32 research outputs found
Stimuli-Responsive Poly(caprolactone) Vesicles for Dual Drug Delivery under the Gastrointestinal Tract
We report the first example of carboxylic
functionalized polyÂ(caprolactone)
(PCL) block copolymer vesicles as a novel dual drug delivery pH responsive
vehicle for oral administration under the gastrointestinal (GI) tract.
A new carboxylic functionalized caprolactone monomer was custom designed
through multistep organic reactions and polymerized under controlled
ROP using polyethylene glycol (PEG-2000) to produce amphiphilic diblocks,
PEG-<i>b</i>-CPCL<sub><i>x</i></sub>, with <i>x</i> = 25, 50, 75, and 100. These carboxylic PCL block copolymers
were self-organized into 100â250 nm vesicular assemblies in
water. The size and shape of the vesicular assemblies were confirmed
by light scattering, zeta potential, and electron microscopes. These
vesicles were capable of loading both hydrophilic molecules (Rhodamine
B, RhâB) and hydrophobic drugs such as ibuprofen (IBU) and
camptothecin (CPT) in the core and layer, respectively. These pH-responsive
PCL vesicles were stable in strong acidic conditions (pH < 2.0,
stomach) and ruptured to release the loaded cargoes under neutral
or basic pH (7.0 †pH, similar to that of small intestine).
The drug release kinetics under simulated GI tract revealed that the
individual drug loaded vesicles followed the combination of diffusion
and erosion pathway, whereas the dual drug loaded vesicles predominantly
followed the diffusion controlled process. Thus, the custom designed
PCL vesicles open up new area of pH stimuli responsive polymer vehicles
for delivering multiple drugs in oral drug delivery which are yet
to be explored for biomedical applications
Triple Block Nanocarrier Platform for Synergistic Cancer Therapy of Antagonistic Drugs
A unique biodegradable
triple block nanocarrier (TBN) is designed
and developed for synergistic combination therapy of antagonistic
drugs for cancer treatment. The TBN was built with hydrophilic polyethylene
glycol (PEG) outer shell; a middle hydrophobic and biodegradable polycaprolactone
(PCL) block for encapsulating anthracycline anticancer drug like doxorubicin
(DOX), and an inner carboxylic-functionalized polycaprolactone (CPCL)
core for cisplatin (CP) drug conjugation. TBN-cisplatin drug conjugate
self-assembled as stable nanoparticles in saline (also in PBS) wherein
the hydrophobic PCL block functions as a shield for Pt-drug stability
against GSH detoxification. Enzymatic-biodegradation of TBN exclusively
occurred at the intracellular environment to deliver both cisplatin
(CP) and doxorubicin (DOX) simultaneously to the nucleus. As a result,
the TBN-cisplatin conjugate and its DOX-loaded nanoparticles accomplished
100% cell growth inhibition in GSH overexpressed breast cancer cells.
Combination therapy revealed that free drugs were antagonistic to
each other, whereas the dual drug-loaded TBN exhibited excellent synergistic
cell killing at much lower drug concentrations in breast cancer cells.
Confocal microscopic analysis confirmed the localization of drugs
in the cytoplasm and at peri-nuclear site. Flow cytometry analysis
revealed that the drugs were taken up 4-fold better while delivering
them from TBN platform compared to free form. The TBNs approach is
a perfect platform to overcome the GSH detoxification in Pt-drugs
and enable the codelivery of antagonistic drugs like cisplatin and
DOX from single polymer dose to accomplish synergistic killing in
breast cancer cells
Structural Engineering of Biodegradable PCL Block Copolymer Nanoassemblies for Enzyme-Controlled Drug Delivery in Cancer Cells
Biodegradable
block copolymer chemical structures were engineered
as drug nanocarriers to precisely program the enzyme-controlled release
of anticancer drugs at intracellular compartments in cancer cells.
New classes of amide and ester side chain-substituted caprolactone
monomers were designed by multistep organic synthesis and polymerized
under ring opening processes to make new classes of substituted polycaprolactone-<i>block</i>-polyethylene glycol copolymers. These block copolymers
were self-assembled as stable nanoparticles of <200 nm in water.
