Projects
National
Submitted Project: TUBITAK 1001
Project title: Thermal, Spectroscopic, and Crystallographic Analysis of Novel
Cocrystals and Polymorphic Forms in the Isoniazid - Pyrazinamide - Rifampicin -
Ethambutol / Acetylsalicylic Acid Dual System
Project summary:
Tuberculosis (TB) remains one of the infectious
diseases with the highest global mortality rate, according to the World Health
Organization. The standard treatment regimen has been applied unchanged for
nearly forty years and relies on combinations of multiple drugs. However,
factors such as the increasing prevalence of resistant strains, long treatment
duration, and issues related to drug solubility and bioavailability limit the
overall effectiveness of therapy. At this point, innovative research on
pharmaceutical solid forms represents a valuable strategy with the potential to
directly contribute to improved treatment outcomes.
The originality of this project lies in
obtaining cocrystal forms and exploring the polymorphic diversity of isoniazid
(INH), pyrazinamide (PZA), rifampicin (RIF), and ethambutol (EMB)—the key
active substances used in TB treatment—in combination with acetylsalicylic acid
(ASA). There is no comprehensive and multidisciplinary study in the literature
addressing these dual systems. Investigating how molecular interactions between
these active ingredients and ASA can be modulated in the solid state, supported
by ASA’s known anti-inflammatory and antiplatelet properties, will enable the
discovery of novel and functional pharmaceutical solid forms.
This study aims to synthesize new
cocrystal forms based on dual systems formed between ASA and the four active
pharmaceutical ingredients mentioned above, and to obtain different polymorphic
varieties of these cocrystals followed by detailed characterization. Advanced
analytical techniques (DSC, FTIR, Raman, PXRD, SCXRD) will be employed to
conduct extensive structural, thermal, and molecular-level characterization of
these solid forms. This project is significant in terms of methodological
innovation as well as revealing pharmaceutical solid forms of the INH–ASA,
PZA–ASA, RIF–ASA, and EMB–ASA dual systems, which have not been previously
reported in the literature. If successful, the outcomes are expected to
contribute to improving critical properties of these active
substances—including solubility, stability, and bioavailability.
Project coordinator: Ainur Syeitkhajy
-------------------------------------------------------------------------
National
Submitted project: IKU BAP
Project title: Design, Fabrication, and
Validation of a Laboratory-Scale Apparatus for Co-Crystal Synthesis via the
Spray-Drying Method
Project summary
Cocrystal synthesis, widely used in
pharmaceutical applications, is one of the methods employed to enhance
properties such as drug stability, solubility, and dissolution rate, as well as
to reduce the harmful effects of pharmaceutical components. However, it
involves highly challenging and complex chemical processes. This project aims
to design, manufacture, and validate a device that will enable the
laboratory-scale production of pharmaceutical cocrystals using the spray-drying
method.
The system will consist of a glass drying
chamber, a two-fluid nozzle, a closed-loop structure suitable for safe
operation with organic solvents, a cyclone separator, a HEPA filtration unit,
and microcontroller-based control and safety modules. The originality of the
project lies in the development of a domestic, low-cost prototype for a
technology that is currently accessible in our country only through expensive
imported devices, thereby contributing a novel capability to university-level
research.
Within the scope of the project,
cocrystals containing anti-tuberculosis active pharmaceutical ingredients
(APIs) synthesized at IKU-SPECTRA and their formation mechanisms will be taken
into account for the validation of the laboratory-scale spray-drying device to
be developed. Additionally, new anti-tuberculosis cocrystals will be
synthesized using this device, and the production parameters will be optimized.
At the end of the project, it is planned
to file a patent application for the designed device prototype. With its
compact and portable structure, the prototype will be introduced into the
university’s R&D infrastructure as a domestic, low-cost piece of equipment.
Thanks to its inert closed-loop system, the improvement of occupational safety
and environmental performance will also be among the project outcomes.
Project coordinator: Bahadır Bozkurt
-------------------------------------------------------------------------
National
Submitted Project: TUBITAK 1001
Project Title:
Investigation of the Preclinical Therapeutic Effects of Peptides Targeting the
NOTCH1 NRR Region in T-Cell Acute Lymphoblastic Leukemia Using In Vitro and In
Vivo Models
Project Summary:
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological
malignancy characterized by uncontrolled proliferation of T cells. This disease
is especially prevalent in childhood and presents significant clinical
challenges due to high relapse rates and limited treatment options despite
existing therapies. Genetic mutations in the NOTCH1 signaling pathway play a
critical role in the pathogenesis of T-ALL in a significant portion of
patients. Mutations occurring particularly in the Negative Regulatory Region
(NRR) of NOTCH1 cause the receptor to remain constitutively active in a
ligand-independent manner, leading to disease progression and treatment
resistance. This situation necessitates a better understanding of resistance
mechanisms against γ-secretase inhibitors (GSIs) and the development of
alternative therapeutic strategies.
