A leishmaniose é considerada uma doença tropical extremamente negligenciada, que afeta regiões de extrema pobreza. Trata-se de doença emergente com alta morbidade e mortalidade. Aproximadamente 20 diferentes espécies de parasitas intracelulares obrigatórios do gênero Leishmania têm sido identificadas como patogênicas. Estes protozoários são transmitidos ao hospedeiro humano por meio da picada de insetos hematófagos, conhecidos como flebotomíneos. A quimioterapia é escassa, limitada e muito cara. Os fármacos disponíveis apresentam elevada toxicidade, bem como suscitam número elevado de casos de resistência. Considerando-se que a descoberta e o desenvolvimento de novos agentes leishmanicidas são extremamente necessários o objetivo deste trabalho foi contribuir com essa busca utilizando-se o método de modificação molecular, a latenciação. Tendo em vista que os dendrímeros têm sido muito utilizados como transportadores de fármacos, propôs-se a síntese de fármacos dirigidos dendriméricos de primeira geração de hidroximetilnitrofural (NFOH), composto que apresenta potencial atividade leishmanicida. Assim, pretendeu-se desenvolver fármacos dirigidos de NFOH, que apresentem ação seletiva nos macrófagos, devido à presença de manose na estrutura, além de fármacos dirigidos, que apresentem ação seletiva no parasita, devido à presença de inositol em sua estrutura. Variedade de métodos sintéticos foi utilizada com o intuito de obter os dendrímeros dirigidos propostos. Os estudos sintéticos desenvolvidos indicam a provável obtenção dos dendrímeros dirigidos de manose e de inositol, embora os produtos estejam impuros e sem o agente bioativo incorporado. A maior dificuldade encontrada foi a purificação dos compostos obtidos. Em adição, métodos de modelagem molecular foram empregados para compreender os mecanismos de liberação dos fármacos dendriméricos dirigidos de primeira geração. Características moleculares, tais como disponibilidade espacial e potencial eletrostático, foram avaliadas para predizer a região mais suscetível à ação enzimática com vistas à liberação do composto ativo. / Leishmaniasis is considered a superneglected tropical disease and affects primarily areas of extreme poverty. It represents an emergent illness with high morbidity and mortality. About 20 different species of intracellular parasites of Leishmania spp. have been identified as pathogenic. Those protozoans are transmitted to human hosts by means of the female phlebotomine sandflies bite. The chemotherapy is scarce, limited, and expensive. The drugs available can cause undesirable side effects and there are already reports of the increased number of drug resistance. Considering that, the discovery and the development of new leishmanicide agents are urgently needed, the objective of this work as to contribute to this search using the method of molecular modification, prodrug design. Taken into account that dendrimers can be used as drug carriers, the purpose of this work was the synthesis of first generation dendrimer targeted drugs of hydroxymethylnitrofurazone (NFOH), that shows potential leishmanicide activity. Thus, we designed NFOH targeted drugs with selective action in macrophages, due to the presence of mannose in the structure, and also NFOH targeted drugs that present selectivity for the parasite, due to the presence of inositol in the structure. Several synthetic methods have been used with the aim of synthesizing the targeted dendrimers with NFOH. Synthetic studies suggested the targeted dendrimers of D-mannose and of myo-inositol have been obtained, although impure and without the bioactive agent. The major difficulty was the purification of the compounds. In addition, molecular modeling methods were applied to understand the bioactive compound releasing from the first generation leishmanicide targeted dendrimers. Molecular features as spatial hindrance and electrostatic potential were evaluated to predict which region would be the most available to an enzymatic action regarding the bioactive compound release.

The advent of effective oral, molecular-targeted drugs in oncology has changed many incurable malignancies such as chronic myeloid leukemia into chronic diseases similar to coronary artery disease and diabetes mellitus. Oral agents including monoclonal antibodies, kinase inhibitors and hormone receptor blockers offer cancer patients incremental improvements in both overall survival and quality of life. As it is imperative to recognize and manage side effects of platelet inhibitors, beta blockers, statins, HIV drugs, and fluoroquinolones by all healthcare providers, the same holds true for these newer targeted therapies, patients may present to their generalist or other subspecialist with drug-related symptoms. Cardiovascular adverse events are among the most frequent, and potentially serious, health issues in outpatient clinics, and among the most frequent side effects of targeted chemotherapy. Data support improved patient outcomes and satisfaction when primary care and other providers are cognizant of chemotherapy side effects, allowing for earlier intervention and reduction in morbidity and health care costs. With the implementation of accountable care and pay-for-performance, improved communication between generalists and subspecialists is essential to deliver cost-effective patient care.

