Aditi Jhaveri | Northeastern University (original) (raw)

Papers by Aditi Jhaveri

Journal of Immunology, May 1, 2020

Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XVII, 2019

Glioblastomas are brain cancers with very poor patient prognosis. We have developed a Glioblastom... more Glioblastomas are brain cancers with very poor patient prognosis. We have developed a Glioblastoma U87 MR model, using 4-dimensional imaging in multi-day tracking experiments. The cells have a tendency to form long-term cellular associations, and quantifying their motility by standard approaches is difficult. We cultured the cells in a structured environment (wound healing template), separated the X and Y information to define cumulative directionality plots providing a metric of the overall cell population movement analyzed by holographic imaging cytometry. With cellular tomography, we obtained 3D time lapse tomographs of cells at 0.2 um resolution, enabling sub-cellular analysis at levels not previously possible. Even in label-free cultures, sub-cellular components can be distinguished and color-coded based on differences of their refractive index values. We discovered that there are numerous mitochondria present, both single and also actively undergoing fission and fusion processes. Many thin mitochondrial networks are present within the cytoplasm, and also extending away from the cell in tunneling nanotubes. There is fusion of these networks to form larger structures that form connections between cells. Substances can be seen moving bi-directionally between cells. After several days of culture, the cells form large multicellular and highly connected spheroids. This is evident in widefield stitched images of the spheroids. While the tendency of U87 cells to form spheroids was previously known, the combined results from our multi-modality quantitative imaging platforms provide new insights into the cellular dynamics of glioblastoma cells, and the networks that they form. This knowledge is being applied to the development anti-glioblastoma treatments.

Acta biomaterialia, 2017

A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was dev... more A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was developed. DOX was incorporated in micelles (M-DOX) of polyethylene glycol-phosphatidylethanolamine (PEG-PE) which in turn were adsorbed by the clay, montmorillonite (MMT). The nano-structures of the PEG-PE/MMT composites of LOW and HIGH polymer loadings were characterized by XRD, TGA, FTIR, size (DLS) and zeta measurements. These measurements suggest that for the LOW composite a single layer of polymer intercalates in the clay platelets and the polymer only partially covers the external surface, while for the HIGH composite two layers of polymer intercalate and a bilayer may form on the external surface. These nanostructures have a direct effect on formulation stability and on the rate of DOX release. The release rate was reversely correlated with the degree of DOX interaction with the clay and followed the sequence: M-DOX>HIGH formulation>LOW formulation>DOX/MMT. Despite the slow...

International journal of pharmaceutics, Jan 24, 2017

Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growt... more Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2-deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL-240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive...

Pharmaceutical Research, 2016

To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NC... more To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NCL-240, TRAIL [tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand] and anti-survivin siRNA and to test the combination preparation for anti-cancer effects in different cancer cells. Polyethylene glycol-phosphoethanolamine (PEG-PE) - based polymeric micelles were prepared carrying NCL-240. These micelles were used in combination with TRAIL-conjugated micelles and anti-survivin siRNA-S-S-PE containing micelles. All the micelles were characterized for size, zeta potential, and drug encapsulation efficiency. Different cancer cells were used to study the cytotoxicity potential of the individual as well as the combination formulations. Other cell based assays included cellular association studies of transferrin-targeted NCL-240 micelles and study of cellular survivin protein downregulation by anti-survivin siRNA-S-S-PE containing micelles. NCL-240 micelles and the combination NCL-240/TRAIL micelles significantly increased cytotoxicity in the resistant strains of SKOV-3, MCF-7 and A549 as compared to free drugs or single drug formulations. The NCL-240/TRAIL micelles were also more effective in NCI/ADR-RES cancer cell spheroids. Anti-survivin siRNA micelles alone displayed a dose-dependent reduction in survivin protein levels in A2780 cells. Treatment with NCL-240/TRAIL after pre-incubation with anti-survivin siRNA inhibited cancer cell proliferation. Additionally, a single multifunctional system composed of NCL-240/TRAIL/siRNA PM also had significant cytotoxic effects in vitro in multiple cell lines. These results demonstrate the efficacy of a combination of small-molecule PI3K inhibitors, TRAIL, and siRNA delivered by micellar preparations in multiple cancer cell lines.

