Glioblastoma multiforme (GBM) is one of the most aggressive cancers, where the aggressiveness of ... more Glioblastoma multiforme (GBM) is one of the most aggressive cancers, where the aggressiveness of tumor has been associated to its high vascularization rate. Bevacizumab (Avastin®), an anti-angiogenic monoclonal antibody, has been used to decrease the angiogenic profile. To circumvent the blood-brain barrier (BBB) and decrease off-target organ toxicity, bevacizumab-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NP) were developed and intranasally administrated in CD-1 mice to study their pharmacokinetic and pharmacodynamic profile. After 7 days of administration, PLGA NP showed a higher brain bioavailability of bevacizumab when compared to intranasally administrated free bevacizumab. On the other hand, bevacizumab-loaded PLGA NP were able to increase the penetration (higher Cmáx) and the residence time of bevacizumab into the brain (higher Clast). Furthermore, PLGA NP formulation totally prevented bevacizumab systemic exposure. The efficacy of this nanosystem was next evaluated in a validated orthotopic GBM nude mice model, studying the tumor growth over time by bioluminescence and the anti-angiogenic effects. After 14 days, bevacizumab-loaded PLGA NP demonstrated a reduction in the tumor growth accompanied by a higher anti-angiogenic effect compared to the free bevacizumab. These results can be explained by the fact that bevacizumab was found in the brain just for bevacizumab-loaded PLGA NP group, after 14 days of formulation administration. Therefore, we believe that our strategy would be an efficient alternative to improve GBM treatment with high impact for patient life quality and survival.
The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics... more The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics of cyclosporine-A (CsA) following intranasal (IN) administration versus intravenous (IV) administration in Sprague−Dawley rats using an oil-in-water nanoemulsion delivery system. CsA, a hydrophobic peptide that is also a substrate for P-glycoprotein, is a well-known immunosuppressive agent. In the brain, CsA has been shown to be a potent anti-inflammatory and neuroprotective agent. CsA nanoemulsions (CsA-NE) and solution formulations (CsA-S) were prepared using an ultrasonication method and were characterized for drug content, encapsulation efficiency, globule size, and zeta potential. We compared the uptake of CsA-NE and CsA-S in brain regions and peripheral organs following IN and IV administration using LC-MS/MS based bioanalytical method. CsA-NE IN resulted in the highest accumulation compared to that with any other treatment and route of administration; this was consistent for all three regions of brain that were evaluated (olfactory bulbs, mid brain, and hind brain). The brain/blood exposure ratios of 4.49, 0.01, 0.33, and 0.03 for CsA-NE (IN), CsA-NE (IV), CsA-S (IN), and CsA-S (IV), respectively, indicated that CsA-NE is capable of direct nose-to-brain transport, bypassing the blood− brain barrier. Furthermore, CsA-NE administration reduces nontarget organ exposure. These studies show that IN delivery of CsA-NE is an effective way of brain targeting compared to that of other treatment strategies. This approach not only enhances the brain concentration of the peptide but also significantly limits peripheral exposure and the potential for off-target toxicity.
In this study, we have investigated the biodistribution and pharmacokinetic analysis of paclitaxe... more In this study, we have investigated the biodistribution and pharmacokinetic analysis of paclitaxel (PTX) and the apoptotic signaling molecule, C 6-ceramide (CER), when administered in a multifunctional polymer-blend nanoparticle formulation to female nude mice bearing an orthotopic drug sensitive MCF7 and multidrug resistant MCF7 TR (MDR-1 positive) human breast adenocarcinoma. A polymer-blend nanoparticle system was engineered to incorporate temporally controlled sequential release of the combination drug payload. Hereby, PTX was encapsulated in the pH-responsive rapid releasing polymer, poly(beta-amino ester) (PbAE), while CER was present in the slow releasing polymer, poly(D,L-lactide-co-glycolide) (PLGA) within these blend nanoparticles. When particle formulations were administered intravenously to MCF7 and MCF7 TR tumor bearing mice, higher concentrations of PTX were found in the blood due to longer retention time and an enhanced tumor accumulation relative to administration of free drug. In addition, the PLGA/PbAE blend nanoparticles were effective in enhancing the residence time of both drugs at the tumor site by reducing systemic clearance. Overall, these results are highly encouraging for development of multifunctional polymer-blend nanoparticle formulations that can be used for temporal-controlled administration of two drugs from a single formulation.