Targeted delivery of drugs directly to the lung epithelium is a promising, though challenging, strategy for the treatment of diseases that affect the lung tissues, such as infections caused by cell-penetrating pathogens, cystic fibrosis, and cancer. With appropriate surface functionality, such as through the attachment of ligands that recognize receptors on cellular surfaces, particulate carriers show improved efficiency in penetrating cells in vitro. A useful class of ligands is produced by many natural human pathogens that infect the respiratory tract. A variety of phylogenetically distinct respiratory bacterial pathogens, such as Haemophilus influenzae, invade host cells in the upper airways by binding of the platelet-activating factor (PAF) receptor via lipooligosaccharide (LOS) glycoforms. By expressing host carbohydrate structures, including phosphorylcholine (ChoP), as a terminal structure on the LOS, the bacteria exhibit molecular mimicry of the host and are able to evade the host immune system. The effectiveness of LOS to induce cellular uptake of the bacteria is dependent on the specific glycoform, with higher ChoP content inducing more bacterial adherance into the lung epithelial. These ligands naturally expressed on bacterial cell surfaces can be isolated and utilized as targeting ligands for delivery vehicles. The studies described in this thesis focus on the development of particulate drug carriers coated with LOS bacterial ligands to enhance the targeting and binding of the carriers to the lung epithelium. Three NTHi clinical isolates were screened to select the strain with the highest ChoP level, and NTHi 3198, an isolate from a patient with chronic obstructive pulmonary disease (COPD), was selected due to its high ChoP activity. LOS from NTHi 3198 was isolated from the bacterial cell membrane, and its activity verified using dot immunoblot and ELISA techniques. Particles (0.2 and 1 µm) composed of polystyrene or poly(lactic-co-glycolic acid) were passively coated with 0.005-50 µg/mL of the isolated LOS 3198 with or without gelatin, coated with gelatin alone, or left uncoated. The LOS coating on the particles was verified using either XPS or ELISA. The association of particles with human bronchial epithelial cells was investigated using two cell culture models, 16HBE14o- and Calu-3, as a function of particle concentration and incubation time. The expression of PAFR on both cells types was confirmed, though the expression of PAFR on 16HBE14o- cells was significantly greater than on Calu-3 cells. Enhancement of 0.2 µm particle-cell association was achieved through coating of the particles with LOS. However, no significant difference in particle-cell association was observed for the 1 µm particles based on particle coating. Control particles of 0.2 µm size, those coated with gelatin (with or without LOS) or uncoated, exhibited low cell binding with a maximum of about 10-18% of cells associated with particles. The ability of the LOS ligand to enhance particle-cell association was coating concentration dependent, with a low coating concentration of LOS having little effect on association, but a concentration 1000-fold higher causing a doubling of the percentage of cells associated with particles at 24 hours. This enhancement was attributed to increased cellular binding of the 0.2 µm particles to the cell surface by confocal microscopy, and was further increased by activating the PAFR prior to incubation with particles. These results suggest the potential application of LOS as a targeting ligand for lung epithelial cells, especially under conditions where PAFR has been activated, such as occurs in lungs infected with Haemophilus influenzae. A significant reduction in particle-cell association was observed when particles were incubated with Calu-3 cells due to the presence of mucus on the cellular surface. This suggests that further optimization of the drug carrier system is needed to efficiently overcome the mucosal fluids.