The polymer nanoparticles were found to be excellent scaffolds for
loading a wide range of anticancer drugs and stabilized them at extracellular
circulating conditions (37 °C in PBS). At the intracellular level,
lysosomal-esterase enzyme biodegraded the aliphatic polyester PCL
backbone and facilitated the release of drugs in a steady and controlled
manner. In vitro drug release studies confirmed that the amide-PCL
block copolymers exhibited controlled drug release compared to that
of their non-hydrogen-bonded ester-PCL blocks or unsubstituted PCL
blocks. The influence of hydrogen bonding interactions on the drug
release profiles of PCL nanoparticles were studied by FT-IR and time-resolved
fluorescent decay measurements. Cytotoxicity experiments in cervical
cancer (HeLa) and breast cancer (MCF-7) cell lines demonstrated that
amide diblock copolymer nanoassemblies show slow and prolonged cell
killing. The new block copolymers were capable of loading multiple
anticancer drugs like doxorubicin (DOX), curcumin (CUR), camptothecin
(CPT), and methotrexate (MTX) that largely differ in pharmacokinetics
as well as fluorescent regions for cellular imaging. Interestingly,
these different drugs could be delivered to the intracellular compartments
of the cancer cells by an identical enzyme-controlled delivery pathway
from a single biodegradable block copolymer nanoscaffold. Confocal
microscopic images exhibited that the engineered block copolymer nanoparticles
were capable of transporting all of these drugs across the cell membrane
and accumulating them predominantly in the cytoplasm and peri-nuclear
region. The present investigation presents a new opportunity in the
structural engineering of biodegradable diblock copolymer nanoassemblies
for enzyme-controlled multiple-anticancer-drug administration in cancer
therapy
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Abstract P07: Inhibition of androgen-regulated TMPRSS2 and lipogenic enzymes in prostate and lung carcinoma cell lines by a cisplatin prodrug
Abstract The main causative agent for the global pandemic of COVID-19 is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Developing therapeutic strategies to stop the virus is the hour of need. According to the recent clinical reports, it is seen that an androgen-regulated host cell serine protease TMPRSS2 acts on the spike protein of the SARS-CoV-2 virus which interacts with the host angiotensin-converting enzyme 2 (ACE2) and enters the host cell to cause the infection. Reports also suggest that TMPRSS2 is regulated by androgen present in prostate cells and it is highly expressed in PCa patients. Our lab has recently synthesized a new cisplatin prodrug which is a conjugate of lauric acid and cisplatin that potentially works very effectively in various androgen dependent and independent prostate cancer (PCa) cells. The cisplatin prodrug unlike other conventional platinum drugs is involved in inhibition of one of the major metabolic pathways of the PCa cells. Preliminary results show that, the prodrug in combination with the anti-androgen bicalutamide has an increased inhibition on the expression of TMPRSS2 in androgen dependent PCa and lung carcinoma cells along with down-regulation of some the lipogenic enzymes in-vitro. Here, we propose that the prodrug inhibits one of the mitochondrial metabolic pathways making the PCa cells sensitive towards cisplatin-based chemotherapy along with reducing the expression of TMPRSS2. Once completed, our work will provide an inside story of cisplatin prodrug mediated alteration of lipogenesis of cells in PCa tumor microenvironment resulting in a platform that has the potential to reduce the burden of cancer aggressiveness in both androgen dependent and independent PCa and also can be used as a potent chemotherapeutic agent against COVID-19. Citation Format: Subham Guin, Bapurao Surnar, Uttara Basu, Shanta Dhar. Inhibition of androgen-regulated TMPRSS2 and lipogenic enzymes in prostate and lung carcinoma cell lines by a cisplatin prodrug [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P07
Polymer Topology Driven Enzymatic Biodegradation in Polycaprolactone Block and Random Copolymer Architectures for Drug Delivery to Cancer Cells
The
present investigation reports polymer topology design principle
for programming the enzymatic biodegradation and delivery of anticancer
drugs at the intracellular compartments of breast and cervical cancers.
To accomplish this goal, new classes of biodegradable amphiphilic
block and random copolymers based on hydrophilic carboxylic-functionalized
polycaprolactone (CPCL) and hydrophobic polycaprolactone (PCL) units
were designed via ring-opening polymerization methodology. The interchain
interactions and their packing were directly controlled by the topology
of the polymers, and the block copolymers were found to be as semicrystalline
materials. These amphiphilic block and random polymers were readily
dispersible in water, and they self-assembled into <200 nm nanoparticles.