Frontiers in Pharmacology, 2014

Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers with a core-shell s... more Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers with a core-shell structure have been used as versatile carriers for delivery of drugs as well as nucleic acids. They have gained immense popularity owing to a host of favorable properties including their capacity to effectively solubilize a variety of poorly soluble pharmaceutical agents, biocompatibility, longevity, high stability in vitro and in vivo and the ability to accumulate in pathological areas with compromised vasculature. Moreover, additional functions can be imparted to these micelles by engineering their surface with various ligands and cell-penetrating moieties to allow for specific targeting and intracellular accumulation, respectively, to load them with contrast agents to confer imaging capabilities, and incorporating stimuli-sensitive groups that allow drug release in response to small changes in the environment. Recently, there has been an increasing trend toward designing polymeric micelles which integrate a number of the above functions into a single carrier to give rise to "smart," multifunctional polymeric micelles. Such multifunctional micelles can be envisaged as key to improving the efficacy of current treatments which have seen a steady increase not only in hydrophobic small molecules, but also in biologics including therapeutic genes, antibodies and small interfering RNA (siRNA). The purpose of this review is to highlight recent advances in the development of multifunctional polymeric micelles specifically for delivery of drugs and siRNA. In spite of the tremendous potential of siRNA, its translation into clinics has been a significant challenge because of physiological barriers to its effective delivery and the lack of safe, effective and clinically suitable vehicles. To that end, we also discuss the potential and suitability of multifunctional polymeric micelles, including lipid-based micelles, as promising vehicles for both siRNA and drugs.

Cancer Research, 2017

Purpose: The purpose of this study was to develop transferrin (Tf)-modified liposomes loaded with... more Purpose: The purpose of this study was to develop transferrin (Tf)-modified liposomes loaded with resveratrol (RES) (Tf-RES-L) to achieve an effective therapy for glioblastomas (GBMs) by eliminating both, the bulk tumor cell (BTC) and tumor-initiating cell (TIC) populations within GBMs, and to provide an effective delivery system for RES to overcome its limitations as a free drug. We hypothesize that Tf-RES-L will show an improved efficacy versus the free drug or non-targeted liposomes and will act as a suitable platform for effective delivery of RES into GBM cells. Background: GBMs harbor a sub-population of extremely chemo and radio-resistant cells known as TICs or cancer stem-like cells which are highly tumorigenic and can sustain the growth, invasiveness and recurrence of GBMs. Conventional chemotherapeutics act on the rapidly dividing BTCs but leave behind the quiescent TICs, which can lead to tumor relapse. They also exhibit severe toxicities to the surrounding normal tissues....

Purpose: Glioblastomas (GBM) harbor a sub-population of slow-dividing cells known as tumor-initia... more Purpose: Glioblastomas (GBM) harbor a sub-population of slow-dividing cells known as tumor-initiating cells (TIC) that are responsible for the formation, maintenance, invasiveness and recurrence of GBM. Conventional chemotherapeutics result in toxicities on normal tissues and act mainly on the tumor bulk while sparing the TICs, which results in tumor relapse. Resveratrol (RES), a natural polyphenol has been shown to exhibit chemopreventive effects in all the major stages of cancer including initiation, promotion and progression 1 . However, RES as a free drug has several limitations including a poor water solubility, chemical instability, low bioavailability, and poor pharmacokinetics 2 . To counter these drawbacks, we have developed liposome encapsulated RES (RES-L) and aimed to evaluate its effects on both, the bulk of cancer cells as well as TIC in GBM. RES-L were then modified with transferrin (Tf) as a targeting ligand (Tf-RES-L) to take advantage of the over-expressed Tf recep...

