This document describes the design of hyaluronic acid-based nanosystems for targeted cancer drug delivery. Hyaluronic acid was functionalized with lipids, PEG, and thiols using click chemistry to form polymer blocks. These blocks were able to self-assemble into nanoparticles and encapsulate anticancer drugs. The nanoparticles were characterized and shown to effectively deliver drugs to cancer cells overexpressing CD44 receptors, demonstrating their potential as a targeted drug delivery platform.
Validation of Clomipramine interactions identified by BioBind against experim...Marie-Julie Denelle
Based on the now accepted principle that
similar receptors bind similars ligands, we have developed BioBind, a patented comparison algorithm
dedicated to the retrieval and assessment of local surface similarities. Clomipramine appears to be a
good “real life” candidate to challenge BioBind. In a couple of hours, BioBind was able to retrieve all
known targets having structural data described in the literature and to provide a valuable list of unknown
yet sensible putative targets currently being experimentally validated. This analysis hence demonstrates the
robustness and relevance of BioBind.
Validation of Clomipramine interactions identified by BioBind against experim...Marie-Julie Denelle
Based on the now accepted principle that
similar receptors bind similars ligands, we have developed BioBind, a patented comparison algorithm
dedicated to the retrieval and assessment of local surface similarities. Clomipramine appears to be a
good “real life” candidate to challenge BioBind. In a couple of hours, BioBind was able to retrieve all
known targets having structural data described in the literature and to provide a valuable list of unknown
yet sensible putative targets currently being experimentally validated. This analysis hence demonstrates the
robustness and relevance of BioBind.
Novel Hybrid Molecules of Quinazoline Chalcone Derivatives: Synthesis and Stu...Ratnakaram Venkata Nadh
Abstract: Background: A new series of quinazoline linked chalcone conjugates were synthesized
and evaluated for their in vitro cytotoxicity.
Methods: The quinazoline-chalcone derivatives (13a-r) have been prepared by the Claisen-Schmidt
condensation of various substituted benzaldehydes (12a-r) with substituted l-(4-(3,4-
dihydroquinazolin-4-ylamino)phenyl)ethanone (11a-b) in the presence of aqueous NaOH. Three
potential compounds 13f, 13g and 13h exhibited cytotoxicity against leukemia (GI50 value of
1.07, 0.26 and 0.24 μM), Non-small lung (GI50 values of 2.05,1.32 and 0.23 μM), colon (GI50
values of 0.54, 0.34 and 0.34 μM) and breast (GI50 values of 2.17, 1.84 and 0.22 μM) cell line,
respectively.
Results and Conclusion: Based on these biological results, it is evident that compound 13h has the
potential to be considered for further detailed studies either alone or in combination with existing
therapies as potential anticancer agents.
Applications of click chemistry in drug discoveryrita martin
his article focus mainly on click chemistry mechanisms and its applications, click chemistry is an easy way to generate substances quickly and reliably by joining small units together, with this ease of use mechanism, click chemistry as found its applications in various technologies especially in drug discovery ,medicinal chemistry, enzyme activity, chemistry natural products, material science, polymers, nanotechnology and bioconjugation
A Randomized, Split-Face, Histomorphologic Study Comparing a Volumetric Calci...kpyu
Soft-tissue augmentation with dermal fillers is a popular, minimally invasive aesthetic procedure. In 2012, in the USA, most non-surgical augmentation treatments performed with a dermal filler used a product based on hyaluronic acid (HA), with the second most popular type being the calcium hydroxylapatite (CaHA)-based filler, Radiesse® (Merz Pharmaceuticals GmbH, Frankfurt, Germany), hereafter referred to as CaHA gel matrix.
Aptamer-Drug Conjugate (ApDC) Current Research Progress.pdfDoriaFang
ADCs, PDCs, ISACs, SMDC and Aptamer-Drug Conjugate (ApDC) are the conjugated drugs currently being developed. Here we will introduce the current research progress and challenges of ApDC.
