Synthesis and biopharmaceutical characterisation of new poly(hydroxyethylaspartamide) copolymers as drug carriers.

Abstract Four new poly(hydroxyethylaspartamide)-based copolymers bearing (a) poly(ethylene glycol) 2000, (b) poly(ethylene glycol) 5000, (c) poly(ethylene glycol) 2000 and hexadecylalkyl, (d) poly(ethylene glycol) 5000 and hexadecylalkyle, as pendant groups were synthesised. The copolymers were obtained by partial aminolysis of polysuccinimide with poly(ethylene glycol) and hexadecylalkyl amino derivatives followed by reaction with ethanolamine. Naked polyhydroxyaspartamide was obtained by polysuccinimide reaction with ethanolamine. The nuclear magnetic resonance, infrared, light scattering and elemental analysis allowed for the extensive physico-chemical characterisation of the carriers. T…

SUPRAMOLECULAR ASSOCIATION OF RECOMBINANT HUMAN GROWTH HORMONE WITH HYDROPHOBIZED POLYHYDROXYETHYLASPARTAMIDES

Abstract The protein delivery properties of polymer supramolecular assemblies were investigated by using recombinant human growth hormone (rh-GH) and two polyhydroxyethylaspartamide (PHEA) derivatives: (a) PHEA-C 16 obtained by PHEA random grafting with hexadecylalkylamine; (b) PHEA-PEG 5000 -C 16 obtained by PHEA random co-grafting with hexadecylalkylamine and 5 kDa poly(ethylene glycol). The two polymers possessed similar self-assembling properties: critical micelle concentration (CMC) and particle size. The protein loading (protein/polymer, w/w, %) was 12.1 ± 1.3% and 8.5 ± 0.4% with PHEA-C 16 and PHEA-PEG 5000 -C 16 , respectively. The rh-GH/polymer association constant calculated by Sc…

SYNTHESIS, PHYSICO-CHEMICAL AND BIOLOGICAL CHARACTERIZATION OF A PACLITAXEL MACROMOLECULAR PRODRUG

Paclitaxel was attached to poly(hydroxyethylaspartamide) via a succinic spacer arm by a two-step protocol: (1) synthesis of 2'-O-succinyl-paclitaxel; (2) synthesis of PHEA-2'-O-succinyl-paclitaxel. The 2'-O-succinyl-paclitaxel derivative and the macromolecular conjugate were characterized by UV, IR, NMR and mass spectrometry analysis. The reaction yields were over 95% and the purity of products over 98%. Paclitaxel release and degradation from 2'-O-succinyl-paclitaxel occurred at a faster rate at pH 5.5 than 7.4. After 30 h of incubation at pH 5.5 and 7.4 the released free paclitaxel was about 40 and 20%, respectively. In plasma both drug release and degradation were found to occur at a hig…

Poly(hydroxyethylaspartamide) derivatives as colloidal drug carrier systems

Abstract Poly(hydroxyethylaspartamide) (PHEA) derivatives bearing at the polyaminoacidic backbone poly(ethyleneglycol) (2000 or 5000 Da) or both poly(ethyleneglycol) and hexadecylalkylamine as pendant moieties were investigated as polymeric colloidal drug carriers. The ability of the PHEA derivatives to solubilize hydrophobic drugs was investigated using paclitaxel, amphotericin B and methotrexate. The results demonstrated that the drug solubility depends on both macromolecule composition and drug physicochemical properties. In particular, PEG/hexadecylalkylamine co-grafting increased significantly the solubilization properties of PHEA for the considered drugs while the conjugation of PEG o…

Corrigendum to “Folate-mediated targeting of polymeric conjugates of gemcitabine” [Int. J. Pharm. 307 (2006) 258–269]

MACROMOLECULAR CONJUGATES OF ANTIVIRAL DRUGS FOR LIVER TARGETED THERAPY

Glycosylated macromolecular conjugates of antiviral drugs with a polyaspartamide.

Two new polymeric conjugates for specific liver targeting were prepared by conjugation of sugar moieties and antiviral drugs to alpha, beta-poly[N-2-(hydroxyethyl)-DL-aspartamide] (PHEA). PHEA-galactopyranosylphenylthiocarbamide-mono-O-succinylganciclovir (conjugate 7) and PHEA-mannopyranosylphenylthiocarbamide-O-succinylacyclovir (conjugate 8) were synthesized according to a multi-step procedure which allowed for obtaining high product yield and process standardization. Conjugate 7 contained 7.5 and 8.5% of galactose and ganciclovir (substituent/repeating unit, mol/mol), respectively, and conjugate 8 contained 14.2 and 10.8% of mannose and acyclovir, respectively. In vitro studies demonstr…