Pharmaceutics and Drug Design Commons^™

Tumor Targeting With Peptide-Drug Conjugates: Showcasing Key Progress And Hurdles, Keykavous Parang, Thuy Do, Clare Dinh, Dorna Davanidavari, Max Foroughi, Troy Khong, Mahsa Moazen, Amir Nasrolahi Shirazi

Pharmacy Faculty Articles and Research

Peptide-drug conjugates (PDCs) are modular, targeted therapeutics composed of a homing peptide linked to a cytotoxic or modulating drug payload via a cleavable/non-cleavable linker. PDCs utilize peptide targeting to enhance the delivery of potent drugs to tumors, providing advantages such as superior tissue penetration, reduced immunogenicity, and simpler manufacture compared to antibody-drug conjugates (ADCs). A comparison of PDCs versus ADCs highlights that PDCs’ small size (~1-3 kDa) enables deeper tumor penetration and faster clearance, whereas ADCs (~150 kDa) benefit from prolonged circulation but suffer from limited tissue diffusion. This review surveys recent advances in PDC design and application. We discuss …

Multidrug Resistance: Are We Still Afraid Of The Big Bad Wolf, Abdulelah Alhazza, Adenike Oyegbesan, Emira Bousoik, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

After the era of multidrug resistance (MDR) against cytotoxic chemotherapy, the development of resistance against newly developed molecularly targeted drugs also seems inevitable. While the mechanisms involved in resistance against these two categories of anticancer drugs are different, the principles are similar: inherent resistance (also known as primary resistance) is a result of heterogeneity in cancer cells where a subpopulation of the cells do not show a favorable initial response to the drug, while acquired resistance (or secondary resistance), as the name suggests, is developed after repeated treatments due to the plasticity of cancer cells. Despite the introduction of a …

Studies To Understand The Stability And Liabilities Of Legumain-Cleavable Antibody-Drug Conjugates, Michele Yi

Undergraduate Honors Theses

Antibody-drug conjugates (ADCs) offer targeted drug delivery of potent cytotoxic payloads, minimizing systemic toxicity. However, the stability of the linker is integral to ensure that there is minimal off-target payload release and little systemic toxicity. This study analyzes the physical and biological stability of our new legumain-cleavable vs traditional cathepsin-cleavable antibody-drug conjugates (ADCs), with a focus on hydrophobicity, thermal stability, aggregation, and biological payload release. Our findings indicate that decreased hydrophobicity of the legumain-cleavable ADCs compared to cathepsin-cleavable ADCs is correlated with decreased aggregation (predicting lower uptake by liver macrophages and therefore slower clearance and less systemic toxicity) and lower …

Selective And Brain-Penetrant Acss2 Inhibitors Target Breast Cancer Brain Metastatic Cells, Emily Esquea, Lorela Ciraku, Riley Young, Jessica Merzy, Alexandra Talarico, Nusaiba Ahmed, Mangalam Karuppiah, Anna Ramesh, Adam Chatoff, Claudia Crispim, Adel Rashad, Simon Cocklin, Nathaniel Snyder, Joris Beld, Nicole Simone, Mauricio Reginato, Alexej Dick

Kimmel Cancer Center Faculty Papers

Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to …

Assessment Of In-Vitro And In-Vivo Pre-Clinical Pharmacokinetics Of Epz015666; A Novel Small Molecule For Medulloblastoma Treatment, Pratiksha U. Kshirsagar

Theses & Dissertations

Group 3 medulloblastoma (MB) has the worst prognosis of the MB subgroups associated with elevated MYC expression and a 5-year survival rate of

Quantitation of EPZ was performed on a Shimadzu LC-MS/MS system utilizing electrospray ionization operated in positive mode. The validated assay was linear from 0.2 to 500 ng/mL. Metabolic stability studies demonstrated slow intrinsic clearance of EPZ in mouse and human liver microsomes, suggesting no CYP-mediated metabolism. Additionally, EPZ exhibited low binding affinity to plasma and brain proteins and high apparent permeability across artificial membranes, indicating efficient membrane penetration. Drug transporter studies identified EPZ as a substrate of …