Novel Hybrid Molecules of Quinazoline Chalcone Derivatives: Synthesis and Stu...Ratnakaram Venkata Nadh
Abstract: Background: A new series of quinazoline linked chalcone conjugates were synthesized
and evaluated for their in vitro cytotoxicity.
Methods: The quinazoline-chalcone derivatives (13a-r) have been prepared by the Claisen-Schmidt
condensation of various substituted benzaldehydes (12a-r) with substituted l-(4-(3,4-
dihydroquinazolin-4-ylamino)phenyl)ethanone (11a-b) in the presence of aqueous NaOH. Three
potential compounds 13f, 13g and 13h exhibited cytotoxicity against leukemia (GI50 value of
1.07, 0.26 and 0.24 μM), Non-small lung (GI50 values of 2.05,1.32 and 0.23 μM), colon (GI50
values of 0.54, 0.34 and 0.34 μM) and breast (GI50 values of 2.17, 1.84 and 0.22 μM) cell line,
respectively.
Results and Conclusion: Based on these biological results, it is evident that compound 13h has the
potential to be considered for further detailed studies either alone or in combination with existing
therapies as potential anticancer agents.
Applications of click chemistry in drug discoveryrita martin
his article focus mainly on click chemistry mechanisms and its applications, click chemistry is an easy way to generate substances quickly and reliably by joining small units together, with this ease of use mechanism, click chemistry as found its applications in various technologies especially in drug discovery ,medicinal chemistry, enzyme activity, chemistry natural products, material science, polymers, nanotechnology and bioconjugation
A Randomized, Split-Face, Histomorphologic Study Comparing a Volumetric Calci...kpyu
Soft-tissue augmentation with dermal fillers is a popular, minimally invasive aesthetic procedure. In 2012, in the USA, most non-surgical augmentation treatments performed with a dermal filler used a product based on hyaluronic acid (HA), with the second most popular type being the calcium hydroxylapatite (CaHA)-based filler, Radiesse® (Merz Pharmaceuticals GmbH, Frankfurt, Germany), hereafter referred to as CaHA gel matrix.
Aptamer-Drug Conjugate (ApDC) Current Research Progress.pdfDoriaFang
ADCs, PDCs, ISACs, SMDC and Aptamer-Drug Conjugate (ApDC) are the conjugated drugs currently being developed. Here we will introduce the current research progress and challenges of ApDC.
QPS Regulated Bioanalysis of Antibody Drug ConjugatesQPS Holdings, LLC
PK profiling reflects molecular complexity. Since 2001 QPS’ bioanalytical teams have contributed to ADC drug development,
supporting the filing of one of the first drug targeting
programs and continue to develop customized
strategies for novel conjugate molecules.
1. Design of Customizable Self-Assembling Nanosystems Using ‘Clickable’ Hyaluronic Acid-Based Functional
Macrostructures for CD44 Target Mediated Drug Delivery
Arun K. Iyer, Ganesan Venkatesan, Faryal Mir, and Mansoor M. Amiji
Graduate
Category: Health Sciences
Degree Level: Masters
Abstract ID# 265
Figure 1: Copper mediated “click” synthesis of HA based functional
macrostructures. A 20 kDa HA was first reacted with an alkynyl moiety using
EDC/NHC coupling to form alkynyl-HA which further reacts with corresponding
azides using Cu+1 based “click” synthesis to form lipid modified HA, thiol modified
HA and PEG modified HA polymer blocks, respectively.
Polymer Characterization
Figure 2: 1H-NMR spectroscopy of unmodified HA and C12-lipid modified HA. The
appearance of additional peaks (methyl and methylene peaks) indicates successful conjugation of
the C12 lipid moiety .