Deafness is the most common sensory deficit in humans, affecting 278 million people worldwide. Non-syndromic hearing loss (NSHL), hearing loss not associated with other symptoms, is the most common type of hearing loss and most NSHL in developed countries is due to a genetic cause. The inner ear is a remarkably complex organ, and as such, there are estimated to be hundreds of genes with mutations that can cause hearing loss. To date, 62 of these genes have been identified. This extreme genetic heterogeneity has made comprehensive genetic testing for deafness all but impossible due to low-throughput genetic testing methods that sequence a single gene at a time. The human genome project was completed in 2003. Soon after, genomic technologies, including massively parallel sequencing, were developed. MPS gives the ability to sequence millions or billions of DNA base-pairs of the genome simultaneously. The goal of my thesis work was to use these newly developed genomic technologies to create a comprehensive genetic testing platform for deafness and use this platform to answer key scientific questions about genetic deafness. This platform would need to be relatively inexpensive, highly sensitive, and accurate enough for clinical diagnostics. In order to accomplish this goal we first determined the best methods to use for this platform by comparing available methods for isolation of all exons of all genes implicated in deafness and massively parallel sequencers. We performed this pilot study on a limited number of patient samples, but were able to determine that solution-phase targeted genomic enrichment (TGE) and Illumina sequencing presented the best combination of sensitivity and cost. We decided to call this platform and diagnostic pipeline OtoSCOPE®. Also during this study we identified several weaknesses with the standard method for TGE that we sought to improve. The next aim was to focus on these weaknesses to develop an improved protocol for TGE that was highly reproducible and efficient. We developed a new protocol and tested the limits of sequencer capacity. These findings allowed us to translate OtoSCOPE® to the clinical setting and use it to perform comprehensive genetic testing on a large number of individuals in research studies. Finally, we used the OtoSCOPE® platform to answer crucial questions about genetic deafness that had remained unanswered due to the low-throughput genetic testing methods available previously. By screening 1,000 normal hearing individuals from 6 populations we determined the carrier frequency for non-DFNB1 recessive deafness-causing mutations to be 3.3%. Our findings will also help us to interpret variants uncovered during analysis of deafness genes in affected individuals. When we used OtoSCOPE® to screen 100 individuals with apparent genetic deafness, we were able to provide a genetic diagnosis in 45%, a large increase compared to previous gene-by-gene sequencing methods. Because it provides a pinpointed etiological diagnosis, genetic testing with a comprehensive platform like OtoSCOPE® could provide an attractive alternative to the newborn hearing screen. In addition, this research lays the groundwork for molecular therapies to restore or reverse hearing loss that are tailored to specific genes or genetic mutations. Therefore, a molecular diagnosis with a comprehensive platform like OtoSCOPE® is integral for those affected by hearing loss.

This dissertation focuses on the design, modeling, characterization and experimental verification of a class of nonlinear energy sink, based on a cantilever beam vibrating laterally between two specially shaped surfaces that limit the vibration amplitude, thus providing a variable beam length throughout its deflection, therefore producing a smooth nonlinear restoring force. First, a methodology to evaluate and visualize the energy interactions between the nonlinear energy sink and its host structure is developed. Then, an semi-analytical dynamic model for simulating the device under actual working conditions is proposed, and finally, an experimental verification step is conducted where the numerical results are compared and correlated to the experimental results.<br>

Medulloblastoma is the most common malignant brain tumor in children. Genetic profiling has identified four principle tumor subgroups; each subgroup is characterized by different initiating mutations, genetic and clinical profiles, and prognoses. The two most well-defined subgroups are caused by overactive signaling in the WNT and SHH mitogenic pathways; less is known about Groups 3 and 4 medulloblastomas. Identification of tumor subgroup using molecular classification is poised to become an important component of the medulloblastoma diagnosis and staging and will likely guide therapeutic options. G-protein coupled receptors (GPCR) possess characteristics that make them ideal targets for molecular imaging and therapeutics. While expression patterns of many proteins in human medulloblastoma subgroups have been discerned, the expression pattern of GPCRs in medulloblastoma has not been investigated. We have found that clusters of medulloblastoma tumors arise based solely on differential GPCR expression patterns. Further, two of these clusters correspond with high fidelity to the WNT and SHH subgroups. Distinct over-expressed GPCRs emerge; for example, LGR5 and GPR64 are significantly and uniquely over-expressed in the WNT subgroup of tumors, while PTGER4 is over-expressed in the SHH subgroup. Uniquely under-expressed GPCRs were also observed. Our results identify GPCRs with potential to act as imaging and therapeutic targets; elucidating tumorigenic mechanisms is a secondary benefit to identifying differential GPCR expression patterns in medulloblastoma tumors. Current imaging for diagnosis, staging, and measuring response to therapy for medulloblastoma patients relies heavily on MRI; single photon emission tomography (SPECT) using 111In-DTPA-Octreotide targeting the somatostatin type 2 receptor (SSTR2) is also available. Positron emission tomography (PET) affords a more sensitive and specific imaging modality than SPECT; however, the most common tracer 18FDG, is of limited usefulness for the delineation of brain tumors. Smoothened (SMO) is a GPCR that is overexpressed in a subset of medulloblastoma; we hypothesized that SMO overexpression could be exploited as a specific PET target in these tumors. Genentech generously provided the synthetically-derived small-molecule SMO ligand, GDC-0449, for use as the lead compound for development of a PET tracer. GDC-0449 has already been demonstrated to localize in brain tumors and has Cl- atoms incorporated in positions that are predicted to readily exchange with fluorine-18 to generate a fluorinated analog of the compound. We have successfully fluorinated GDC-0449, with very high radiochemical purity. Binding assays reveal affinities of the fluorinated analog of GDC-0449 for SMO to be comparable to precursor GDC-0449, and biodistribution experiments demonstrate accumulation of the fluorinated compound in tumors. The fluorinated analog of GDC-0449 holds promise as a novel PET imaging agent in medulloblastoma, providing highly specific and sensitive imaging for use in diagnosis, staging and measurement of response-to-treatment.