The primary objective of this study was to compare the biodistribution and pharmacokinetic profil... more The primary objective of this study was to compare the biodistribution and pharmacokinetic profile of 17-β-estradiol (17-βE) on systemic delivery using either the cationic or the CREKA-peptide-modified (Cysteine-Arginine-Glutamic-acid-Lysine-Alanine) omega-3-fatty acid oil containing nanoemulsion system in vivo in the wild type C57BL/6 mice. Higher blood concentrations of 17-βE, higher accumulation in the tissues of interest - heart and aorta, and higher accumulation within the other tissues - liver and kidney was observed on delivering 17-βE using the CREKA-peptide-modified nanoemulsion system (AUClast in plasma - 263.89±21.81min*%/injected dose/ml) as compared to the cationic nanoemulsion (AUClast in plasma - 20.2±1.86min*%/injected dose/ml) and solution form (AUClast in plasma - 44.9±1.24min*%/injected dose/ml) respectively. Both, the cationic nanoemulsion and the CREKA-peptide-modified nanoemulsion showed a higher relative targeting efficiency of 4.57 and 4.86 respectively for 17-βE than the relative targeting efficiency of 1.78 observed with the solution form. In conclusion, since the maximum exposure (highest AUClast for plasma and tissues) for 17-βE was observed with the CREKA-peptide-modified nanoemulsion system, the study shows that CREKA-peptide-modified nanoemulsion system was the most suitable vehicle for systemic delivery of 17-βE in the wild type C57BL/6 mice.
The clinical significance of Cluster of Differentiation 44 (CD44) remains controversial in human ... more The clinical significance of Cluster of Differentiation 44 (CD44) remains controversial in human ovarian cancer. The aim of this study is to evaluate the clinical significance of CD44 expression by using a unique tissue microarray, and then to determine the biological functions of CD44 in ovarian cancer. In this study, a unique ovarian cancer tissue microarray (TMA) was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. CD44 expression in TMA was assessed by immunohistochemistry. Both the metastatic and recurrent ovarian cancer tissues expressed higher level of CD44 than the patient-matched primary tumor. A significant association has been shown between CD44 expression and both the disease free survival and overall survival. A strong increase of CD44 was found in the tumor recurrence of mouse model. Finally, when CD44 was knocked down, proliferation, migration/invasion activity, and spheroid formation were significantly suppressed, while drug sensitivity was enhanced. Thus, up-regulation of CD44 represents a crucial event in the development of metastasis, recurrence, and drug resistance to current treatments in ovarian cancer. Developing strategies to target CD44 may prevent metastasis, recurrence, and drug resistance in ovarian cancer.
macrophage re-polarization from predom - inant M2 to M1 phenotype can be an effective approach to... more macrophage re-polarization from predom - inant M2 to M1 phenotype can be an effective approach to achieve anti-tumor immunity and therapeutic response. Ho - lographic time-lapse imaging cytometer HoloMonitor® M4 (Phase Holographic Imaging, Sweden) was used to assess the efficacy of reprogramming M2 polarized macrophages to a M1 polarized state in a macrophage-tumor co-culture system. Also, the miR-155 polarized macrophages were seen to cause tumor cells morphological changes suggesting cell death after co-culture indicating potential anti-tumor activity. INTRODUCTIONare one of the important micro-environmental components of solid tumors, whose polarization to M2 phe - notype aids in regulation of all steps of tumor pathogenesis 1 . Thus prevention of these pro-tumoral macrophage functions can be an important strategy to attain anti-tumor activity. Out of many approaches available, the phenotypic reprogram- ming or repolarization to the anti-tumoral M1 state is a prom - ising approac...
In the version of this Correspondence originally published, Christine Dufès was incorrectly writt... more In the version of this Correspondence originally published, Christine Dufès was incorrectly written as Christine Dufés. This has been corrected in the online versions of the Correspondence.
