Technologies
Abstract
Peptides are recognized as highly promising
therapeutics due to their high selectivity, efficacy, and safety. Enormous
research development efforts have been devoted to developing peptide
therapeutics, and more than 170 peptides therapeutics are currently being evaluated in
clinical trials. However, the major drawback of peptide therapeutics is their short
plasma half-life. Dr. Moon has developed linker peptides/proteins
for intracellularly delivering small molecules such as drugs, nucleic acids,
and peptides, as well as proteins and other larger molecules. These linker
peptides/proteins are made of plurality of oligo( amino acid)s or poly( amino
acid)s, where the acid residues can bear one or more positively charged
guanylurea units. Many hydrophilic or
hydrophobic functional groups can then be introduced at the units via guanylurea
chemistry to modulate the linker peptides/proteins properties. Their C and N terminals can also be functionalized
with small molecules such as drugs, antibodies, targeting moieties, detectable
entities, further tailoring the linker peptides/proteins to specific needs.Benefit
Enhanced blood circulation time and peptide serum stabilityEnhanced intracellular drug delivery and specific targeting, and pharmacokineticsMarket Application
Drug deliveryDrug development
Abstract
Labeling and monitoring of biological substances and
activities in live cells are crucial for understanding complex biological systems
and can permit development of biological/biomedical sensors or therapeutic
means for various diseases. Some techniques employ small fluorescent molecules
for labeling and sensing cellular substances.
Unfortunately, since these small molecular weight compounds often enter
the cells through passive diffusion mechanisms, high concentrations are
required, increasing the likeliness of non-specific labeling and cellular
toxicity. Polymeric nanoparticles (NPs) can improve the limitation of
concentration of small molecules; however, due to their high molecular weights,
these nanoparticles are inefficient for labeling intracellular molecules and
organelles.Researchers at FIU have been able to combine the
intracellular targeting advantages of both small molecules and nanoparticles by
creating conjugated polymer nanoparticles comprising
poly(p-phenyleneethynylene)s (PPEs) having a flexible linker between a portion
of phenylene units. The flexible linkers can be sites for biodegradability of
the PPEs into relatively small oligomers. The polymers can be tailored to a
specific application through the modulation of their physical, biological and
optical properties by structural modifications of the rigid conjugated backbone
and the pendant sidechains.Benefit
Offers an efficient one-pot synthesis that saves time, regents and eliminates the need for multiple production stepsProvides a customizable, biocompatible, and biodegradable delivery systemAllows for controlled release of molecules at target site and specific labellingMarket Application
Imaging of live cells including disease cells and tissuesSensing and monitoring of biological events at targeted organellesTargeted in vivo drug/gene deliveryPublications
Chem.
Commun., 2016,52, 4910-4913
Abstract
Fluorescent labelling of intracellular
organelles, proteins, or nucleic acids (NAs) is an essential way of studying
the structure and function of live cells. With their excellent photophysical
and biophysical properties, conjugated polymers (CPs) and conjugated polymer
nanoparticles (CPNs) are useful for labelling, sensing, and delivery of
biological substances. However, relatively large molecular weights and broad
molecular weight distributions of CP-based materials often limit their
intracellular applications in live cells. Due to a smaller hydrodynamic
volume, molecularly defined short conjugated oligomers (COs) appear to enter
cells by fast diffusion through the cell membranes, whereas CPs and CPNs are
most likely endocytosed and entrapped in endosomes or lysosomes. Despite their advantages,
there are few examples of COs being used for fluorescent labelling applications
in live cells.