Current chemotherapeutic approaches are
highly toxic and can cause severe side effects on healthy cells. Additionally,
many patients develop drug resistance during treatment, leading to disease
relapse. Therefore, the development of safer and more effective therapeutic
approaches specifically targeting NOTCH1 NRR mutations is of high importance.
This project aims to design peptide-based
therapeutic agents capable of directly targeting the frequently observed NOTCH1
NRR mutations in T-ALL patients. In the first phase, molecular docking and
molecular dynamics simulation analyses will be performed to identify peptide
candidates with high binding capacity to NOTCH1 mutations. Subsequently, the
biological activities of the selected peptides will be evaluated in in vitro
T-ALL cell cultures, and their effects on the Notch signaling pathway will be
investigated. Peptide binding kinetics, cellular uptake mechanisms, and
receptor activation effects will be analyzed in detail using fluorescence labeling
and imaging techniques.
In later stages of the project, the
therapeutic efficacy of the peptides will be evaluated in in vivo models.
Zebrafish larvae models injected with T-ALL cells will be used to monitor the
effects of the peptides on tumor progression through live imaging techniques.
Moreover, apoptotic processes and Notch target gene expression levels induced
by peptide treatment will be analyzed in detail using RNA sequencing,
quantitative PCR, and immunohistochemical analyses.
This project will provide preclinical
validation of peptide-based biological agents targeting NOTCH1 NRR mutations,
contributing to the development of an innovative therapeutic platform for T-ALL
with high specificity and low toxicity. The resulting data will guide the design
of next-generation personalized biological agents for T-ALL treatment and
provide a solid foundation for future clinical studies. Furthermore, the
peptide-based agents developed in this project are expected to offer potential
therapeutic strategies not only for T-ALL but also for other NOTCH1-dependent
cancers.
A multidisciplinary approach will be
adopted, involving five different research groups. The study will be conducted
by experts in molecular biology, biochemistry, pharmacology, genetics, and
bioinformatics. Initially, bioinformatics analyses will identify peptide
candidates with specific binding to NOTCH1 mutations, followed by evaluation of
their biological efficacy in in vitro and in vivo models. The genetics team
will analyze the peptides’ effects on cellular uptake mechanisms and gene
expression regulation, while the molecular biology team will elucidate the
mechanisms underlying their therapeutic effects. Through the coordinated work
of five distinct disciplines, novel therapeutic approaches targeting NOTCH1
mutations will be developed, offering innovative and effective treatment
strategies for T-ALL patients.
Project coordinator: Dr. Öğr. Üyesi Kübra Telli
-------------------------------------------------------------------------
National
Submitted project: General Research Project
Project Title:
In Vitro and In Vivo Evaluation of DAPT and MK-0752 Notch Inhibitors with
Dexamethasone in Nano-flower and Co-Crystal Forms in T-Cell Acute Lymphoblastic
Leukemia (T-ALL), a Rare Hematological Malignancy
Project Summary:
T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive
hematological malignancy characterized by uncontrolled proliferation associated
with disrupted T-cell developmental stages in the thymus. NOTCH1 mutations,
frequently observed in a significant proportion of patients, lead to
ligand-independent constitutive activation of the Notch signaling pathway,
promoting both cellular proliferation and anti-apoptotic processes, thereby
increasing treatment resistance. The central role of the Notch axis
rationalizes targeting with γ-secretase inhibitors (GSIs; DAPT and MK-0752);
however, constitutive NICD production and intracellular escape mechanisms can
limit GSI efficacy.
Meanwhile, dexamethasone (DEX), a
clinically essential component, induces cell death in T-lymphoblasts by
activating pro-apoptotic genes via the glucocorticoid receptor pathway.
However, disruptions in NR3C1 levels and Notch-mediated signaling changes
contribute to glucocorticoid resistance, increasing relapse risk. This project
aims to overcome resistance and enhance the therapeutic index in T-ALL by
co-delivering DEX with GSIs within microarchitectures that localize drugs at
cell-cell (juxtacrine) contact sites.