On the issue of transparency and reproducibility in nanomedicine Following our call to join in th... more On the issue of transparency and reproducibility in nanomedicine Following our call to join in the discussion over the suitability of implementing a reporting checklist for bio-nano papers, the community responds. Below we report short extracts highlighting the main messages of the correspondences we received. The interested readers can find the complete pieces in the accompanying Supplementary Information.
Endothelial dysfunction has been implicated in the pathophysiology of multiple cardiovascular dis... more Endothelial dysfunction has been implicated in the pathophysiology of multiple cardiovascular diseases and involves components of both innate and acquired immune mechanisms. Identifying signature patterns and targets associated with endothelial dysfunction can help in the development of novel nanotherapeutic platforms for treatment of vascular diseases. This review discusses nucleic acid-based regulation of endothelial function and the different nucleic acid-based nanotherapeutic approaches designed to target endothelial dysfunction in cardiovascular disorders.
Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emerg... more Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emergence of inherent and acquired drug resistance in cancer cells. As a common strategy to overcome drug resistance, higher doses of chemo-agents are administered. However, adverse side effects are usually increased as a consequence. A potentially effective approach is to combine chemotherapy with other therapeutic strategies such as small interfering RNAs (siRNAs) that allow the use of lower yet efficient doses of the anticancer drugs. We previously developed epidermal growth factor receptor (EGFR)-targeted chitosan (CS) nanoparticles as a versatile delivery system for silencing the essential mitotic checkpoint gene Mad2, and induce cell death. Here, we tested this system as a single therapy and in combination with cisplatin in cisplatin sensitive and resistant lung cancer models, and characterized its in vivo efficacy and safety.
Nanomedicine: Nanotechnology, Biology and Medicine, 2016
Neuroinflammation is a hallmark of acute and chronic neurodegenerative disorders. Activated micro... more Neuroinflammation is a hallmark of acute and chronic neurodegenerative disorders. Activated microglia and secreted factors such as tumor necrosis factor-alpha (TNFα) are key mediators of neuroinflammation and may contribute to neuronal dysfunction. The main aim of this study was to evaluate the therapeutic efficacy of intranasal cationic nanoemulsions encapsulating an anti-TNFα siRNA, for potential anti-inflammatory therapy, tested in an LPS induced model of neuroinflammation. The strategy of developing a cationic nanoemulsion system for silencing the TNFα gene was to efficiently provide neuroprotection against inflammation. TNFα siRNA nanoemulsions were prepared and characterized for particle size, surface charge, morphology, and stability and encapsulation efficiency. Qualitative and quantitative intracellular uptake studies by confocal imaging and flow cytometry, respectively, showed higher uptake compared to Lipofectamine ® transfected siRNA. Nanoemulsions showed significantly lower (p<0.01) levels of TNFα in LPS-stimulated cells. Upon intranasal delivery of cationic nanoemulsions almost 5 fold higher uptake was observed in the rat brain compared to non-encapsulated siRNA. More importantly, intranasal delivery of TNFα siRNA nanoemulsions in vivo markedly reduced the unregulated levels of TNFα in an LPS-induced model of neuroinflammation where TNFα functions as a signaling molecule, which aggravates inflammation. These results indicate that intranasal delivery of cationic nanoemulsions encapsulating TNFα siRNA offered an efficient means of gene knockdown and this approach has significant potential in prevention of neuroinflammation.
Introduction: Macrophages perform a wide range of tasks, including bacterial suppression, tumor s... more Introduction: Macrophages perform a wide range of tasks, including bacterial suppression, tumor suppression, immune-stimulation, tissue repair, angiogenesis, and cellular debris phagocytosis Behavior is controlled by a large number of chemo-stimulants, and broadly are classified into two polarization groups, M1 (classically activated, pro-inflammatory) and M2 (alternatively activated, anti-inflammatory). Understanding the macrophage phenotype is essential in the development of pharmacological agents designed to influence macrophage behavior. Due to the plethora of macrophage stimulants, it is desirable to do analysis under label-free conditions. Materials and Methods: The murine macrophage cell line, J774A.1 was analyzed untreated (M0), stimulated with LPS to drive M1, and stimulated with IL-4 to drive M2. Efficacy of the stimulations was monitored by PCR analysis of the expression levels of iNOS and TNF-Alpha (up-regulated in the M1 state) and Arginase-1 and IL-10 (up-regulated in ...