A major problem regarding public health is the emergence of antibiotic resistant bacterial strains, especially methicillin resistant Staphylococcus aureus (MRSA). This is mainly attributed to the unnecessary overuse of antimicrobial drugs by patients; however, one aspect that is often neglected is their untargeted mechanism of action, affecting not only the infection itself but also commensal bacteria which are often opportunistic pathogens causing many diseases as well. Therefore, our goal was to develop a bioresponsive antibiotic delivery system triggered by virulence factors. The designed system is comprised of a polymer to enhance its pharmacokinetic profile, a peptide cleavable linker, and the antibiotic agent itself. The bacterial protease aureolysin which is expressed by S. aureus during infections would cleave the linker and partially release the antibiotic which would be still attached to a remaining tetrapeptide. These would be cleaved by a group of proteases naturally present in plasma called aminopeptidases, finally releasing the compound. In the first part of this project, we searched for a suitable sequence to serve as a cleavable linker. It should be sensitive towards the target bacterial protease but not be cleaved by any human enzymes to guarantee the specificity of the system. Therefore, we synthesized three peptide sequences via Solid Phase Peptide Synthesis and incubated them with aureolysin as well as with many human matrix Metalloproteases. The analysis and quantification of enzymatic activity was monitored chromatographically (RP-HPLC). The plasminogen originated sequence was chosen since it was not sensitive towards MMPs, but cleaved by aureolysin. In the second part, we tried to incorporate the chosen peptide sequences as crosslinkers in hydrogel formulations. The purpose was to physically incorporate the antibiotic within the hydrogel, which would be released by the cleavage of those sequences and the consequent loosening the hydrogel net. For that purpose we used a commercially available hydrogel kit with a PVA matrix modified with maleimide, which allows a conjugation reaction with thiol functionalized crosslinkers. Three fluorophores were chosen to serve as antibiotic models and a diffusion assay was performed. Only the glomerular structured Green Fluorescent Protein (GFP) presented a low diffusion rate, thus the aureolysin release assays were performed only using this prototype. Assays showed that with a low hydrogel polymer concentration, the fluorophore either quickly diffused into the medium or was not released at all. The physical incorporation of the antibiotic within the hydrogel pores was therefore abolished as a suitable release approach. For a second attempt, we covalently bound a fluorophore to the linker, which was conjugated to the hydrogel matrix. The incubation with aureolysin and subsequent RP-HPLC analysis showed a peak with the same retention time correspondent to the fragment product after cleavage of the free linker. This is a proof that the concept of linking the peptide sequence to the antibiotic is a promising strategy for its bioresponsive release. Within the third part of this study, we analyzed the degradation of the resulted fragment after aureolysin activity and subsequent full release of the antibiotic by human aminopeptidases. We determined the concentration of those enzymes in human plasma and synthesized the fragment by conjugating the tetrapeptide sequence to aminofluorescein via EDC/NHS reaction. By incubating the construct with the lowest aminopeptidase concentration measured in plasma, the fluorophore was completely released within two hours, showing the efficacy of these enzymes as bioresponsive agents. The last part was the construction of the PEGylated linker-antibiotic. For this purpose we chose the tetracycline like antibiotic chelocardin (CHD) as our prototype. The conjugation of the linker- CHD to the polymer was performed by copper free click chemistry. The cleavage rate of the linker by aureolysin was very similar to the one obtained for the free peptide, indicating that the PEGylation does not interfere on the enzymatic activity. However, by trying to increase the loading ratio of chelocardin onto the polymer, we observed a very low cleavage rate for the system, indicating the formation of aggregates by those constructs. The designed system has proved to be a smart strategy for the delivery on demand of antibiotics in which the drug is only released by the presence of S. aureus during their virulent state. / Ein weltweites Problem des Gesundheitswesens ist die Entstehung von antibiotikaresistenten Bakterienstämmen, besonders Methicillin-resistenter Staphylococcus aureus (MRSA). Eine wichtige Ursache für Resistenzentwicklungen