Formulation Development of Anti-Cancer Drugs

Formulation issues, including stability, solubility and bioavailability, have been identified as key concerns in anti-cancer drug development. The challenges in pharmaceutical formulation often arise from the different physicochemical attributes of a molecule and the need to deliver the compound to a desired site. The major problems of small molecule drug formulation development are poor water solubility and off target toxicity. In chapter 2 of this dissertation, a prostate specific membrane antigen (PSMA) targeted micelle was made to deliver a PI3K inhibitor, TGX-221, for prostate cancer treatment. The in vitro cell culture based study indicated that the targeted micelle significantly improved cellular uptake by PSMA positive cells. The in vivo animal efficacy study showed that the targeted micelle significantly reduced tumor size and progression in a xenograft model. Ridaforolimus, a non-prodrug rapamycin analog, has entered clinical trials for cancer treatment. Formulations of ridaforolimus being evaluated in the clinical trials include intravenous infusion and oral administration. The intravenous bolus formulation of this drug is very limited due to poor water solubility (ca. 200 µg/mL). In chapter 3, we showed that a new formulation of ridaforolimus using DSPE-PEG2000 micelle as a carrier greatly improved the drug solubility, increasing it 40 times. In addition, the pharmacokinetic properties examined in rats showed that this formulation significantly increased drug retention in the plasma. In chapter 4, a hyaluronic acid-rapamycin conjugate was synthesized and characterized. The disposition and efficacy of the drug conjugate were studied and demonstrated that the hyaluronic acid drug conjugate could be used for treating localized CD44 positive cancer. In chapter 5, a doxorubicin prodrug was developed for enhancing oral bioavailability. Doxorubicin was chemically conjugated with quercetin, a flavonoid, via a glycine linker. Quercetin is a P-glycoprotein inhibitor; thus, it prevents doxorubicin efflux by this mechanism. The oral bioavailability of DOX was significantly improved in rats through this prodrug strategy. In the last chapter, an HPLC method was developed for the separation of active compounds from degraded alternol, which could be used for alternol manufacturing and stability studies

CD44-Tropic Polymeric Nanocarrier for Breast Cancer Targeted Rapamycin Chemotherapy

In contrast with the conventional targeting of nanoparticles to cancer cells with antibody or peptide conjugates, a hyaluronic acid (HA) matrix nanoparticle with intrinsic-CD44-tropism was developed to deliver rapamycin for localized CD44-positive breast cancer treatment. Rapamycin was chemically conjugated to the particle surface via a novel sustained-release linker, 3-amino-4-methoxy-benzoic acid. The release of the drug from the HA nanoparticle was improved by 42-fold compared to HA-temsirolimus in buffered saline. In CD44 positive MDA-MB-468 cells, using HA as drug delivery carrier, the cell-viability was significantly decreased compared to free rapamycin and CD44-blocked controls. Rat pharmacokinetics showed that the area-under-the-curve of HA nanoparticle formulation was 2.96-fold greater than that of the free drug, and the concomitant total body clearance was 8.82-fold slower. Moreover, in immunocompetent BALB/c mice bearing CD44-positive 4T1.2neu breast cancer, the rapamycin1loaded HA particles significantly improved animal survival, suppressed tumor growth and reduced the prevalence of lung metastasis

Nitrogen Doped Carbons Derived From Graphene Aerogel Templated Triazine-Based Conjugated Microporous Polymers for High-Performance Supercapacitors

Conjugated microporous polymers (CMPs) have attracted intensive attention owing to their permanent nanoporosity, large surface area and possibility for functionalization, however their application in energy storage suffers from poor conductivity and low hetero-atom content. Here, we demonstrate a hybrid of conjugated microporous polymers and graphene aerogel with improved conductivity. After treating at 800°C in NH3, the nitrogen content increases to 9.8%. The resulting microporous carbon exhibits a significant rise in supercapacitive performance up to 325 F g−1, 55% higher than pristine triazine-based CMPs, with energy density up to 12.95 Wh kg−1. Moreover, it has high stability with 99% retention after 10,000 cycles at 5 A g−1. The synergy of hierarchical porous structure, graphene-based conduction path and high percentage of hybridization with nitrogen ensures effective ion/electron transport and diffusion, making NH3-treated graphene aerogel/CMP hybrid a promising electrode material in high-performance supercapacitor