Proceedings of the National Academy of Sciences

Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for th... more Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for the treatment of autoimmune diseases, including multiple sclerosis (MS). Based on its role in the control of the immune response, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is a candidate target for novel immunotherapies. Here, we report the development of AhR-activating nanoliposomes (NLPs) to induce antigen-specific tolerance. NLPs loaded with the AhR agonist ITE and a T cell epitope from myelin oligodendrocyte glycoprotein (MOG)35–55 induced tolerogenic dendritic cells and suppressed the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, in preventive and therapeutic setups. EAE suppression was associated with the expansion of MOG35–55-specific FoxP3+ regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells), concomitant with a reduction in central nervous system-infiltrating effector T cells (Teff ce...

Journal of Drug Targeting

Glioblastomas (GBMs) are known to harbor subsets of cells known as tumor-initiating cells (TICs),... more Glioblastomas (GBMs) are known to harbor subsets of cells known as tumor-initiating cells (TICs), which are responsible for the maintenance, invasiveness and recurrence of GBMs. Conventional chemotherapeutics act on rapidly dividing cells, sparing the TICs and result in tumor relapse. Resveratrol, (RES) has shown chemopreventive effects in all the major stages of cancer including initiation, promotion and progression, but poor physico-chemical and pharmacokinetic properties limit its use as a free drug. Hence we developed a liposomal formulation of RES (RES-L) to eradicate both the bulk tumor cells and TICs in GBMs. Since both these sub-populations of cells are known to over-express transferrin receptors, we developed transferrin-targeted RES-L (Tf-RES-L) to enhance tumor-specific delivery. We studied the effects of RES on neurospheres (NS) used as an in vitro model to study TICs derived from GBM cell lines. Free RES and RES-formulations inhibited the anchorage-independent growth of GBM neurospheres. The NS-derived cells expressed TfRs and the Tf-targeted liposomes showed a significantly higher association with NS versus the non-targeted liposomes. Finally an increased activation of caspases 3/7 was seen when NS were treated with RES formulations. Together, these studies advocate for further investigations with RES-L and the use Tf to target the TIC populations.

Journal of Controlled Release

Drug delivery, 2018

Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to... more Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to enhance the delivery of therapeutics to tumors. Among many approaches for active tumor-targeting, arginine-rich cell penetrating peptides (AR-CPP) and ligands specific to target over-expressed receptors on cancer-cell surfaces, are popular. Earlier, we showed that the attachment of an AR-CPP octaarginine (R8) to the surface of DOXIL(Doxorubicin encapsulated PEGylated liposomes) improved cytoplasmic and nuclear DOX delivery that enhanced the cytotoxic effect in vitro and improved therapeutic efficacy in vivo. Here, we report on DOX-loaded liposomes, surface-modified with, R8 and transferrin (Tf) (Dual DOX-L), to improve targeting of A2780 ovarian carcinoma cells via the over-expressed transferrin receptors (TfRs) with R8-mediated intracellular DOX delivery. Flow cytometry analysis with fluorescently labeled DualL (without DOX) showed two-fold higher cancer-cell association than other tre...

Advances in Nanobottles and Active Nanoparticles, 2015

Smart Pharmaceutical Nanocarriers, 2016

Expert opinion on drug delivery, 2016

Recent trends in drug delivery indicate a steady increase in the use of targeted therapeutics to ... more Recent trends in drug delivery indicate a steady increase in the use of targeted therapeutics to enhance the specific delivery of biologically active payloads to diseased tissues while avoiding their off-target effects. However, in most cases, the distribution of therapeutics inside cells and their targeting to intracellular targets still presents a formidable challenge. The main barrier to intracellular delivery is the translocation of therapeutic molecules across the cell membrane, and ultimately through the membrane of their intracellular target organelles. Another prerequisite for an efficient intracellular localization of active molecules is their escape from the endocytic pathway. Pharmaceutical nanocarriers have demonstrated substantial advantages for the delivery of therapeutics and offer elegant platforms for intracellular delivery. They can be engineered with both intracellular and organelle-specific targeting moieties to deliver encapsulated or conjugated cargoes to speci...