Nanotechnology platforms have emerged as versatile carrier systems for delivery of active molecul... more Nanotechnology platforms have emerged as versatile carrier systems for delivery of active molecules to tumors. Nanoparticle-based formulations have demonstrated enhanced efficacy and decreased toxicity in comparison to conventional drugs. These carrier systems often encounter rapid uptake by phagocytic cells of the reticuloendothelial system (RES), which is a major obstacle to tumor accumulation. Experimental models are required that can predict RES sequestration, and allow for optimization of nanoparticle properties, such as size, surface charge, and PEGylation.
To increase the flexibility of surface-attached bio-relevant ligands on gold nanoparticle (NP), h... more To increase the flexibility of surface-attached bio-relevant ligands on gold nanoparticle (NP), hetero-bifunctional poly(ethylene glycol) (PEG), was synthesized having two different functional groups on both the terminals. Coumarin was conjugated to the gold NP through the PEG spacer. The results of cellular cytotoxicity and fluorescence microscopy showed that these NPs were non-toxic and could be internalized in the cells within one hour of incubation.
Iron oxide nanoparticles are used for contrast enhancement in magnetic resonance imaging (MRI). W... more Iron oxide nanoparticles are used for contrast enhancement in magnetic resonance imaging (MRI). We have prepared gold-coated iron oxide nanoparticles that show no change in their superparamagnetic behavior as a consequence of coating. Their potential use as MRI contrast agents was investigated by monitoring their T2 relaxation time with concentration. Cytotoxicity of these nanoparticles was also studied. The results of these studies are presented.
Chronic wounds are characterized by impaired healing and uncontrolled inflammation, which comprom... more Chronic wounds are characterized by impaired healing and uncontrolled inflammation, which compromise the protective role of the immune system and may lead to bacterial infection. Upregulation of miR‐223 microRNAs (miRNAs) shows driving of the polarization of macrophages toward the anti‐inflammatory (M2) phenotype, which could aid in the acceleration of wound healing. However, local‐targeted delivery of microRNAs is still challenging, due to their low stability. Here, adhesive hydrogels containing miR‐223 5p mimic (miR‐223*) loaded hyaluronic acid nanoparticles are developed to control tissue macrophages polarization during wound healing processes. In vitro upregulation of miR‐223* in J774A.1 macrophages demonstrates increased expression of the anti‐inflammatory gene Arg‐1 and a decrease in proinflammatory markers, including TNF‐α, IL‐1β, and IL‐6. The therapeutic potential of miR‐223* loaded adhesive hydrogels is also evaluated in vivo. The adhesive hydrogels could adhere to and cov...
The development of new vaccine adjuvants represents a key approach to improvingi the immune respo... more The development of new vaccine adjuvants represents a key approach to improvingi the immune responses to recombinant vaccine antigens. Emulsion adjuvants, such as AS03 and MF59, in combination with influenza vaccines, have allowed antigen dose sparing, greater breadth of responses and fewer immunizations. It has been demonstrated previously that emulsion adjuvants can be prepared using a simple, low-shear process of self-emulsification (SE). The role of alpha tocopherol as an immune potentiator in emulsion adjuvants is clear from the success of AS03 in pandemic responses, both to influenza and COVID-19. Although it was a significant formulation challenge to include alpha tocopherol in an emulsion prepared by a low-shear process, the resultant self-emulsifying adjuvant system (SE-AS) showed a comparable effect to the established AS03 when used with a quadrivalent influenza vaccine (QIV). In this paper, we first optimized the SE-AS with alpha tocopherol to create SE-AS44, which allowe...
Epidermal growth factor (EGF) is required for various regulations of skin tissue, including wound... more Epidermal growth factor (EGF) is required for various regulations of skin tissue, including wound healing; however, it has limited stability due to the physicochemical conditions of the wound milieu.