ist die unüberlegte Verschreibung von Antibiotika; allerdings das breite Wirkspektrum der meisten Substanzen ist ein stets vernachlässigter Aspekt. Dies betrifft nicht nur die Pathogene selbst, sondern auch die bakterielle Mikroflora des Patienten, die opportunistische Pathogene darstellen und in machen Fallen ebenfalls verschiedene Erkrankungen hervorrufen können. Unser Ziel ist die Entwicklung eines bioresponsiven Freisetzungssystems für Antibiotika. Das System besteht aus einem Polymer zur Optimierung der Pharmakokinetik, einem Peptidlinker sowie dem eigentlichen Antibiotikum. Die bakterielle Protease Aureolysin wird von S. aureus exprimiert, sobald sich das Bakterium in seinem virulenten Zustand befindet. Das Enzym schneidet den Linker, wodurch das Antibiotikum zum Teil freigesetzt wird. Da es noch an Aminosäureartefakte gebunden ist, muss es im Anschluss durch eine Aminopeptidase, einer Gruppe von Exoproteasen des humanen Plasmas, abgespalten werden. Die erste Phase des Projektes war die Suche nach einer passenden Peptidsequenz, die als Linker geeignet ist. Diese soll nur durch die Zielprotease und nicht durch andere humane Proteasen geschnitten werden, um die Spezifizität des Systems zu gewährleisten. Es wurden drei Sequenzen ausgewählt und mittels Festphasen-Peptidsynthese hergestellt. Diese wurden mit Aureolysin sowie humanen Matrix-Metalloproteasen (MMP) inkubiert; die Produkte wurden chromatographisch (RP-HPLC) charakterisiert und die enzymatische Aktivität bestimmt. Die von Plasminogen abgeleitete Sequenz wurde von keiner der Matrix-Metalloproteasen geschnitten, wohl aber von Aureolysin. Eine ausführliche Analyse des Aureolysin-Verdaus zeigte, dass der Linker innerhalb weniger Stunden komplett geschnitten wird. In der zweiten Phase wurde die Peptidsequenz als Crosslinker in verschiedene Hydrogelmatrices inkorporiert. Die Strategie war der physikalische Einschluss des Antibiotikums in das Hydrogel und die anschließende Freisetzung durch Spaltung dieser Sequenzen und Lockerung des Hydrogelnetzes auf molekularer Ebene. Hierfür wurde ein kommerzielles Hydrogelkit mit Maleinsäureamid-modifizierter PVA Matrix verwendet, die mit Thiol-funktionalisierten Linkern konjugiert werden können. Drei verschiedene Fluorophore wurden als Modelle für die Diffusionsversuche verwendet. Nur das glomeruläre green fluorescent protein (GFP) besaß eine ausreichend niedrige Diffusionskonstante und wurde deshalb als Prototyp für die weiteren Schneidversuche verwendet. Die Ergebnisse zeigen, dass der Fluorophor bei niedrigen Matrixkonzentrationen schnell aus den Poren in das umgebende Medium diffundiert, während er bei höheren Konzentrationen nicht freigesetzt wird. Die physikalische Inkorporierung des Antibiotikums wurde aus diesen Gründen verworfen und nicht durchgeführt. Als zweiter Versuch wurde der Fluorophor kovalent an den Linker gekoppelt, welcher im Anschluß an die Matrix konjugiert wurde. Die Inkubation mit Aureolysin und die nachfolgende RP-HPLC-Analyse zeigte einen Peak bei der Retentionszeit entsprechend dem Fragmentprodukt, das durch Inkubation des freien Linkers entsteht. Die kovalente Bindung zwischen der antimikrobiellen Substanz und dem Linker ist eine vielversprechende Strategie für eine bio-responsive Freisetzung. In der dritten Phase des Projektes wurde die Zersetzung des resultierenden Fragments nach Aureolysin-Verdau und die anschließende vollständige Freisetzung des Antibiotikums durch humane Aminopeptidasen untersucht. Die Konzentration an Aminopeptidasen im humanen Plasma wurde bestimmt und die durch Aureolysin entstehende Peptidsequenz an Aminofluorescein mittels EDC/NHS-Reaktion gekoppelt. Die Inkubation des Konstruktes mit der niedrigsten Aminopeptidase-Konzentration, die im Plasma bestimmt werden konnte zeigte, dass der Fluorophor in zwei Stunden vollständig freigesetzt wurde. Die letzte Phase hat sich mit der PEGylierung des Linker-Antibiotikum-Komplexes beschäftigt. Das Tetracyclin-analoge Antibiotikum Chelocardin wurde als Prototyp ausgewählt und am Helmholtz-Institut für Pharmazeutische Forschung des Saarlandes synthetisiert. Die Konjugation des Linker-CHD-Konstruktes an das Polymer wurde mittels kupferfreier Click-Chemie durchgeführt. Der PEGylierte Linker wurde in einer ähnlichen Rate durch Aureolysin geschnitten wie der freie Linker, was beweist, dass das Polymer keinen Einfluss auf die enzymatische Aktivität hat. Allerdings wurde während der Optimierung der Beladung von CHD je Polymermolekül eine sehr niedrige Freisetzung des Antibiotikums beobachtet, was durch Aggregatbildung der Konstrukte erklärt werden kann. Das entwickelte System ist eine interessante Delivery-Strategie für Antibiotika, welche hierdurch nur durch virulente S. aureus-Erreger freigesetzt werden.

