Raphael M. Ottenbrite

Perspectives on: Chitosan Drug Delivery Systems Based on their Geometries:

Chitosan is a natural polymer that has many physicochemical (polycationic, reactive OH and NH2 groups) and biological (bioactive, biocompatible, biodegradable) properties. These unique properties make chitosan an excellent material for the development of new biomedical applications. One of the most well known biomedical chitosan applications is in drug delivery systems. Chitosans have been used in the design of many different types of drug carriers for various administration routes such as oral, bucal, nasal, transdermal, parenteral, vaginal, cervical, intrauterine and rectal. Chitosan can be engineered into different shapes and geometries such as nanoparticles, microspheres, membranes, sponges and rods. This paper is a perspective on the preparation of the chitosan drug delivery systems based on different structural geometries. In this respect, special preparation techniques are used to prepare chitosan drug carriers by altering such parameters as crosslinker concentration, chitosan molecular weight, drug/polymer ratio and processing conditions all of which affect the morphology of chitosan drug carriers and release rate of the loaded drug.

Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells

A variety of anti-cancer drugs elevate endogenous ceramide, thereby inducing apoptosis in tumor cells. Recently, we have introduced novel ceramide analogs of the beta-hydroxy alkyl amide type, which trigger pro-apoptotic signaling pathways without prior elevation of endogenous ceramide. They induce apoptosis specifically in rapidly dividing neuroblastoma cells, but not in resting or differentiated cells. We characterize new ceramide mimics that have been derived from N-acylation of serinol (S), diethanolamine (B), propanolamine (P), and tris(hydroxy-methyl)methylamine (T) with myristic (14), palmitic (16), or oleic (18) acid. The water solubility of these compounds exceeds that of ceramide by more than 100-fold (up to 5 mM). Apoptosis of human neuroblastoma, glioma, medulloblastoma, and adenocarcinoma cells is induced by N-(2-hydroxy-1-(hydroxymethyl)ethyl)-palmitoylamide, C16-serinol (S16), N-(2-hydroxy-1-(hydroxymethyl)ethyl)-oleoylamide, C18-serinol (S18), N-bis(2-hydroxyethyl)-myristoyl-amide (B16), and N-tris(hydroxymethyl)methyl-oleoylamide (T18) within 60 min of incubation, and is completed even after removal of the compound from the medium. This is most likely due to a rapid uptake of the analogs followed by their slow release from the cells. Alteration of the acyl chain length to less than 14 methylene units, removal of the amino group, or reducing the number of hydroxyalkyl residues to less than two significantly lowers or eliminates the pro-apoptotic potential of these compounds. The target specificity of novel ceramide analogs for tumor cells, their water solubility, and fast pro-apoptotic mechanism indicates a high therapeutic potential for cancer treatment.

Modification of porous silica particles with poly(acrylic acid)

The surface of porous silica particles was modified with poly(acrylic acid) by reacting the carboxyl groups on poly(acrylic acid) with the amino groups of pregrafted aminopropyltriethoxysilane (APS). The chemical modifications by APS and polymer were characterized by infrared spectroscopy and the amount of APS and poly(acrylic acid) grafted to the surface were determined by thermal gravimetric analyses. The wettability of the modified silica particles, based on the rate of water penetration, was pH-dependent with PAA; at pH 1.5 the wettability increased but at pH 5.5 it decreased dramatically. The pore size and size distribution of the silica particles decreased with APS and polymer grafting. Copyright

Perspectives On: Polymeric Drugs and Drug Delivery Systems

Therapeutic uses of a variety of drug carrier systems have significant impact on the treatment and potential cure of many chronic diseases, including cancer, diabetes, mellitus, rheumatoid arthritis, HIV infection, and drug addiction. Drug delivery technology is a multidisciplinary science involving the physical, biological, medicinal, pharmaceutical, biomedical engineering and biomaterial fields. Polymeric systems can deliver drugs directly to the intended site of action and can also improve efficacy while minimizing unwanted side effects elsewhere in the body, which often limit the long-term use of many drugs. In this article, some recent publications on several polymeric drug conjugates, gene delivery systems and polymer implants are addressed.

Antitumor Activity of Polycarboxylic Acid Polymers

Abstract We have synthesized several polyanionic polymers for biological evaluation and to probe the mechanism of macrophage activation. We have determined that, while the molecular weight of the polymers is toxicologically important, the hydrophlicity, chain rigidity, and surface charge play a significant role with respect to the degree of macrophage activation. Macrophages elicited with polyanionic polymers with hydrophobic groups were cytotoxic to Lewis lung carcinoma both in vitro and in vivo. However, macrophages stimulated by polymers with high carboxylic acid group density but little hydrophobicity did not demonstrate significant antitumor activity.