Targeting Strategies To Optimize The Therapeutic Potential Of Gold Compounds Against Her2-Positive Breast Cancers, Afruja Ahad

Dissertations, Theses, and Capstone Projects

The overexpression of HER2 accounts for 20-30% of breast cancer tumors and not only serves as a marker for poor predictive clinical outcomes but also as a target for treatment. Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutic drugs to provide targeted treatment without toxicity to normal tissue. Most of the ADCs currently in the clinic for cancer chemotherapy are based on complex organic molecules. In contrast, the conjugation of metallodrugs to mAbs has been overlooked when there is enormous potential in this area with the resurgence of metal-based drugs as prospective cancer …

Identification Of Translesion Synthesis Inhibitors That Target Rev7/Rev3 Protein-Protein Interactions, Seema Patel

Honors Scholar Theses

Translesion synthesis (TLS) is a cellular mechanism utilized by cancer cells to tolerate DNA damage caused by chemotherapeutics, like cisplatin, by replicating past unrepaired lesions. This increases the rate of mutations, which leads to the emergence of drug-resistant cancer cells. Preliminary studies have shown that disrupting the protein-protein interactions (PPI) in the TLS heteroprotein complex increases cells’ sensitivity to first-line genotoxic chemotherapy, illustrating how inhibiting TLS assembly and function can significantly increase cancer cell death. These results underscore the therapeutic potential of targeting TLS PPI. Our current work in this area is focusing on inhibitors capable of disrupting the Rev7/Rev3 …

[(Wr)8Wkβa]-Doxorubicin Conjugate: A Delivery System To Overcome Multi-Drug Resistance Against Doxorubicin, Khalid Zoghebi, Hamidreza Montazeri Aliabadi, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)₈WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the …

Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides As A Drug Delivery System, Saghar Mozaffari

Pharmaceutical Sciences (PhD) Dissertations

A number of cyclic peptides containing a positively charged ring composed of arginine residues attached to hydrophobic tail made of tryptophan residues through a lysine linker namely [R₅K]W₅, [R₆K]W₅, [R₅K]W₆, [R₇K]W₅, [R₅K]W₇, [R₆K]W₆, and [R₇K]W₇ were synthesized and evaluated as molecular transporters. The peptides were evaluated for their ability to deliver, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI), and fluorescent labeled anti-HIV drugs (F′-FTC and F′-d4T). The results indicated that the presence of positively …

Car T Cells As A Patentable Therapeutic, Mckenzie List

Honors Program Theses

The development of a therapeutic to treat a particular disease is a complicated process that incorporates numerous components such as drug discovery, clinical trials, FDA approval and patentability. In the last two decades, cancer research and development has shifted from identifying small molecule therapeutic agents to focusing research on a novel approach designated as immunotherapy. Today, immunotherapy has progressed from a twentieth century scientific theory into an innovative treatment to cancer. In particular, CAR T cells have demonstrated therapeutic properties for certain types of cancers, but these living cells are not compatible with the traditional therapeutic model. First, the drug …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Towards The Rational Design And Application Of Polymers For Gene Therapy: Internalization And Intracellular Fate, Landon Alexander Mott

Theses and Dissertations--Chemical and Materials Engineering

Gene therapy is an approach for the treatment of acquired cancers, infectious disease, degenerative disease, and inherited genetic indications. Developments in the fields of immunotherapies and CRISPR/Cas9 genome editing are revitalizing the efforts to move gene therapy to the forefront of modern medicine. However, slow progress and poor clinical outcomes have plagued the field due to regulatory and safety concerns associated with the flagship delivery vector, the recombinant virus. Immunogenicity and poor transduction in certain cell types severely limits the utility of viruses as a delivery agent of nucleic acids. As a result, significant efforts are being made to develop …

Amine Containing Analogs Of Sulindac For Cancer Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Background:

Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity.