No description available.

<p>Conventional cancer treatment based on radiotherapy or chemotherapy affects all dividing cells. By directing the therapy specifically to the tumor cells, normal cells can be spared. Tumor targeting molecules carrying a cytotoxic moiety is then an attractive approach. </p><p>In this thesis, an affibody molecule with high affinity for the protein HER-2, that is strongly associated with aggressive forms of breast cancer, was selected. After radiolabeling with ¹²⁵I, the affibody molecule, in monovalent and bivalent form, was tested <i>in vitro</i> in HER-2 overexpressing tumor cells and in transplanted tumors in mice. </p><p>It was shown that the HER-2 targeting affibody molecule bound its target in a specific manner, both <i>in vitro</i> and <i>in vivo</i>. The small size of the affibody molecule resulted in fast clearance through the kidneys. An impressive tumor-to-blood ratio of 10 eight hours post injection was achieved and the tumors could easily be visualized in a gamma camera. </p><p>The biologic effects of the bivalent affibody molecule and a monovalent affinity maturated version was measured and compared with the effects of the monoclonal antibody trastuzumab. It was found that although all molecules target the same protein, the effects differed greatly.</p><p>The affibody molecule was also labeled with the alpha-emitting radionuclide ²¹¹At. Specific decrease in survival was seen in HER-2 overexpressing cells receiving the ²¹¹At labeled affibody molecule. The sensitivity to the treatment differed between cell lines, probably as a result of differences between the cell lines in internalization and nuclear size. The ²¹¹At labeled affibody molecules were also tested <i>in vivo</i>, where stability of the ²¹¹At label was a problem. To circumvent this problem, more stable conjugation chemistry was tested, as well as strategies to prevent uptake of released ²¹¹At by normal organs.</p><p>This thesis describes the selection and optimization of affibody molecules for medical use for the first time.</p>

The invasive nature and undesirable side-effects related to conventional cancer therapy, such as surgery and chemotherapy, have led to the development of novel drug delivery systems (DDS). A minimally invasive DDS using near-infrared (NIR) light as a trigger for drug release is investigated to reduce the adverse side-effects triggered by systemic delivery of chemotherapeutic drugs. The low tissue absorbance in the NIR region, λ = 650–2500 nm, allows the irradiation to penetrate through tissues to release cisplatin from a NIR-sensitive nanocomposite of Au-Au₂S. Our laboratory has recently shown that cisplatin can be effectively released from Au-Au₂S upon NIR irradiation. Cisplatin was loaded onto Au-Au₂S through its adsorption on COOH-functionalized alkanethiols coated on Au-Au₂S. The current work focuses on the development of methods to control the release of cisplatin. Drug release is controlled by either the irradiation parameters or the type of coatings. The effect of different coatings on NIR sensitivity and drug release is investigated. Molecular layers of HS-(CH₂)n-COOH and HS-CH₂-COO-CH₂(CH₂CH₂O)xCH₂-COOH have been successfully coated onto Au-Au₂S. The effect of different surface layers on drug adsorption is being examined. In addition, a mathematical model has been developed to describe the thermal effects of different irradiation parameters on soft tissues. / Singapore-MIT Alliance (SMA)