Smart Pharmaceutical Nanocarriers, 2016

Fundamentals, Applications and Recent Developments(In 4 Volumes)Volume 1: Materials for NanomedicineVolume 2: Applications in TherapyVolume 3: Applications in DiagnosticsVolume 4: Biology, Safety and Novel Concepts in Nanomedicine, 2014

Journal of Immunology, May 1, 2020

Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XVII, 2019

Glioblastomas are brain cancers with very poor patient prognosis. We have developed a Glioblastom... more Glioblastomas are brain cancers with very poor patient prognosis. We have developed a Glioblastoma U87 MR model, using 4-dimensional imaging in multi-day tracking experiments. The cells have a tendency to form long-term cellular associations, and quantifying their motility by standard approaches is difficult. We cultured the cells in a structured environment (wound healing template), separated the X and Y information to define cumulative directionality plots providing a metric of the overall cell population movement analyzed by holographic imaging cytometry. With cellular tomography, we obtained 3D time lapse tomographs of cells at 0.2 um resolution, enabling sub-cellular analysis at levels not previously possible. Even in label-free cultures, sub-cellular components can be distinguished and color-coded based on differences of their refractive index values. We discovered that there are numerous mitochondria present, both single and also actively undergoing fission and fusion processes. Many thin mitochondrial networks are present within the cytoplasm, and also extending away from the cell in tunneling nanotubes. There is fusion of these networks to form larger structures that form connections between cells. Substances can be seen moving bi-directionally between cells. After several days of culture, the cells form large multicellular and highly connected spheroids. This is evident in widefield stitched images of the spheroids. While the tendency of U87 cells to form spheroids was previously known, the combined results from our multi-modality quantitative imaging platforms provide new insights into the cellular dynamics of glioblastoma cells, and the networks that they form. This knowledge is being applied to the development anti-glioblastoma treatments.

Acta biomaterialia, 2017

A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was dev... more A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was developed. DOX was incorporated in micelles (M-DOX) of polyethylene glycol-phosphatidylethanolamine (PEG-PE) which in turn were adsorbed by the clay, montmorillonite (MMT). The nano-structures of the PEG-PE/MMT composites of LOW and HIGH polymer loadings were characterized by XRD, TGA, FTIR, size (DLS) and zeta measurements. These measurements suggest that for the LOW composite a single layer of polymer intercalates in the clay platelets and the polymer only partially covers the external surface, while for the HIGH composite two layers of polymer intercalate and a bilayer may form on the external surface. These nanostructures have a direct effect on formulation stability and on the rate of DOX release. The release rate was reversely correlated with the degree of DOX interaction with the clay and followed the sequence: M-DOX>HIGH formulation>LOW formulation>DOX/MMT. Despite the slow...

International journal of pharmaceutics, Jan 24, 2017

Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growt... more Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2-deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL-240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive...

Pharmaceutical Research, 2016

To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NC... more To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NCL-240, TRAIL [tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand] and anti-survivin siRNA and to test the combination preparation for anti-cancer effects in different cancer cells. Polyethylene glycol-phosphoethanolamine (PEG-PE) - based polymeric micelles were prepared carrying NCL-240. These micelles were used in combination with TRAIL-conjugated micelles and anti-survivin siRNA-S-S-PE containing micelles. All the micelles were characterized for size, zeta potential, and drug encapsulation efficiency. Different cancer cells were used to study the cytotoxicity potential of the individual as well as the combination formulations. Other cell based assays included cellular association studies of transferrin-targeted NCL-240 micelles and study of cellular survivin protein downregulation by anti-survivin siRNA-S-S-PE containing micelles. NCL-240 micelles and the combination NCL-240/TRAIL micelles significantly increased cytotoxicity in the resistant strains of SKOV-3, MCF-7 and A549 as compared to free drugs or single drug formulations. The NCL-240/TRAIL micelles were also more effective in NCI/ADR-RES cancer cell spheroids. Anti-survivin siRNA micelles alone displayed a dose-dependent reduction in survivin protein levels in A2780 cells. Treatment with NCL-240/TRAIL after pre-incubation with anti-survivin siRNA inhibited cancer cell proliferation. Additionally, a single multifunctional system composed of NCL-240/TRAIL/siRNA PM also had significant cytotoxic effects in vitro in multiple cell lines. These results demonstrate the efficacy of a combination of small-molecule PI3K inhibitors, TRAIL, and siRNA delivered by micellar preparations in multiple cancer cell lines.