Objective:

Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities.

Method:

A series of sulindac amine analogs were designed and synthesized and then further modified in a “libraries from libraries” approach to produce amide, sulfonamide and N,N-disubstituted …

Evaluation Of A Drug Delivery System Based On Cyclodextrins For Cancer Therapy, Caroline Mendes

Doctoral

Due to the side-effects caused by regular chemotherapy, the development of drug delivery systems that can specifically target cancer cells and deliver the therapeutic dose is required. In this study, a folate-derivative of β-cyclodextrin has been studied as a vehicle for targeting folate receptors (FR) and delivering the chemotherapeutic drug methotrexate (MTX). FRs can be considered key cell membrane targets since they are commonly over-expressed in cancer cells and play an important role in cancer development and progression. Cyclodextrins (CDs) are cyclic oligosaccharides with a unique structure that allows them to form inclusion complexes with guest molecules, increasing their aqueous …

Development Of Cxcr4-Inhibiting Nanoparticles For The Treatment Of Metastatic Cancer, Yan Wang

Theses & Dissertations

Metastasis is the main cause of cancer mortality and morbidity, leading to several million deaths every year. Less than 20% of pancreatic cancer (PC) patients are candidates for surgery due to spread beyond the pancreas. Desmoplasia presents substantial barriers to perfusion, diffusion, and convection of antitumor therapeutics into the PC tissues. We focus on developing novel therapies that regulates tumor microenvironment, chemosensitizing tumor to therapeutics and preventing metastasis.

Gene therapy is emerging as a promising new therapeutic agents for cancer treatment. A targeted, systemic, effective and safe gene delivery system should be developed. CXCR4/SDF-1 axis plays a crucial role in …

Novel Ph-Sensitive Cyclic Peptides, Dhammika Weerakkody, Anna Moshnikova, Naglaa Salem El-Sayed, Ramona-Cosima Adochite, Gregory Slaybaugh, Jovana Golijanin, Rakesh Tiwari, Oleg A. Andreev, Keykavous Parang, Yana K. Reshetnyak

Pharmacy Faculty Articles and Research

A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4WC], and asymmetric, c[E4W5C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH- and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in …

Investigating Mechanisms Determining Cancer Cell Sensitivity To Carfilzomib And Novel Strategies To Overcome Resistance, Lin Ao

Theses and Dissertations--Pharmacy

Proteasome inhibitors (PIs) are a class of FDA-approved anti-cancer agents which includes the first-generation PI bortezomib (BTZ) and second-generation carfilzomib (CFZ). Drug resistance is a major challenge in PI therapy with no solution currently available. While a few resistance mechanisms had been proposed for BTZ, little was known about CFZ resistance before the start of our studies. In this dissertation work, we investigated multiple mechanisms contributing to CFZ resistance—alterations in the drug transporter activity, metabolic stability, and proteasome activity profiles—and evaluated potential strategies to overcome CFZ resistance.

We observed marked upregulation of the drug efflux transporter P-glycoprotein (P-gp) in our …

Biodegradable Hybrid Nanogels For Combination Chemotherapy, Swapnil Desale

Theses & Dissertations

Combination chemotherapy is commonly used to treat cancer, because such a therapy regimens usually involve sequential administration of multiple drugs and allow targeting different cell signaling pathway. The co-delivery of drug combination at a controlled ratio via the same vehicle is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and suppression of drug resistance. Undoubtedly, there are several molecular and pharmacological factors that determine the effectiveness of drug combinations. A rationally designed drug combination is required since certain drug ratios and the definitive exposure to the targets of interest can only be synergistic while others …

Analyzation Of Metabolic Reprogramming In Drug-Resistant Mcf-7 Cells, Derick Han, Ho Leung, Andrew Vo

Student Scholar Symposium Abstracts and Posters

The Warburg effect states that cancer cells mainly receive their energy from anaerobic glycolysis. Thus, mitochondria play a different role in the metabolism of cancer cells as opposed to normal, healthy cells. In chemotherapy, there is always a chance of the cancer regressing. Making drug-resistant cancer cells to analyze their metabolism may change how cancer is treated. This study aimed to create drug-resistant MCF-7 cell lines with doxorubicin in order to determine the metabolic changes that have occurred in the process of becoming resistant to drug treatments.