To achieve this, two complementary
formulation platforms will be developed: (i) drug-inorganic hybrid nano-flowers
(hNFs) and (ii) binary co-crystals. Single and dual combinations of DEX, DAPT,
and MK-0752 will be used with Cu²⁺ ions to synthesize DEX@Cu²⁺ hNF, DAPT@Cu²⁺
hNF, MK0752@Cu²⁺ hNF, DAPT-DEX@Cu²⁺ hNF, and MK0752-DEX@Cu²⁺ hNF, followed by
structural/morphological characterization and biological stability analyses. In
parallel, DEX:DAPT and MK0752:DEX co-crystals will be produced via slow
evaporation; solubility and stability improvements will be evaluated through
theoretical and experimental validation. These systems are designed to enhance
solubility and bioavailability while reducing toxicity and systemic exposure,
preserving combination synergy.
In the in vitro phase, formulations will
be systematically assessed through cell viability assays and biomarkers such as
Notch receptor expression and NR3C1 autoregulation. Drug interactions will be
quantitatively analyzed using Bliss, HSA, and Loewe models to generate synergy
profiles. For in vivo validation, tumor progression and toxicity parameters
will be concurrently evaluated in zebrafish models. These juxtacrine-targeted
therapeutic architectures are expected to enhance local drug accumulation,
achieving similar or superior efficacy with lower overall doses, enabling dose
sparing and resensitization potential, particularly for DEX.
The anticipated outcome is preclinical
evidence of a combination strategy integrating DAPT/MK-0752/DEX within
nano-flower and co-crystal platforms, offering high specificity, low toxicity,
and strong synergy in T-ALL with translational potential. By targeting
juxtacrine interactions at the core of Notch-dependent pathobiology, this
project will fill a gap in the literature and provide a robust foundation for
future translational studies.
Project coordinator: Dr. Öğr. Üyesi Kübra Telli
-------------------------------------------------------------------------
National
Submitted project: TUBİTAK 2218
Project Title:
Investigation of the Effect of Innovative Curcumin@Inorganic Hybrid Nanoflower
Therapies Combined with Presenilin Inhibitors on Neural Differentiation and
Alzheimer's Disease in the SH-SY5Y Cell Model
Project Summary:
Alzheimer’s disease (AD) is one of the major neurodegenerative disorders for
which no curative treatment currently exists, arising from the interplay of
age-related degenerative processes, genetic predisposition, and environmental
factors. In familial forms of the disease, mutations in presenilin 1 (PSEN1),
presenilin 2 (PSEN2), and amyloid precursor protein (APP) alter the substrate
specificity of the γ-secretase complex, leading to excessive production of
pathological amyloid-β (Aβ) species. However, γ-secretase is also the main
catalytic component of the Notch signaling pathway, which plays essential roles
in cell differentiation, proliferation, and apoptosis. Therefore, therapeutic
use of γ-secretase inhibitors requires a delicate balance between efficacy and
toxicity.
In recent years, natural compounds and
nanobiotechnological approaches have offered promising strategies to achieve
this balance. Curcumin, with its polyphenolic structure and multiple mechanisms
of action, has emerged as a potent neuroprotective candidate by simultaneously
targeting Aβ accumulation, oxidative stress, and neuroinflammation.
Nevertheless, its poor bioavailability limits clinical applicability. To
overcome this limitation, organic–inorganic hybrid nanoflower (hNF) structures—first
discovered in 2012—present an ideal carrier system due to their high surface
area, porosity, biocompatibility, and low toxicity. In these structures,
proteins or natural organic molecules interact with metal ions (e.g., Cu²⁺,
Zn²⁺), forming flower-like architectures.
Within this project, curcumin-based hybrid
nanoflowers (K@Cu²⁺ hNF and K@Zn²⁺ hNF) will be synthesized and characterized
using curcumin in combination with Cu²⁺ and Zn²⁺ ions. Their biological effects
will be evaluated in human neuroblastoma SH-SY5Y cells and their neuronally
differentiated derivatives, in which an Alzheimer’s disease model will be
established. Aβ aggregation will be confirmed using Congo red staining, while
cell viability, neurotoxicity, neuroprotection, and gene expression profiles
will be assessed through multidimensional analyses. Additionally, combinations
of curcumin-hNFs with γ-secretase inhibitors DAPT and MK-0752 will be examined,
and synergistic effects will be quantified using Bliss, HSA, and Loewe
interaction models.