A comparative study of antitumour and toxicologic properties of related polyanions

Poly(maleic anhydride) (PMA) homopolymer, DIVEMA copolymer (PCP) and poly(acrylic acid—maleic anhydride) (PAAMA) copolymer were synthesised and separated into discrete molecular weight (MW) fractions. These fractions were tested for antitumour (Lewis lung carcinoma LLC), anti-Friend leukemia (FLV), immunoadjuvant activity, phagocytic activity, sensitization to bacterial lipopolysaccharide (LPS) and inhibition of microsomal mixed functional oxidase enzymes (MMFO). Molecular weight preparations of the three polymers, 10 000 and above, possess pronounced activity against LLC (increased life-span > 35%), FLV (ED50 between 1.6–4.0 mg/kg) and enhanced B lymphocyte activity as measured by increased number of hemolytic plaque forming cells. Molecular weight preparations below 1000 were devoid of these activities. PCP was the most potent inhibitor of MMFO as measured by prolongation of hexabarbital sleeping times. All polymers induced a sensitization to LPS. PCP was the most potent sensitizer followed by PAAMA and PMA. PCP at MW 30 000 and above markedly suppressed phagocytosis as measured by the vascular clearance rate of colloid carbon in mice while MW preparations 2000 stimulated phagocytosis. PMA inhibited phagocytosis to a much lesser degree than PCP. In contrast to PCP, PMA did not stimulate phagocytosis until 7 days after drug administration. Peritoneal exudate cells (PEC) and serum from PCP and PMA-treated mice conferred complete protection against FLV but not LLC in recipient mice. Supernatants from the PEC also transferred protection but not to the same degree as whole cells. These studies begin to delineate the structures and polymer size which possess therapeutic and toxicologic potential.

Drug delivery systems based on inorganic materials: I. Synthesis and characterization of a zeolite-cyclophosphamide system

Porous material of the CuX zeolite type has been synthesized and used as support for a classic antitumoral drug--cyclophosphamide (CP). The new material obtained represents a physical mixture of the two components. In vivo tests allowed biochemical and anatomopathological evaluation of antitumoral effects determined by oral administration of the CuX zeolite-CP system. Data obtained show that the intensity of the antitumoral effects of the CuX zeolite-CP system is similar as compared to that achieved by CP. A possible advantage of the CuX zeolite-CP system is the continual maintenance in the blood of a CP concentration ranging between 100 and 1,000 ng ml-1 plasma.

Grafting of poly(acrylic acid) onto nonporous glass bead surfaces

The surface of glass beads were modified with covalently bonded poly(acrylic acid). The optimum reaction conditions were determined to graft poly(acrylic acid) effectively onto the glass surface. The dependence of the graft polymer molecular weight, grafting percentage and monomer weight conversion based on these reaction conditions were consistent with free radical kinetics. Grafting efficiency for azobisisobutyronitrile was more complex compared with the benzyl peroxide initiator system

Benzocaine-modified maleic anhydride-cyclohexyl-1,3-dioxepin copolymer: preparation and potential medical applications

This paper presents a new synthetic polycarboxylic compound, i.e. a benzocaine-modified maleic anhydride-cyclohexyl-1,3-dioxepin copolymer. p-Aminobenzoic acid is linked via an anaesthesine (p-aminoethylbenzoate, benzocaine) to the carboxylic groups of the copolymer, both as a spacer and to increase the hydrophobicity of the polymer through the phenyl group. The structure of the modified copolymer is characterized by thin-layer chromatography and by i.r. and n.m.r. spectroscopy.

Biological activity of maleic anhydride copolymers. I. Biocompatibility and antitumoural effects of maleic anhydride - vinyl acetate, maleic anhydride - methyl methacrylate and maleic anhydride- styrene copolymers

A series of maleic anhydride (MA)-vinyl acetate (VA), MA-methyl methacrylate (MM), and MA-styrene (S) copolymers were prepared and characterized. On employing various amounts of initiator, maleic anhydride-vinyl acetate, methyl methacrylate, and styrene copolymers with molecular weights ranging between 18,000 and 200,000 have been obtained. The in vivo and in vitro tests performed on K562 cellular cultures (human chronic myeloid leukemia) have shown that, as a function of the molecular weight, the synthesized copolymers demonstrate a 50% in vitro cytotoxicity and an average tumour regression of maximum 68%.