To combine the advantages of conjugated
polymers (CPs) with more chromophores per molecule and conjugated oligomers
(COs) with monodispersed molecular weights and fast cellular entry, the
inventor has synthesized phenyleneethynylene macrocycles (PEMCs). The macrocycles
are prepared by using imine coupling between aldehyde end-capped
phenyleneethynylene (PE) trimer units and flexible diamines. For polycyclic
macrocycles, the amine can be triamines or tetraamines. Because the equilibrium
in the imine bond formation can be quantitatively shifted to thermodynamically favored
products, the target macrocycles can be obtained in high yields without
accompanying by-products.Benefit
Can be obtained in high yields without accompanying byproductsExhibit fast cellular entry, RNA selectivity, and nontoxicityMarket Application
Visualization and imaging of cellular RNA using standard microscopy techniquesPublications
Moon et al. Phenyleneethynylene trimer-based rigid-flexible [2+2] macrocycles for
nucleic acid labelling in live cells. Chem. Commun., 2019,55, 5930-5933
Abstract
This invention is a novel monomer design for the synthesis
of poly-p-(phenyleneethynylene)s (PPE)-type polymers containing conjugated segments of well-defined length
connected by flexible linkers. This has many applications including solar cell
fabrications, chemical sensors, various light emitting devices, biological
sensors, gene delivery, drug delivery, etc. Also, oligomers may be used for the
investigation of processes governing the physical and photophysical properties
of the corresponding larger, polydisperse polymeric materials. These polymers
are also biocompatible and biodegradable. This synthetic approach is carried
out in one step, eliminating the need for the traditional multi-step approaches
which are very low yielding, time consuming, and costly.Benefit
One step synthetic approach which eliminates low yielding, time consuming, costly approachesBiocompatible & biodegradableMarket Application
Solar cell fabricationsChemical sensorsBiological sensorsGene deliveryDrug deliveryVarious light emitting devicesTissues imagingMicroscopic imagingPublications
Vokata, T., Twomey, M., Mendez, E., and Moon, J. H. (2015)
Synthesis of biodegradable conjugated polymers with controlled backbone
flexibility. J. Polym. Sci., Part A: Polym. Chem. 53, 1403– 1412, DOI: 10.1002/pola.27622
Abstract
Aromatic
Ï€-electron conjugated polymers (CPs) are innovative fluorescent materials that
have a high potential as therapeutic carriers. Because of excellent
photophysical properties, such as high brightness and sensing ability, and
excellent biophysical properties, such as biocompatibility, nontoxicity, high cellular
interaction, and ease of entry, CPs have been used for live cell and tissue
imaging, biochemical sensing, and gene and drug delivery. Biodegradable CPs can be formed by introducing
flexible degradable functional groups along the backbone of the CPs.
Conventional method of synthesizing CPs with diverse
functional group is tedious and problematic. In addition to intrinsic
synthetic challenge of optimizing polymerization conditions for each monomer,
the resulting CP with different functional group will have different molecular
weight and polydispersity, which will influence their physical and biophysical
behaviors.
FIU inventors have synthesized modulated guanidine
substituted polymer and modulated guanidine substituted nanoparticle with
guanidine moieties. These polymers and nanoparticles can be prepared by direct
amination of a N-Boc protected guanidine substituted conjugated polymer or
nanoparticle, where an amine or alcohol is combined in solution or suspension
with the protected conjugated polymer or nanoparticle and the resulting mixture
is heated. The synthetic method can be
applied to a wide range of nanoparticles, synthetic and natural polymers, as
well as conjugated and non-conjugated polymers having a flexible backbone.
Benefit
Allows for the synthesize of structurally diverse polymers without tedious polymerization stepsProvides a catalyst free post polymerization technique to incorporate a variety of hydrophilic and hydrophobic functional groupProduces high yields of modulated CPs with enhanced cellular entry, modulated intracellular localization, and better siRNA deliveryMarket Application
Drug and gene deliveryWater treatmentSensorsPublications
Ahmed MS , Dutta RK , Manandhar P , et al. A
guanylurea-functionalized conjugated polymer enables RNA interference in ex
vivo human airway epithelium. Chem Commun (Camb). 2019;55(54):7804-7807.