Frontiers in Pharmacology, 2014

Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers with a core-shell s... more Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers with a core-shell structure have been used as versatile carriers for delivery of drugs as well as nucleic acids. They have gained immense popularity owing to a host of favorable properties including their capacity to effectively solubilize a variety of poorly soluble pharmaceutical agents, biocompatibility, longevity, high stability in vitro and in vivo and the ability to accumulate in pathological areas with compromised vasculature. Moreover, additional functions can be imparted to these micelles by engineering their surface with various ligands and cell-penetrating moieties to allow for specific targeting and intracellular accumulation, respectively, to load them with contrast agents to confer imaging capabilities, and incorporating stimuli-sensitive groups that allow drug release in response to small changes in the environment. Recently, there has been an increasing trend toward designing polymeric micelles which integrate a number of the above functions into a single carrier to give rise to "smart," multifunctional polymeric micelles. Such multifunctional micelles can be envisaged as key to improving the efficacy of current treatments which have seen a steady increase not only in hydrophobic small molecules, but also in biologics including therapeutic genes, antibodies and small interfering RNA (siRNA). The purpose of this review is to highlight recent advances in the development of multifunctional polymeric micelles specifically for delivery of drugs and siRNA. In spite of the tremendous potential of siRNA, its translation into clinics has been a significant challenge because of physiological barriers to its effective delivery and the lack of safe, effective and clinically suitable vehicles. To that end, we also discuss the potential and suitability of multifunctional polymeric micelles, including lipid-based micelles, as promising vehicles for both siRNA and drugs.

Cancer Research, 2017

Purpose: The purpose of this study was to develop transferrin (Tf)-modified liposomes loaded with... more Purpose: The purpose of this study was to develop transferrin (Tf)-modified liposomes loaded with resveratrol (RES) (Tf-RES-L) to achieve an effective therapy for glioblastomas (GBMs) by eliminating both, the bulk tumor cell (BTC) and tumor-initiating cell (TIC) populations within GBMs, and to provide an effective delivery system for RES to overcome its limitations as a free drug. We hypothesize that Tf-RES-L will show an improved efficacy versus the free drug or non-targeted liposomes and will act as a suitable platform for effective delivery of RES into GBM cells. Background: GBMs harbor a sub-population of extremely chemo and radio-resistant cells known as TICs or cancer stem-like cells which are highly tumorigenic and can sustain the growth, invasiveness and recurrence of GBMs. Conventional chemotherapeutics act on the rapidly dividing BTCs but leave behind the quiescent TICs, which can lead to tumor relapse. They also exhibit severe toxicities to the surrounding normal tissues....

Purpose: Glioblastomas (GBM) harbor a sub-population of slow-dividing cells known as tumor-initia... more Purpose: Glioblastomas (GBM) harbor a sub-population of slow-dividing cells known as tumor-initiating cells (TIC) that are responsible for the formation, maintenance, invasiveness and recurrence of GBM. Conventional chemotherapeutics result in toxicities on normal tissues and act mainly on the tumor bulk while sparing the TICs, which results in tumor relapse. Resveratrol (RES), a natural polyphenol has been shown to exhibit chemopreventive effects in all the major stages of cancer including initiation, promotion and progression 1 . However, RES as a free drug has several limitations including a poor water solubility, chemical instability, low bioavailability, and poor pharmacokinetics 2 . To counter these drawbacks, we have developed liposome encapsulated RES (RES-L) and aimed to evaluate its effects on both, the bulk of cancer cells as well as TIC in GBM. RES-L were then modified with transferrin (Tf) as a targeting ligand (Tf-RES-L) to take advantage of the over-expressed Tf recep...