Despite wide recognition as a disease of pandemic proportions, effective treatments for nonalcoho... more Despite wide recognition as a disease of pandemic proportions, effective treatments for nonalcoholic fatty liver disease (NAFLD) remain elusive. Most of the current clinical programs aim to reduce hepatic fat accumulation and, thus, prevent downstream inflammation and fibrosis. To date, this therapeutic approach has helped identify a potential disconnect between steatosis reduction and disease resolution. Mounting preclinical evidence indicates liver inflammation may play a major role in steatosis development and fibrosis but has not garnered the same clinical representation. This may be owing to deficiencies in standard therapeutic modalities that limit their application in NAFLD. RNA interference (RNAi) is an attractive approach to targeting liver inflammation owing to its clinical safety profile, target specificity, and limited biodistribution. In this study, we characterize a simple cholesterol-short-interfering RNA (siRNA) conjugate system targeting Tnf mRNA in liver macrophages for the treatment of NAFLD. First, we observed delivery and anti-inflammatory activity in an acute liver inflammation model. In a follow-up murine NAFLD model, we observed total prevention of nearly all hallmarks of this disease: steatosis, inflammation, and fibrosis. This simple conjugate siRNA delivery system may be the first to show RNAi activity in liver macrophages and provide evidence for a novel therapeutic approach to inflammation in NAFLD.
Upon systemic administration, nanoparticles encounter serum proteins in the biological system res... more Upon systemic administration, nanoparticles encounter serum proteins in the biological system resulting in the formation of "protein corona" on the surface. Increased understanding of the relationship between nanoparticles' "chemical identity" and "biological identity" can contribute to improved clinical translation. Recent studies of protein corona composition on nanoparticles, including from our group, suggest that a strategic choice of materials can influence the types of protein adsorbed from plasma and lead to improved delivery efficiency. This mini-review reflects on the fundamental knowledge of nanoparticle protein corona and highlights the recent applications of protein corona on nanoparticles' systemic circulation, cell, and tissue-specific delivery. Important considerations on the safety and efficacy aspects pertaining to the exploration of nanoparticle protein corona's targeting effect are also summarized. Finally, the future perspectives of protein corona research are discussed.
Glioblastoma multiforme (GBM) is one of the most aggressive cancers, where the aggressiveness of ... more Glioblastoma multiforme (GBM) is one of the most aggressive cancers, where the aggressiveness of tumor has been associated to its high vascularization rate. Bevacizumab (Avastin®), an anti-angiogenic monoclonal antibody, has been used to decrease the angiogenic profile. To circumvent the blood-brain barrier (BBB) and decrease off-target organ toxicity, bevacizumab-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NP) were developed and intranasally administrated in CD-1 mice to study their pharmacokinetic and pharmacodynamic profile. After 7 days of administration, PLGA NP showed a higher brain bioavailability of bevacizumab when compared to intranasally administrated free bevacizumab. On the other hand, bevacizumab-loaded PLGA NP were able to increase the penetration (higher Cmáx) and the residence time of bevacizumab into the brain (higher Clast). Furthermore, PLGA NP formulation totally prevented bevacizumab systemic exposure. The efficacy of this nanosystem was next evaluated in a validated orthotopic GBM nude mice model, studying the tumor growth over time by bioluminescence and the anti-angiogenic effects. After 14 days, bevacizumab-loaded PLGA NP demonstrated a reduction in the tumor growth accompanied by a higher anti-angiogenic effect compared to the free bevacizumab. These results can be explained by the fact that bevacizumab was found in the brain just for bevacizumab-loaded PLGA NP group, after 14 days of formulation administration. Therefore, we believe that our strategy would be an efficient alternative to improve GBM treatment with high impact for patient life quality and survival.