doi:10.1039/c9cc02856k
Abstract
The design and synthesis of new
nanomaterials that enhance or assist the passage of therapeutics across
cellular membranes both in vitro and in vivo is of immense significance in
research and therapy. Many drug candidates fail to advance clinically as they
do not have the properties needed to cross biological membranes and reach their
intracellular target. Additionally, poor pharmacokinetics, stability, and
off-target effects leads to undesirable biological responses. Polymeric
systems, specifically, cell-penetrating peptides (CPPs) and their synthetic
mimics (CPPMs) offer hope for new therapeutic approaches and have played a
vital role in the advancement of drug delivery technology. The synthesis of molecular
transporters using ring-opening metathesis polymerization (ROMP) is advantageous
due to its living polymerization character. ROMP polymers offer great benefits
over other polymerization techniques such as controlled polymer length, low
polydispersity index (PDI) and easy of copolymer design. Several groups have
increased their efforts toward improving the transportation ability of
guanidine-rich molecular transporters. To date, the main modification done to
CPPs and their synthetic mimics have included the addition of hydrophobic
moieties to the polymer sequence, however, the guanidine group itself has
mostly been kept “untouched.â€쳌 Mono and di-alkylation of guanidine has resulted
in decreased cellular uptake of CPPs and mimics, leading researchers in other
directions.FIU inventors have expanded the
field of guanidine-rich molecular transporters into systems with modified
guanidines. Guanylureas, also referred to as amidinoureas, are moieties with
extended hydrogen bonding capacity as compared to guanidine. Utilizing
well-defined polymers, a function-oriented synthesis approach has been employed
and the initial results demonstrate improved intracellular protein delivery
using guanylurea functionalized molecular transporters.Benefit
Allows for the synthesize of structurally diverse polymers without tedious polymerization stepsProvides a catalyst free post polymerization technique to incorporate a variety of hydrophilic and hydrophobic functional groupProduces high yields of modulated CPs with enhanced cellular entry, modulated intracellular localization, and better siRNA deliveryMarket Application
Drug and gene deliveryWater treatmentSensors
Abstract
Antimicrobial drug resistance has emerged rapidly and thwarted treatment
options, leading to prolonged illness, disability, and death. Despite
considerable efforts to develop new antimicrobial drugs, many bacterial
infections remain difficult to treat due to acquired drug resistance. Compared
to small molecular antibiotics designed to interrupt the bacterial intracellular
biochemical processes, antimicrobial polymers disrupt the membrane integrity,
offering a promising strategy to overcome drug resistance. Bacteria have little
chance of developing resistance mechanism against the physical disruption, which
often leads to cell death.FIU inventors have developed a new class of linear polymers containing positively
charged guanylurea backbones. Compared with most antimicrobial polymers with
positively charged side chains, the new polymer design introduces both positive
charge and hydrophobicity into the flexible polymer backbones.The initial structure−activity relationship studies demonstrate that
poly-(guanylurea piperazine)s (PGU-Ps) exhibit excellent antimicrobial activity
against different types of bacteria with high selectivity. The simplicity of
polymerization without requiring any catalysts or specialized conditions, the
availability of numerous commercial amines, and the biocompatible guanylurea functional
groups are clear advantages over the existing materials. The new design concept
provides a promising method toward the realization of potent antimicrobial
polymers exhibiting high selectivity over mammalian cells and/or high specificity
toward a target microorganism.Benefit
Less toxic, more efficient and selective than low molecular weight antimicrobial agents Slows/inhibits the progress of drug-resistant microorganism strains because of the distinctive antimicrobial mechanism Overcomes antimicrobial resistance associated problems Provides a simplified synthesis that does not require any catalysts or specialized conditions Provides a simplified polymer architecture by linearly combining the key functional units along the backboneMarket Application
Antimicrobial coating for surgical instruments, medical devices, drugs, wound-dressings, textiles, and food packaging and storagePublications
Ahmed MS, Annamalai T,
Li X, et al. Synthesis of Antimicrobial Poly(guanylurea)s. Bioconjug Chem.
2018;29(4):1006-1009. doi:10.1021/acs.bioconjchem.8b00057