Proceedings of the National Academy of Sciences

Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for th... more Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for the treatment of autoimmune diseases, including multiple sclerosis (MS). Based on its role in the control of the immune response, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is a candidate target for novel immunotherapies. Here, we report the development of AhR-activating nanoliposomes (NLPs) to induce antigen-specific tolerance. NLPs loaded with the AhR agonist ITE and a T cell epitope from myelin oligodendrocyte glycoprotein (MOG)35–55 induced tolerogenic dendritic cells and suppressed the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, in preventive and therapeutic setups. EAE suppression was associated with the expansion of MOG35–55-specific FoxP3+ regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells), concomitant with a reduction in central nervous system-infiltrating effector T cells (Teff ce...

Journal of Drug Targeting

Glioblastomas (GBMs) are known to harbor subsets of cells known as tumor-initiating cells (TICs),... more Glioblastomas (GBMs) are known to harbor subsets of cells known as tumor-initiating cells (TICs), which are responsible for the maintenance, invasiveness and recurrence of GBMs. Conventional chemotherapeutics act on rapidly dividing cells, sparing the TICs and result in tumor relapse. Resveratrol, (RES) has shown chemopreventive effects in all the major stages of cancer including initiation, promotion and progression, but poor physico-chemical and pharmacokinetic properties limit its use as a free drug. Hence we developed a liposomal formulation of RES (RES-L) to eradicate both the bulk tumor cells and TICs in GBMs. Since both these sub-populations of cells are known to over-express transferrin receptors, we developed transferrin-targeted RES-L (Tf-RES-L) to enhance tumor-specific delivery. We studied the effects of RES on neurospheres (NS) used as an in vitro model to study TICs derived from GBM cell lines. Free RES and RES-formulations inhibited the anchorage-independent growth of GBM neurospheres. The NS-derived cells expressed TfRs and the Tf-targeted liposomes showed a significantly higher association with NS versus the non-targeted liposomes. Finally an increased activation of caspases 3/7 was seen when NS were treated with RES formulations. Together, these studies advocate for further investigations with RES-L and the use Tf to target the TIC populations.

Journal of Controlled Release

Drug delivery, 2018

Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to... more Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to enhance the delivery of therapeutics to tumors. Among many approaches for active tumor-targeting, arginine-rich cell penetrating peptides (AR-CPP) and ligands specific to target over-expressed receptors on cancer-cell surfaces, are popular. Earlier, we showed that the attachment of an AR-CPP octaarginine (R8) to the surface of DOXIL(Doxorubicin encapsulated PEGylated liposomes) improved cytoplasmic and nuclear DOX delivery that enhanced the cytotoxic effect in vitro and improved therapeutic efficacy in vivo. Here, we report on DOX-loaded liposomes, surface-modified with, R8 and transferrin (Tf) (Dual DOX-L), to improve targeting of A2780 ovarian carcinoma cells via the over-expressed transferrin receptors (TfRs) with R8-mediated intracellular DOX delivery. Flow cytometry analysis with fluorescently labeled DualL (without DOX) showed two-fold higher cancer-cell association than other tre...

Advances in Nanobottles and Active Nanoparticles, 2015

Smart Pharmaceutical Nanocarriers, 2016

Expert opinion on drug delivery, 2016

Recent trends in drug delivery indicate a steady increase in the use of targeted therapeutics to ... more Recent trends in drug delivery indicate a steady increase in the use of targeted therapeutics to enhance the specific delivery of biologically active payloads to diseased tissues while avoiding their off-target effects. However, in most cases, the distribution of therapeutics inside cells and their targeting to intracellular targets still presents a formidable challenge. The main barrier to intracellular delivery is the translocation of therapeutic molecules across the cell membrane, and ultimately through the membrane of their intracellular target organelles. Another prerequisite for an efficient intracellular localization of active molecules is their escape from the endocytic pathway. Pharmaceutical nanocarriers have demonstrated substantial advantages for the delivery of therapeutics and offer elegant platforms for intracellular delivery. They can be engineered with both intracellular and organelle-specific targeting moieties to deliver encapsulated or conjugated cargoes to speci...

Smart Pharmaceutical Nanocarriers, 2016

Fundamentals, Applications and Recent Developments(In 4 Volumes)Volume 1: Materials for NanomedicineVolume 2: Applications in TherapyVolume 3: Applications in DiagnosticsVolume 4: Biology, Safety and Novel Concepts in Nanomedicine, 2014