Continuous intraperitoneal carboplatin delivery for the treatment of late-stage ovarian cancer.

The rate of failure of chemotherapy treatment in ovarian cancer remains high, resulting in a low 5-year survival rate of 20-40% in patients that present with advanced-stage disease. Treatment-free periods between cycles of chemotherapy may contribute to accelerated tumor cell proliferation and decreased treatment response. The elimination of treatment-free breaks has been deemed beneficial in the context of cell-cycle-specific agents. The potential benefit of this approach for non-cell-cycle-specific agents has not yet been elucidated. The present study is the first to address this issue by investigating the impact of continuous versus intermittent intraperitoneal administration of carboplatin over a 14 day period to SCID mice bearing SKOV-3 ovarian cancer xenografts. Immunostaining of tumor sections was employed to quantify tumor proliferation, angiogenesis, and apoptosis using Ki-67, CD-31, caspase-3 (CASP3), and terminal deoxytransferase-mediated dUTP nick-end labeling (TUNEL). Continuous ip administration of carboplatin resulted in greater tumor growth inhibition than intermittent therapy (p < 0.05). Significantly greater tumor cell apoptosis and less cell proliferation and angiogenesis were measured in tumors of mice treated with continuous carboplatin as compared to both intermittent and control groups. These results indicate that continuous local administration may be a promising approach to improve the effectiveness of platinum-based chemotherapy regimens.

Controlled release of octreotide and assessment of peptide acylation from poly(D,L-lactide-co-hydroxymethyl glycolide) compared to PLGA microspheres.

PURPOSE: To investigate the in vitro release of octreotide acetate, a somatostatin agonist, from microspheres based on a hydrophilic polyester, poly(D,L-lactide-co-hydroxymethyl glycolide) (PLHMGA). METHODS: Spherical and non-porous octreotide-loaded PLHMGA microspheres (12 to 16 µm) and loading efficiency of 60-70% were prepared by a solvent evaporation. Octreotide release profiles were compared with commercial PLGA formulation (Sandostatin LAR(®)); possible peptide modification with lactic, glycolic and hydroxymethyl glycolic acid units was monitored. RESULTS: PLHMGA microspheres showed burst release (~20%) followed by sustained release for 20-60 days, depending on the hydrophilicity of the polymer. Percentage of released loaded peptide was high (70-90%); > 60% of released peptide was native octreotide. PLGA microspheres did not show peptide release for the first 10 days, after which it was released in a sustained manner over the next 90 days; > 75% of released peptides were acylated adducts. CONCLUSIONS: PLHMGA microspheres are promising controlled systems for peptides with excellent control over release kinetics. Moreover, substantially less peptide modification occurred in PLHMGA than in PLGA microspheres.

Hydrophilic polyester microspheres: effect of molecular weight and copolymer composition on release of BSA.

PURPOSE: To study the release of a model protein, bovine serum albumin (BSA), from microspheres of an hydroxylated aliphatic polyester, poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA). METHODS: BSA-loaded microspheres were prepared by a double emulsion solvent evaporation method. The effect of copolymer composition and the molecular weight of the copolymer on in vitro release and degradation were studied. The integrity of the released BSA was studied by fluorescence spectroscopy and size exclusion chromatography (SEC). RESULTS: Microspheres prepared from PLHMGA with 50% hydroxymethyl glycolic acid (HMG) showed a burst release followed by a sustained release in 5-10 days. PLHMGA microspheres prepared from a copolymer with 35% and 25% HMG showed a sustained release of BSA up to 80% for 30 and 60 days, respectively. The release of BSA was hardly affected by the molecular weight of the polymer. Fluorescence spectroscopy and SEC showed that the released BSA preserved its structural integrity. Microspheres were fully degradable, and the degradation time increased from approximately 20 days to 60 days when the HMG content decreased from 50% to 25%. CONCLUSIONS: Taking the degradation and release data together, it can be concluded that the release of BSA from PLHMGA microspheres is governed by degradation of the microspheres.

The microclimate pH in poly(D,L-lactide-co-hydroxymethyl glycolide) microspheres during biodegradation.

The microclimate pH (µpH) in biodegradable polymers, such as poly(D,L-lactic-co-glycolic acid) (PLGA) 50/50, commonly falls to deleterious acidic levels during biodegradation, resulting in instability of encapsulated acid-labile molecules. The µpH distribution in microspheres of a more hydrophilic polyester, poly(D,L-lactide-co-hydroxymethyl glycolide) (PLHMGA), was measured and compared to that in PLGA 50/50 of similar molecular weight and degradation time scales. pH mapping in the polymers was performed after incubation under physiological conditions by using a previously validated ratiometric method employing confocal laser scanning microscopy (CLSM). Confocal µpH maps revealed that PLHMGA microspheres, regardless of copolymer composition, developed a far less acidic µpH during 4 weeks of incubation compared with microspheres from PLGA. A pH-independent fluorescent probe marker of polymer matrix diffusion of µpH-controlling water-soluble acid degradation products, bodipy, was observed by CLSM to diffuse ~3-7 fold more rapidly in PLHMGA compared to PLGA microspheres, consistent with much more rapid release of acids observed from the hydrophilic polymer during bioerosion. Hence, PLHMGA microspheres are less susceptible to acidification during degradation as compared to similar PLGA formulations, and therefore, PLHMGA may be more suitable to deliver acid labile molecules such as proteins.

Enhanced gentamicin loading and release of PLGA and PLHMGA microspheres by varying the formulation parameters.

The purpose of this study was to develop a suitable formulation for gentamicin sulfate (GS) that gives a sustained release of the drug. Therefore this drug was loaded into poly(D,L-lactide-co-glycolide) (PLGA) and poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA) microspheres. The effects of various formulation parameters (ethanol, surfactant, osmotic value of the external phase, polymer type and concentration) on particle characteristics (size, loading and release) were investigated. The GS loaded microspheres were prepared using a double emulsion evaporation technique. The results demonstrate that neither ethanol nor surfactants had beneficial effects on the drug loading efficiency (around 4-10%). However, an increase in buffer concentration (and thus osmotic pressure) of the external phase resulted in a substantial increase of GS-loading (from 10 to 28%). Further, an increase of concentration of PLGA in DCM from 10% to 15/20% caused a 4-time increase of the drug loading. The best formulation identified in this study had a loading efficiency of around 70% resulting in PLGA microspheres with a 6% (w/w) loading. The particles showed a burst release of the drug depending on their porosity, followed by a phase of 35 days where hardly any release occurred. The drug was then slowly released for around 25 days likely due to degradation of the microspheres. The drug loading efficiency of GS in PLHMGA was not significantly different from PLGA microspheres (64%). The release of GS from PLHMGA microspheres was faster than that of PLGA because the degradation rate of PLHMGA is more rapid than PLGA. This study shows that prolonged release of gentamicin can be obtained by loading this drug into microspheres made of biodegradable aliphatic polyesters.

Functional aliphatic polyesters for biomedical and pharmaceutical applications.

Functional aliphatic polyesters are biodegradable polymers with many possibilities to tune physico-chemical characteristics such as hydrophilicity and degradation rate as compared to traditional polyesters (e.g. PLLA, PLGA and PCL), making the materials suitable for drug delivery or as scaffolds for tissue engineering. Lately, a large number of polyesters have been synthesized by homopolymerization of functionalized monomers or co-polymerization with other monomers mainly via ring-opening polymerization (ROP) of cyclic esters. This review presents the recent trends in the synthesis of these materials and their application for protein delivery and tissue engineering.