An essential role for TAK1 in the contact hypersensitivity response

Contact hypersensitivity (CHS) is a delayed-type hypersensitivity that can be induced by haptens, such as 2,4-dinitrofluorobenzene (DNFB). Innate and adaptive immunities are both important for the development of CHS. To treat CHS-related diseases, such as allergic contact dermatitis, a disease prevalent in industrialized countries, ways of interfering with improper immune function during CHS responses need to be identified. Transforming growth factor-β-activated kinase-1 (TAK1), a member of mitogen-activated protein kinase kinase kinase family, is important for both innate and adaptive immunities. We thus hypothesized that the CHS response could be inhibited by interfering with TAK1 activity. Using a mouse model in which TAK1 deletion can be locally induced, we observed that TAK deficiency led to an impaired CHS response and was associated with defective T-cell expansion, activation and interferon (IFN)-γ production. In addition, we investigated the effect of deleting TAK1 specifically in dendritic cells (DC) on the CHS response. We found that when TAK1 is deficient in DC, the CHS response was abolished and hapten-elicited T-cell responses were defective. Collectively, this study demonstrates an essential role of TAK1 in the induction of CHS and suggests that targeting TAK1 could be a viable approach to treat CHS

Span-Level Dual-Encoder Model for Aspect Sentiment Triplet Extraction

Aspect sentiment triplet extraction (ASTE)  is one of the subtasks of aspect-based sentiment analysis, which aims to identify all aspect terms, their corresponding opinion terms and sentiment polarities in sentences. Currently, pipeline or end-to-end models are adopted to accomplish the ASTE task. The former cannot solve the overlapping problem of aspect terms in triplets and ignores the dependency between opinion terms and sentiment polarities. The latter divides the ASTE task into two subtasks of aspect-opinion-extraction and sentiment-polarity-classification, which applies multi-task learning through a shared encoder. However, this setting does not distinguish the differences between the features of the two subtasks, leading to the feature confusion problem. SD-ASTE (span-level dual-encoder model for ASTE), a pipeline model with two modules, is proposed to address the above problems. The first module extracts aspect terms and opinion terms based on spans. The span feature representation incor-porates span head, tail and length information to focus on the boundary information of aspect terms and opinion terms. The second module judges the sentiment polarities expressed by aspect-opinion span pairs. The span-pair feature representation is based on levitated markers to focus on the dependency among triplet elements. The model utilizes two independent encoders to extract different features for each module. Comparative experimental results on multiple datasets show that the model is superior to the state-of-the-art pipeline and end-to-end models. Validity experiments show the effectiveness of the span feature representation, span-pair feature representation and the two independent encoders

Tesseract: Real-Time Cryptocurrency Exchange using Trusted Hardware

We propose Tesseract, a secure real-time cryptocurrency exchange service. Existing centralized exchange designs are vulnerable to theft of funds, while decentralized exchanges cannot offer real-time cross-chain trades. All currently deployed exchanges are also vulnerable to frontrunning attacks. Tesseract overcomes these flaws and achieves a best-of-both-worlds design by using Intel SGX as a trusted execution environment. Furthermore, by running a consensus protocol among SGX-enabled servers, Tesseract mitigates denial-of-service attacks. Tesseract supports not only real-time cross-chain cryptocurrency trades, but also secure tokenization of assets pegged to cryptocurrencies. For instance, Tesseract-tokenized bitcoins can circulate on the Ethereum blockchain for use in smart contracts. We provide a reference implementation of Tesseract that supports Bitcoin, Ethereum, and similar cryptocurrencies

Vorinostat with Sustained Exposure and High Solubility in Poly(ethylene glycol)-b-poly(DL-lactic acid) Micelle Nanocarriers: Characterization and Effects on Pharmacokinetics in Rat Serum and Urine

The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anti-cancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat’s pharmacokinetics in rats were investigated after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) micellar administrations and compared to a conventional PEG400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 mg/ml to 8.15 ± 0.60 mg/ml and 10.24 ± 0.92 mg/ml at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 nm and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19 %, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the oral and intravenous pharmacokinetics and bioavailability of vorinostat, which warrants further investigation