TEM image of blank nanoparticles
Self-assembled Nanosystems
Cancer is a deadly disease and a major threat to mankind. The treatment of several
forms of cancer still remains a great challenge. Cytotoxic chemotherapy has been a
major arsenal against cancers, however it lacks selective tumor targeting. In this
study we have engineered hyaluronic acid (HA) based nanocarries for the targeted
treatment of cancers. Hyaluronic acid (HA) is a naturally occurring polysaccharide
present in the extracellular matrix and synovial fluids. It is biodegradable,
biocompatible, non-toxic, non immunogenic and non inflammatory, which makes it
ideal polymer for designing drug delivery systems. Interestingly, HA inherently acts
like a targeting moiety and specifically recognizes CD44 receptors that are
overexpressed on many tumors cell surfaces including tumor-initiating (stem) cells
that makes it an ideal polymer for targeted anticancer therapeutics. HA can self-
assemble into nanostructures when functionalized with lipophilic moieties. Based on a
customizable combinatorial library approach, we have synthesized a series of lipid
modified, PEGylated and thiol-functionalized HA macrostructures using copper (C+1)
catalyzed ‘click’ chemistry for efficient encapsulation of diverse payloads and
anticancer drugs that could be utilized as a platform technology for tumor targeting.
“Click” Synthesis of Functional HA Polymers
A series of lipid functionalized HA-derivatives with varying lipid chain lengths (C=4,
6, 8…18) were synthesized using copper catalyzed azide-alkyne “click” synthesis
methodology (Figure 1). A new homogenous reaction method was developed to
generate derivatives with high lipid modification that could facilitate efficient
incorporation of diverse anticancer drugs and promoted self-assembly to form
nanostructures in solution. Furthermore, in order to increase the stability of the HA
nanosystems and facilitate superior in vivo performance, PEGylated and thiol-
functionalized HA blocks were also synthesized using “click” methodology (Figure 1),
and incorporated into the nanosystems. The derivatives were purified and characterized
by 1H-NMR spectroscopy. The physicochemical properties of self-assembled
nanostructures were determined by dynamic light scattering (DLS) and the morphology
of the nanoparticles was visualized using transmission electron microscopy (TEM).
Introduction Characterization of Drug Loaded HA Nanosystems
Biological Activity of Drug Loaded HA Nanosystems
Table 1: Characterization of drug loaded HA nanosystems. The physicochemical properties
(size and charge) of HA based self-assembled nanostructures were determined by DLS . The drug
loading and encapsulation efficiency was determined using HPLC and spectrophotometric analysis.
a
b
Table 2: Comparison of cell killing ability of free
drug Vs drug loaded HA nanosystems in SKOV3
ovarian cancer cells.
Figure 5: Dose response curve. (a) Free
idarubicin Vs idarubicin NPs; (b) Free
taxol Vs taxol NPs
In vitro cytotoxicity (MTT) assays using SKOV3 ovarian cancer cells was performed to assess
targeted intracellular uptake and cell killing efficiency of the drug loaded HA nanosystems and
compared against corresponding free drug.
Conclusion
By judicious selection of the functionalized-HA polymer, its lipid chain length, charge, degree of
modification, molecular weight, log p value of the drug, drug class and other pertinent variables,
the HA derivatives can be tailored to encapsulate various drug payloads and inherently target
tumor cells expressing CD44 receptors. The HA-based macrostructures developed using “click”
synthesis thus demonstrated efficient drug encapsulation and comparable in vitro cell killing
efficiency and holds promising potentials for development of more robust nano-delivery systems.
Acknowledgments
This study was supported by the National Cancer Institute’s Alliance for
Nanotechnology in Cancer Center for Cancer Nanotechnology
Excellence (CCNE) grant U54- CA151881 and the Cancer
Nanotechnology Platform Partnership (CNPP) grant U01- CA151452.
Figure 4: Schematic representation of combinatorial approach in designing HA based self-
assembled nanosystems .
Figure 3: Transmission electron micrographs (TEM) of C12-HA blank nanoparticles
Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA 02115
(Email: venkatesan.g@husky.neu.edu)