These nanoparticles exhibited excellent capability for loading anticancer
drug doxorubicin (DOX) in the hydrophobic pocket. <i>In vitro</i> drug release kinetics revealed that the polymer nanoscaffolds were
stable under physiological conditions, and they exclusively ruptured
in the presence of lysosomal esterase enzyme at the intracellular
compartments to deliver DOX. The âburstâ and âcontrolledâ
release of drugs from the polymer nanocarriers was directly controlled
by length and chemical composition of block and random copolymers. <i>In vitro</i> cytotoxicity studies in breast cancer (MCF 7) and
cervical cancer (HeLa) cells revealed that the nascent polymer nanoparticle
was highly biocompatible and nontoxic to cells whereas their DOX-loaded
nanoparticles accomplished >95% cell killing. Confocal microscopy
reinstated the cellular uptake of the DOX-loaded polymer scaffold
wherein the nanoparticle was highly concentrated at the nucleus and
revealed that the drugs were predominantly delivered at the nucleus
of the cells for apoptosis. Flow cytometry investigation confirmed
the enhanced DOX delivering capability of block and random copolymer
nanoparticles compared to free DOX. The newly designed fully biodegradable
PCL-based block and random nanocarriers are excellent scaffolds for
enzyme-mediated intracellular delivery of DOX, and the proof of concept
was established in breast and cervical cancers
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Intersection of Inorganic Chemistry and Nanotechnology for the Creation of New Cancer Therapies
Conspectus Since its discovery in 1965, the inorganic drug cisplatin has become a mainstay of cancer therapies and has inspired many platinum (Pt)-based compounds to solve various issues of toxicity and limitations associated with the original cisplatin. However, many of these drugs/prodrugs continue to be plagued by an array of side effects, limited circulation, and half-life and off-target effects. To solve this issue, we have constructed an array of platinum-based prodrugs on a PtÂ(IV) skeleton, which provides more favorable geometry and hydrophobicity, easier functionalization, and ultimately better targeting abilities. Each of these PtÂ(IV) prodrugs aims to either combine cisplatin with other agents for a combination therapeutic effect or improve the targeting of cisplatin itself, all for the more effective treatment of specific cancers. Our developed prodrugs include Platin-A, which combines cisplatin with the anti-inflammatory agent aspirin, Platin-M, which is functionalized with a mitochondria-targeting moiety, and Platin-B and Platin-Cbl, which combine cisplatin with components to combat cellular resistance to chemotherapy. At the same time, however, we recognize the crucial role of nanotechnology in improving the efficacy of cisplatin prodrugs and other inorganic compounds for the treatment of cancers. We describe several key benefits provided by nanomedicine that vastly improve the reach and utility of cisplatin prodrugs, including the ability of biodegradable polymeric nanoparticles (NPs) to deliver these agents with precision to the mitochondria, transport drugs across the bloodâbrain barrier, and target cisplatin prodrugs to specific cancers using various ligands. In addition, we highlight our progress in the engineering of innovative new polymers to improve the release patterns, pharmacokinetics, and dosages of cancer therapies. In this Account, we aim to describe the growing need for collaboration between the fields of inorganic chemistry and nanotechnology and how new advancements can not only improve on traditional chemotherapeutic agents but also expand their reach to entirely new subsets of cancers. In addition to detailing the design and principles behind our modifications of cisplatin and the efficacy of these new prodrugs against aggressive, cisplatin-resistant, or metastatic cancers, we also shed light on nanotechnologyâs essential role in protecting inorganic drugs and the human body from one another for more effective disease treatment without the off-target effects with which it is normally associated. We hope that this perspective into the important intersection between inorganic medicinal chemistry and nanotechnology will inspire future research on cisplatin prodrugs and other inorganic agents, innovative polymer and NP design, and the ways in which these two fields can greatly advance cancer treatment
Blending of Designer Synthetic Polymers to a Dual Targeted Nanoformulation for SARS-CoV-2 Associated Kidney Damage
As the COVID-19 pandemic has continued to spread, studies have shown that hospitalized COVID-19 patients are at significant risk for developing acute kidney injury (AKI), which can cause increased morbidity, the need for dialysis treatment, chronic kidney diseases, and even death. In this paper, we present a proof-of-concept study for the utilization of combination therapeutic-loaded dual-targeted biodegradable nanoparticles (NPs) to treat concurrent AKI and COVID-19 in patients by delivering the therapeutics across the gut epithelial barrier and to the kidney, in order to lower the viral load as well as reduce the symptoms of AKI. Despite recent vaccination efforts and the end of the COVID-19 pandemic in sight, problems related to the long-term effects of COVID-19 will continue to persist, including impacts on patients suffering from AKI and other chronic renal conditions. Therefore, the dual-targeted blended polymeric NP developed in this study to treat concurrent COVID-19 infection and AKI is a useful proof-of-concept nanoplatform for future treatments of these complications
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Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19
There is urgent therapeutic need
for COVID-19, a disease for which
there are currently no widely effective approved treatments and the
emergency use authorized drugs do not result in significant and widespread
patient improvement. The food and drug administration-approved drug
ivermectin has long been shown to be both antihelmintic agent and
a potent inhibitor of viruses such as Yellow Fever Virus. In this
study, we highlight the potential of ivermectin packaged in an orally
administrable nanoparticle that could serve as a vehicle to deliver
a more potent therapeutic antiviral dose and demonstrate its efficacy
to decrease expression of viral spike protein and its receptor angiotensin-converting
enzyme 2 (ACE2), both of which are keys to lowering disease transmission
rates. We also report that the targeted nanoparticle delivered ivermectin
is able to inhibit the nuclear transport activities mediated through
proteins such as importin α/ÎČ1 heterodimer as a possible
mechanism of action. This study sheds light on ivermectin-loaded,
orally administrable, biodegradable nanoparticles to be a potential
treatment option for the novel coronavirus through a multilevel inhibition.
