POLYMER MICELLES FOR TUNABLE DRUG RELEASE AND ENHANCED ANTITUMOR EFFICACY

Cancer remains a leading cause of death in the United States. The most common treatment options include chemotherapy, but poor solubility, adverse side effects and differential drug sensitivity hamper clinical applications. Current chemotherapy generally aims to deliver drugs at the limit of toxicity, assuming that higher dosage increases efficacy, with little attention paid to potential benefits of tunable release. Growing evidence suggests that releasing drugs at a constant rate will be as effective as a single bolus dose. To test this hypothesis, it is critical to develop drug delivery systems that fine-tune drug release and elucidate the impact of tunable drug release rates on chemotherapeutic efficacy. Block copolymer micelles, spherical nanoassemblies with a core-shell structure, are widely used in recent research. Micelles for this study were engineered to release a model drug (doxorubicin: DOX) at differential rates under acidic conditions, corresponding to tumor tissue (pH \u3c 7). Three specific aims were pursued: to develop drug carriers capable of tuning drug release rates; to determine activity of developed carriers in vitro; and to elucidate effects of tunable drug release rates in vivo. Block copolymers with covalently linked DOX were synthesized and self-associated, forming micelles. Drug binding linkers (glycine, aminobenzoate, or hydrazide) were used to tune release of DOX. Micelles were characterized to determine physicochemical properties such as particle size, drug entrapment yields, and drug release parameters. Characterization revealed that drug release profiles were modulated by interchanging drug binding linkers. Micelles were evaluated in vitro to elucidate the effect of tunable drug release. Micelles delivered drugs at a slower, prolonged rate compared to free DOX. Cytotoxicity and cellular internalization analysis revealed that by slowing release rates, micelles kill cells more efficiently. Biodistribution studies showed that micelles decrease DOX accumulation in peripheral tissue while increasing the maximum tolerated dose. Antitumor activity studies verified that micelles with slower release rates better suppressed tumor growth. This further confirms that release rates play a key role in chemotherapeutic efficacy. Therefore, this thesis provides better insights into the effects of tunable drug release in tumors, leading the way for improved chemotherapy treatments in the future

Degradable Cross-Linked Nanoassemblies as Drug Carriers for Heat Shock Protein 90 Inhibitor 17-\u3cem\u3eN\u3c/em\u3e-Allylamino-17-demethoxy-geldanamycin

Cross-linked nanoassemblies (CNAs) with a degradable core were prepared for sustained release of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a potent inhibitor of heat shock protein 90 (HSP90). The particle size of CNAs ranged between 100 and 250 nm, which changed depending on the cross-linking yields and drug entrapment method. CNAs with a 1% cross-linking yield entrapped 17-AAG in aqueous solutions, yet degraded in 3 hrs. CNAs entrapped 5.2 weight% of 17-AAG as the cross-linking yield increased to 10%, retaining more than 80% of particles for 24 hrs. CNAs with drugs entrapped after the cross-linking reactions were 100 nm and remained stable in both pH 7.4 and 5.0, corresponding to the physiological, tumoral, and intracellular environments. Drug was completely released from CNAs in 48 hrs, which would potentially maximize drug delivery and release efficiency within tumor tissues. Drug release patterns were not negatively affected by changing the cross-linking yields of CNAs. CNAs entrapping 17-AAG suppressed the growth of human non-small cell lung cancer A549 cells as equally effective as free drugs. The results demonstrated that CNAs would be a promising formulation that can be used in aqueous solutions for controlled delivery and release of 17-AAG

Traces of Cu, Mn and Zn in Aquatic Animals, Water and Sediments from the Cris River Basin West Romania. Part II: Distribution Study

The paper presents the determination of Cu, Mn and Zn (TRT r.f.CCP-AES, FAAS) in water, sediment and aquatic animals (fish fillet, freshwater molluscs gills and muscles) collected in the basin of the Cris rivers (White Cris and Black Cris) in West Romania. The concentrations in water were in the range: 1-15 pg Lr1 (Cu), 10-1500 pg L-1 (Mn), 3-100 pg L-1 (Zn). Metal contents, as dry mass fractions, w^m x IO6, were: 5-380 (Cu), 225-2000 (Mn), 23-1140 (Zn) in sediment; 1-11 (Cu), 4-40 (Mn), 8-130 (Zn) in fish fillet, and 5-34 (Cu), 100-600 (Mn) and 50-130 (Zn) in mollusc muscles with higher values for the White Cris samples. Among the seven sample collection sites only one was identified as having concentrations of Mn and Zn in water higher than the admitted levels, but the limits of tolerance for aquatic organisms were not exceeded in either river. In mollusc gills, the metal contents expressed as wdm x IO6 were: 8-60 (Cu), 11000-16000 (Mn), 190-1200 (Zn), and similar for both rivers in the case of Mn