Clinical Applications Of A Combination Chemotherapy Using 8-Chloro Camp And 8-Chloro Adenosine, Erik Munoz, Andrea Saich, Andrew Cox, Yu-An Peter Chang

Student Scholar Symposium Abstracts and Posters

Dr. Cho-Chung from the NIH first thought to use halogenated cAMP derivatives as competitive inhibitors of cAMP to slow down cancer cell mitosis. While the iodine and bromine substituted versions showed very little therapeutic actions, 8-Chloro cAMP has been shown to have strong anti-cancer effects. This has been shown in the phase II clinical trials this drug has undergone. However, these trials have had issues with solubility and toxicity. The drug is similar to vitamin C and is excreted quickly. Scientists tried to overcome this by using a peristaltic pump to give patients a continuous dosage, but this proved too …

Feasibility Of Integrating Tripterygium Wilfordii Into Modern Cancer Therapy For Increased Efficacy And Minimal Toxicity, Ngoc T. Vo

UROP Posters

Cancer is the second leading cause of death in the U.S. and millions of novel cancer cases are being diagnosed each year. While chemotherapy and ionizing radiation are effective treatments against these malignant tumors, the adverse effects that accompany such treatments are devastating. In order to find alternative treatment methods with less side effects, we turn to Eastern herbal medicine. Recent scientific research has found that Tripterygium wilfordii, an herbal medicine traditionally used to treat inflammation in China, contains compounds (triptolide and celastrol) that prevent the growth of solid tumors, induce apoptosis, and prevent metastasis of developed tumors. Investigations …

Inhibition Of The Thioesterase Activity Of Human Fatty Acid Synthase By 1,4- And 9,10-Diones, Herman H. Odens

Faculty Works

Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo. Consequently, FASN is widely recognized as a valuable therapeutic target. In this report, we describe a variety of 1,4-quinones and 9,10- anthraquinones, including several natural compounds and some newly synthesized compounds, that potently inhibit the thioesterase (TE) …

Synthesis And Evaluation Of Antiproliferative Activity Of Substituted N-(9-Oxo-9h-Xanthen-4-Yl)Benzenesulfonamides, Somayeh Motavallizadeh, Asal Fallah-Tafti, Saeedeh Maleki, Amir Nasrolahi Shirazi, Mahboobeh Pordeli, Maliheh Safavi, Sussan Kabudanian Ardestani, Shaaban Asd, Rakesh Tiwari, Donghoon Oh, Abbas Shafiee, Alireza Foroumadi, Keykavous Parang, Tahmineh Akbarzadeh

Pharmacy Faculty Articles and Research

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDAMB- 468) cells. Structure-activity relationship studies revealed …

Rna Interference For Improving The Outcome Of Islet Transplantation And Polymeric Micelle‑Based Nanomedicine For Cancer Therapy, Feng Li

Theses and Dissertations (ETD)

Ex vivo gene transfer has been used to improve the outcome of islet transplantation for treating type I diabetes. RNA interference is an effective approach for reducing gene expressions at the mRNA level. The application of RNA interference to improve the outcome of islet transplantation was reviewed in Chapter 2, where I summarized biological obstacles to islet transplantation, various types of RNAi techniques, combinatorial RNAi in islet transplantation, and different delivery strategies.

Upregulation of inducible nitric oxide synthase (iNOS) and subsequent product of radical nitric oxide (NO) impair islet β cell function. Therefore, we hypothesized that iNOS gene silencing could …