|Release Platforms for Organoplatinum Antitumor Agents
Organoplatinum compounds are broad spectrum, very effective antitumor agents. Cisplatin [cis-dichlorodiammineplatinum(II)] is currently the most widely used cancer drug. It is often used in combination with an organic antitumor compound or Carboplatin [1,1-cyclobutanedicarboxyalato(diammine)platinum(II); the second platinum drug to gain widespread commercial use]. The potential of these drugs has been limited because of the severe side effects which accompany their administration. Among the most debilitating side effects induced by organoplatinum drugs are 1.) severe kidney damage and 2.) extreme nausea (as a class the platinum compounds are among the most effective nausea producing agents known – to the point that some patients refuse to complete the treatment regimen). In an attempt to mitigate the toxicity of these drugs we have, for some time, been using water soluble polymers as platforms on which a platinum drug or prodrug might be supported and from which it might be slowly released into the extracellular fluid. This approach has several major potential advantages over the traditional forced hydration therapy currently practiced. First, the solubility of the drug formulation may be dramatically enhanced such that the volume of fluid required to introduce a satisfactory dose of drug is strongly diminished [Cisplatin has a solubility of about 10 mg/L in aqueous saline]. More importantly, if the release rate is optimal, the drug is released into the blood stream at a level that is beneath the toxicity threshold such that side effects may be mitigated. Most recently we have been able to place approximately forty (1,2-diaminocyclohexane)platinum(II) moieties on the surface of a generation 4.5 PAMAM dendrimer. This polymer-drug conjugate displays a very good release profile for the platinum species [cis-(diaquo)(1,2-diaminocyclohexane)platinum(II)].
Vinylidene Chloride Polymers for Barrier Plastic Packaging
Vinylidene chloride copolymers ontaining >85% vinylidene chloride display outstanding barrier to the transport of oxygen (to prevent food spoilage) and other small molecules as well as flavor/aroma molecules (to prevent flavor scalping on the supermarket shelf). For this reason these materials occupy a place of prominence in the food packaging industry. Unfortunately, these resins tend to undergo degradative dehydrochlorination under process conditions. To permit commercial exploitation of these materials the degredation must be controlled. We are involved in an on-going program to develop vinylidene chloride polymers with enhanced thermal stability. A promising approach is the synthesis of polymers containing a comonomer capable of reacting with (and consequently removing) hydrogen chloride as it is formed to expose functionality capable of scavaging radical species.
Poly(styrene) Containing No Head-to-Head Units
Poly(styrene) is a large volume commodity polymer. It is widely used in inexpensive packaging for baked goods (cookies, muffins, rolls, pastries, etc.) and similar items. Conventional poly(styrene) is produced by radical techniques. Polymerization terminination occurs by radical coupling to introduce a head-to-head unit into the mainchain. At elevated temperature during processing this unit may undergo homoloysis to generate macroradicals which can extrude styrene monomer. The presence of styrene monomer in the finished item, even at very low level, may impart objectionable flavor/aroma to the food item contained. This problem could be avoided by using poly(styrene) containing head-to-head units. We have been able to develop methods for the synthesis of such a material and to demonstrate its superior thermal stability.
Dual Functional Flame Retardants for Polymeric Materials
For most applications polymeric materials must be flame retarded. Traditionally, flame retardants have been organohalogen compounds, particularly brominated aromatics. These compounds are readily available, inexpensive, and very effective as flame retardants. They function by releasing hydrogen halide into the gas phase which traps flame propagating radicals. Because of the release of halogen into the atmosphere, the use of these compounds is increasingly being opposed in many parts of the world. Compounds which might promote solid phase (charring) flame retandance as well as gas phase activity should permit the achievement of an adequate level of flame retardance with much reduced levels of halogen. This has been demonstrated for several series of compounds containing both bromine and phosphorus or bromine, nitrogen, and phosphorus. Several potentially very effective but environmentally friendly flame retardants are under development.
Phospholane Initiators for Radical Polymerization
Phosphplane containing a strained carbon-carbon bond may be prepared from a hindered 1,2-diol and dichloro(phyenyl)phosphine or related compound. The compounds undergo homolysis of the carbon-carbon bond at modest temperature to afford a diradical capable of initiating vinyl polymerization. The polymers produced contain a phosphorus moiety in the mainchain and as a consequence exhibit flammability much lower than the corresponding polymer containing phosphorus. Since the phosphorus unit is part of the polymer structure it is not lost during processing or product manufacture as a simple additive might be.
Alkoxyamine Initiator/Mediators for Radical Polymerization via Diels-Alder Reaction
Nitroxyl-mediated radical polymerization offers a method for the generation of low polydispersity styrene polymers. Hindered dienes, e.g., 1,4-diphenyl-1,3-butadine, react with nitrosobenzene to generate substituted 1,2-oxazines. The carbon-oxygen bond in these compounds undergo thermolysis at modest temperatures (70 – 100° C) to generate both a carbon radical capable of initiating polymerization and a stable nitroxyl radical suitable for mediation of the propagation reaction.
Green Polymeric Materials from Renewable Sources
Renewable raw material bases for polymers are of increasing interest both because of environmental concerns (biodegradability) and the ever-increasing cost of petroleum feed stocks. Succinic acid is available from a number of plant sources. It can be reduced to 1,4-butanediol. Thus, both monomers (the diol and succinic acid) required for the generation of poly(butylene succinate) are available from a single source. The properties of this and related polymers, as both the homopolymers and as blends with more traditional materials, are being examined.
Lignin as a Source of Green Flame Retardants
Lignin is a natural polymer readily available as a by-product of the wood pulping industry. It is a highly aromatic material containing a wealth of functionality (largely phenolic groups) for reaction with phosphorus reagents. The phenolic groups are also activated for electrophilic halogenation. Thus lignin may be converted via several conventional reactions to a material with flame retardant properties. Such materials are being generated and evaluated as flame-retardant additives.