of this Phase I study showed that chromaffincells in the poly-acrylic tube worked well in relieving the continuouspain previously endured by these patients.
Three subjects had complete pain elimination, one of whom stoppedusing morphine entirely, while the other three experienced significantpain reduction but continued their analgesics. The cell implantremained in place from 41 to 176 days. Examination of the tube afterremoval found no fibrous cells sticking to the devices and theremaining chromaffin cells in the tube were viable.
Cytotherapeutics produces the encapsulated bovine chromaffin cellsunder the name CereCRIB. The product formulation currently is inPhase II studies at the University of Lausanne and in Phase I in theU.S.
"This type of encapsulation of immunoisolated cells, proteins, orgenes may be applicable to other conditions such as amyotrophiclateral sclerosis, Parkinson's and Alzheimer's disease, hormonaldeficiencies, coagulation disorders, and, of course, cancer therapy,"Lysaght said.
* In another study of microencapsulated bovine chromaffin cells,Canadian researchers from the University of Toronto, found the celltransplants into the brain of rats with a model of Parkinson's diseasesignificantly reduced disease symptoms after five weeks. P.W. Tsang,H. C. Kwan and Anthony Sun, reported implants of these cells inalginate/poly-lysine/alginate microcapsules injected into the brain ofrats dramatically reduced the measure of Parkinson's disease in theanimals. Encapsulating the chromaffin did not stop them fromproducing catecholamines.
"Ultimately, success in drug delivery is to be gained throughadvancement in biomaterials and such formulations as microspheres,"said Eric Tomlinson, president and CEO of GeneMedicine Inc., ofThe Woodlands, Texas.
"At GeneMedicine we're using lipids, sugars, and polymers to test avariety systems that will deliver genes as `pre-drugs' into cells andorgans to engineer transient therapeutic changes," he said. n
-- Mary Jean Pramik Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.