The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics... more The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics of cyclosporine-A (CsA) following intranasal (IN) administration versus intravenous (IV) administration in Sprague−Dawley rats using an oil-in-water nanoemulsion delivery system. CsA, a hydrophobic peptide that is also a substrate for P-glycoprotein, is a well-known immunosuppressive agent. In the brain, CsA has been shown to be a potent anti-inflammatory and neuroprotective agent. CsA nanoemulsions (CsA-NE) and solution formulations (CsA-S) were prepared using an ultrasonication method and were characterized for drug content, encapsulation efficiency, globule size, and zeta potential. We compared the uptake of CsA-NE and CsA-S in brain regions and peripheral organs following IN and IV administration using LC-MS/MS based bioanalytical method. CsA-NE IN resulted in the highest accumulation compared to that with any other treatment and route of administration; this was consistent for all three regions of brain that were evaluated (olfactory bulbs, mid brain, and hind brain). The brain/blood exposure ratios of 4.49, 0.01, 0.33, and 0.03 for CsA-NE (IN), CsA-NE (IV), CsA-S (IN), and CsA-S (IV), respectively, indicated that CsA-NE is capable of direct nose-to-brain transport, bypassing the blood− brain barrier. Furthermore, CsA-NE administration reduces nontarget organ exposure. These studies show that IN delivery of CsA-NE is an effective way of brain targeting compared to that of other treatment strategies. This approach not only enhances the brain concentration of the peptide but also significantly limits peripheral exposure and the potential for off-target toxicity.
In this study, we have investigated the biodistribution and pharmacokinetic analysis of paclitaxe... more In this study, we have investigated the biodistribution and pharmacokinetic analysis of paclitaxel (PTX) and the apoptotic signaling molecule, C 6-ceramide (CER), when administered in a multifunctional polymer-blend nanoparticle formulation to female nude mice bearing an orthotopic drug sensitive MCF7 and multidrug resistant MCF7 TR (MDR-1 positive) human breast adenocarcinoma. A polymer-blend nanoparticle system was engineered to incorporate temporally controlled sequential release of the combination drug payload. Hereby, PTX was encapsulated in the pH-responsive rapid releasing polymer, poly(beta-amino ester) (PbAE), while CER was present in the slow releasing polymer, poly(D,L-lactide-co-glycolide) (PLGA) within these blend nanoparticles. When particle formulations were administered intravenously to MCF7 and MCF7 TR tumor bearing mice, higher concentrations of PTX were found in the blood due to longer retention time and an enhanced tumor accumulation relative to administration of free drug. In addition, the PLGA/PbAE blend nanoparticles were effective in enhancing the residence time of both drugs at the tumor site by reducing systemic clearance. Overall, these results are highly encouraging for development of multifunctional polymer-blend nanoparticle formulations that can be used for temporal-controlled administration of two drugs from a single formulation.
The primary objective of this study was to compare the biodistribution and pharmacokinetic profil... more The primary objective of this study was to compare the biodistribution and pharmacokinetic profile of 17-β-estradiol (17-βE) on systemic delivery using either the cationic or the CREKA-peptide-modified (Cysteine-Arginine-Glutamic-acid-Lysine-Alanine) omega-3-fatty acid oil containing nanoemulsion system in vivo in the wild type C57BL/6 mice. Higher blood concentrations of 17-βE, higher accumulation in the tissues of interest - heart and aorta, and higher accumulation within the other tissues - liver and kidney was observed on delivering 17-βE using the CREKA-peptide-modified nanoemulsion system (AUClast in plasma - 263.89±21.81min*%/injected dose/ml) as compared to the cationic nanoemulsion (AUClast in plasma - 20.2±1.86min*%/injected dose/ml) and solution form (AUClast in plasma - 44.9±1.24min*%/injected dose/ml) respectively. Both, the cationic nanoemulsion and the CREKA-peptide-modified nanoemulsion showed a higher relative targeting efficiency of 4.57 and 4.86 respectively for 17-βE than the relative targeting efficiency of 1.78 observed with the solution form. In conclusion, since the maximum exposure (highest AUClast for plasma and tissues) for 17-βE was observed with the CREKA-peptide-modified nanoemulsion system, the study shows that CREKA-peptide-modified nanoemulsion system was the most suitable vehicle for systemic delivery of 17-βE in the wild type C57BL/6 mice.