As both ACE2 targeting and the presence of spike protein are features
shared among this class of virus, this platform technology has the
potential to serve as a therapeutic tool not only for COVID-19 but
for other coronavirus strains as well
Dual Functional Nanocarrier for Cellular Imaging and Drug Delivery in Cancer Cells Based on ÏâConjugated Core and Biodegradable Polymer Arms
Multipurpose
polymer nanoscaffolds for cellular imaging and delivery
of anticancer drug are urgently required for the cancer therapy. The
present investigation reports a new polymer drug delivery concept
based on biodegradable polycaprolactone (PCL) and highly luminescent
Ï-conjugated fluorophore as dual functional nanocarrier for
cellular imaging and delivery vehicles for anticancer drug to cancer
cells. To accomplish this goal, a new substituted caprolactone monomer
was designed, and it was subjected to ring opening polymerization
using a blue luminescent bishydroxyloligo-phenylenevinylene (OPV)
fluorophore as an initiator. A series of AâBâA triblock
copolymer building blocks with a fixed OPV Ï-core and variable
chain biodegradable PCL arm length were tailor-made. These triblocks
self-assembled in organic solvents to produce well-defined helical
nanofibers, whereas in water they produced spherical nanoparticles
(size âŒ150 nm) with blue luminescence. The hydrophobic pocket
of the polymer nanoparticle was found to be an efficient host for
loading water insoluble anticancer drug such as doxorubicin (DOX).
The photophysical studies revealed that there was no cross-talking
between the OPV and DOX chromophores, and their optical purity was
retained in the nanoparticle assembly for cellular imaging. <i>In vitro</i> studies revealed that the biodegradable PCL arm
was susceptible to enzymatic cleavage at the intracellular lysosomal
esterase under physiological conditions to release the loaded drugs.
The nascent nanoparticles were found to be nontoxic to cancer cells,
whereas the DOX-loaded nanoparticles accomplished more than 80% killing
in HeLa cells. Confocal microscopic analysis confirmed the cell penetrating
ability of the blue luminescent polymer nanoparticles and their accumulation
preferably in the cytoplasm. The DOX loaded red luminescent polymer
nanoparticles were also taken up by the cells, and the drug was found
to be accumulated at the perinuclear environment. The new nanocarrier
approach reported in the present manuscript accomplishes both cellular
imaging and delivering drugs to intracellular compartments in a single
polymer system. The present investigation is one of the first examples
to demonstrate the dual functional biodegradable luminescence nanocarrier
concept in the literature, and the studies established this proof-of-concept
in cellular imaging and drug delivery in cancer cells
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Dual-Targeted Synthetic Nanoparticles for Cardiovascular Diseases
Atherosclerosis is one of the worldâs most aggressive diseases, claiming over 17.5 million lives per year. This disease is usually caused by high amounts of lipoproteins circulating in the blood stream, which leads to plaque formation. Ultimately, these plaques can undergo thrombosis and lead to major heart damage. A major contributor to these vulnerable plaques is macrophage apoptosis. Development of nanovehicles that carry contrast and therapeutic agents to the mitochondria within these macrophages is attractive for the diagnosis and treatment of atherosclerosis. Here, we report the design and synthesis of a dual-targeted synthetic nanoparticle (NP) to perform the double duty of diagnosis and therapy in atherosclerosis treatment regime. A library of dual-targeted NPs with an encapsulated iron oxide NP, mito-magneto (MM), with a magnetic resonance imaging (MRI) contrast enhancement capability was elucidated. Relaxivity measurements revealed that there is a substantial enhancement in transverse relaxivities upon the encapsulation of MM inside the dual-targeted NPs, highlighting the MRI contrast-enhancing ability of these NPs. Successful in vivo imaging documenting the distribution of MM-encapsulated dual-targeted NPs in the heart and aorta in mice ensured the diagnostic potential. The presence of mannose receptor targeting ligands and the optimization of the NP composition facilitated its ability to perform therapeutic duty by targeting the macrophages at the plaque. These dual-targeted NPs with the encapsulated MM were able to show therapeutic potential and did not trigger any toxic immunogenic response