This approach aims to contribute to the
development of next-generation combination therapies that are pathway-specific
while minimizing toxicity. The project not only provides a strong platform for
elucidating the molecular mechanisms underlying Alzheimer’s disease in Türkiye
but also seeks to produce clinically translatable, innovative solutions through
nanoflower-based curcumin formulations. The study aligns with the goals of the
Twelfth Development Plan in the fields of health technologies and biotechnology,
contributing to scientific capacity building and the advancement of innovative
therapeutics.
Erciyes University, where the project will
be conducted, is among the top ten universities designated as Research
Universities and possesses well-established research centers and infrastructure
suitable for such studies. The advisor, Prof. Dr. Nalan ÖZDEMİR, has extensive
experience, projects, and high-impact international publications on the
synthesis and biocatalytic applications of organic–inorganic hybrid
nanoflowers. The biochemistry research laboratory used by the advisor has
sufficient chemical materials and laboratory equipment required for the
execution of the proposed studies.
Project coordinator: Dr. Öğr. Üyesi Kübra Telli
International
Submitted
Project: Lasers4EU/ Horizon Europe
Project
Title: Gas-to-Solid
Pathways and Reactivity of Isoniazid–Pyrazinamide Co-Crystals
Project
Summary: Co-crystallization
is an effective strategy to tailor the physicochemical properties of active
pharmaceutical ingredients without altering their molecular identity. Although
isoniazid and pyrazinamide are well-established antitubercular agents, the
behaviour of their co-crystal under sublimation, cryogenic trapping, and
irradiation remains largely unexplored. This project integrates conventional
solid-state characterization (infrared and Raman spectroscopy, differential
scanning calorimetry, single-crystal X-ray diffraction) with advanced
low-temperature matrix isolation, neat-vapour deposition, and UV photolysis, supported
by density functional theory calculations. By sublimating the INH–PZA
co-crystal and trapping the vapour at 10 K, we will determine whether
supramolecular units persist in the gas phase or dissociate, and how they
reorganize upon annealing or direct deposition without an inert matrix.
Ultraviolet photolysis using various light sources, including diode-laser-based
systems and tuneable laser systems (pumping laser + MOPO) will probe the
light-induced processes for both the matrix-isolated and different solid
materials. This integrated approach bridges pharmaceutical co-crystal chemistry
with fundamental gas-phase and matrix isolation studies, delivering
unprecedented insight into intermolecular bonding, sublimation dynamics, and
photo-reactivity, and informing rational strategies for controlling drug solid
forms through vapour-phase processes.
Project coordinator: Öğr. Gör. Dilara Kaplanoğlu
-------------------------------------------------------------------------
International
Submitted Project: ReMade@ARI
Project title: Utilization of Saccharin Waste within a Circular Economy Framework through Pharmaceutical Co-Crystallization with Isoniazid
Project
summary:
Saccharin, a widely utilized artificial
sweetener, often becomes part of industrial and consumer waste, presenting
environmental challenges due to its chemical persistence and limited
biodegradability. This study introduces an innovative recycling approach that
adheres to circular economy principles by converting saccharin waste into
high-value pharmaceutical materials. Specifically, saccharin is upcycled
through co-crystallization with isoniazid (INH), a well-established
antitubercular drug. This process not only enhances the physicochemical
properties of the active pharmaceutical ingredient but also transforms
saccharin from a pollutant into a functional component of drug delivery
systems.
The study examines the behavior of INH–SAC co-crystals under conditions of sublimation, cryogenic trapping, and photonic excitation, employing advanced analytical techniques such as infrared and Raman spectroscopy, differential scanning calorimetry, and single-crystal X-ray diffraction. These experimental investigations are augmented by density functional theory (DFT) calculations to elucidate molecular interactions and stability. Sublimation and matrix isolation at 10 K are utilized to determine whether supramolecular structures persist or undergo reorganization during phase transitions. Furthermore, ultraviolet photolysis using diode-laser and tunable laser systems is employed to explore light-induced transformations in both isolated and solid states. This comprehensive approach illustrates how vapor-phase engineering and supramolecular chemistry can facilitate the sustainable recycling of saccharin waste. By transforming a low-value, environmentally persistent compound into a functional pharmaceutical co-crystal, the study contributes to waste valorization and supports the advancement of green technologies within the pharmaceutical sector.
Project
coordinator: Rezvan
Mohammadi