The clinical significance of Cluster of Differentiation 44 (CD44) remains controversial in human ... more The clinical significance of Cluster of Differentiation 44 (CD44) remains controversial in human ovarian cancer. The aim of this study is to evaluate the clinical significance of CD44 expression by using a unique tissue microarray, and then to determine the biological functions of CD44 in ovarian cancer. In this study, a unique ovarian cancer tissue microarray (TMA) was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. CD44 expression in TMA was assessed by immunohistochemistry. Both the metastatic and recurrent ovarian cancer tissues expressed higher level of CD44 than the patient-matched primary tumor. A significant association has been shown between CD44 expression and both the disease free survival and overall survival. A strong increase of CD44 was found in the tumor recurrence of mouse model. Finally, when CD44 was knocked down, proliferation, migration/invasion activity, and spheroid formation were significantly suppressed, while drug sensitivity was enhanced. Thus, up-regulation of CD44 represents a crucial event in the development of metastasis, recurrence, and drug resistance to current treatments in ovarian cancer. Developing strategies to target CD44 may prevent metastasis, recurrence, and drug resistance in ovarian cancer.
macrophage re-polarization from predom - inant M2 to M1 phenotype can be an effective approach to... more macrophage re-polarization from predom - inant M2 to M1 phenotype can be an effective approach to achieve anti-tumor immunity and therapeutic response. Ho - lographic time-lapse imaging cytometer HoloMonitor® M4 (Phase Holographic Imaging, Sweden) was used to assess the efficacy of reprogramming M2 polarized macrophages to a M1 polarized state in a macrophage-tumor co-culture system. Also, the miR-155 polarized macrophages were seen to cause tumor cells morphological changes suggesting cell death after co-culture indicating potential anti-tumor activity. INTRODUCTIONare one of the important micro-environmental components of solid tumors, whose polarization to M2 phe - notype aids in regulation of all steps of tumor pathogenesis 1 . Thus prevention of these pro-tumoral macrophage functions can be an important strategy to attain anti-tumor activity. Out of many approaches available, the phenotypic reprogram- ming or repolarization to the anti-tumoral M1 state is a prom - ising approac...
In the version of this Correspondence originally published, Christine Dufès was incorrectly writt... more In the version of this Correspondence originally published, Christine Dufès was incorrectly written as Christine Dufés. This has been corrected in the online versions of the Correspondence.
On the issue of transparency and reproducibility in nanomedicine Following our call to join in th... more On the issue of transparency and reproducibility in nanomedicine Following our call to join in the discussion over the suitability of implementing a reporting checklist for bio-nano papers, the community responds. Below we report short extracts highlighting the main messages of the correspondences we received. The interested readers can find the complete pieces in the accompanying Supplementary Information.
Endothelial dysfunction has been implicated in the pathophysiology of multiple cardiovascular dis... more Endothelial dysfunction has been implicated in the pathophysiology of multiple cardiovascular diseases and involves components of both innate and acquired immune mechanisms. Identifying signature patterns and targets associated with endothelial dysfunction can help in the development of novel nanotherapeutic platforms for treatment of vascular diseases. This review discusses nucleic acid-based regulation of endothelial function and the different nucleic acid-based nanotherapeutic approaches designed to target endothelial dysfunction in cardiovascular disorders.
Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emerg... more Efficiency of chemotherapy is often limited by low therapeutic index of the drug as well as emergence of inherent and acquired drug resistance in cancer cells. As a common strategy to overcome drug resistance, higher doses of chemo-agents are administered. However, adverse side effects are usually increased as a consequence. A potentially effective approach is to combine chemotherapy with other therapeutic strategies such as small interfering RNAs (siRNAs) that allow the use of lower yet efficient doses of the anticancer drugs. We previously developed epidermal growth factor receptor (EGFR)-targeted chitosan (CS) nanoparticles as a versatile delivery system for silencing the essential mitotic checkpoint gene Mad2, and induce cell death. Here, we tested this system as a single therapy and in combination with cisplatin in cisplatin sensitive and resistant lung cancer models, and characterized its in vivo efficacy and safety.
Nanomedicine: Nanotechnology, Biology and Medicine, 2016
Neuroinflammation is a hallmark of acute and chronic neurodegenerative disorders. Activated micro... more Neuroinflammation is a hallmark of acute and chronic neurodegenerative disorders. Activated microglia and secreted factors such as tumor necrosis factor-alpha (TNFα) are key mediators of neuroinflammation and may contribute to neuronal dysfunction. The main aim of this study was to evaluate the therapeutic efficacy of intranasal cationic nanoemulsions encapsulating an anti-TNFα siRNA, for potential anti-inflammatory therapy, tested in an LPS induced model of neuroinflammation. The strategy of developing a cationic nanoemulsion system for silencing the TNFα gene was to efficiently provide neuroprotection against inflammation. TNFα siRNA nanoemulsions were prepared and characterized for particle size, surface charge, morphology, and stability and encapsulation efficiency. Qualitative and quantitative intracellular uptake studies by confocal imaging and flow cytometry, respectively, showed higher uptake compared to Lipofectamine ® transfected siRNA. Nanoemulsions showed significantly lower (p<0.01) levels of TNFα in LPS-stimulated cells. Upon intranasal delivery of cationic nanoemulsions almost 5 fold higher uptake was observed in the rat brain compared to non-encapsulated siRNA. More importantly, intranasal delivery of TNFα siRNA nanoemulsions in vivo markedly reduced the unregulated levels of TNFα in an LPS-induced model of neuroinflammation where TNFα functions as a signaling molecule, which aggravates inflammation. These results indicate that intranasal delivery of cationic nanoemulsions encapsulating TNFα siRNA offered an efficient means of gene knockdown and this approach has significant potential in prevention of neuroinflammation.
Introduction: Macrophages perform a wide range of tasks, including bacterial suppression, tumor s... more Introduction: Macrophages perform a wide range of tasks, including bacterial suppression, tumor suppression, immune-stimulation, tissue repair, angiogenesis, and cellular debris phagocytosis Behavior is controlled by a large number of chemo-stimulants, and broadly are classified into two polarization groups, M1 (classically activated, pro-inflammatory) and M2 (alternatively activated, anti-inflammatory). Understanding the macrophage phenotype is essential in the development of pharmacological agents designed to influence macrophage behavior. Due to the plethora of macrophage stimulants, it is desirable to do analysis under label-free conditions. Materials and Methods: The murine macrophage cell line, J774A.1 was analyzed untreated (M0), stimulated with LPS to drive M1, and stimulated with IL-4 to drive M2. Efficacy of the stimulations was monitored by PCR analysis of the expression levels of iNOS and TNF-Alpha (up-regulated in the M1 state) and Arginase-1 and IL-10 (up-regulated in ...
Nanotechnology platforms have emerged as versatile carrier systems for delivery of active molecul... more Nanotechnology platforms have emerged as versatile carrier systems for delivery of active molecules to tumors. Nanoparticle-based formulations have demonstrated enhanced efficacy and decreased toxicity in comparison to conventional drugs. These carrier systems often encounter rapid uptake by phagocytic cells of the reticuloendothelial system (RES), which is a major obstacle to tumor accumulation. Experimental models are required that can predict RES sequestration, and allow for optimization of nanoparticle properties, such as size, surface charge, and PEGylation.
To increase the flexibility of surface-attached bio-relevant ligands on gold nanoparticle (NP), h... more To increase the flexibility of surface-attached bio-relevant ligands on gold nanoparticle (NP), hetero-bifunctional poly(ethylene glycol) (PEG), was synthesized having two different functional groups on both the terminals. Coumarin was conjugated to the gold NP through the PEG spacer. The results of cellular cytotoxicity and fluorescence microscopy showed that these NPs were non-toxic and could be internalized in the cells within one hour of incubation.
Iron oxide nanoparticles are used for contrast enhancement in magnetic resonance imaging (MRI). W... more Iron oxide nanoparticles are used for contrast enhancement in magnetic resonance imaging (MRI). We have prepared gold-coated iron oxide nanoparticles that show no change in their superparamagnetic behavior as a consequence of coating. Their potential use as MRI contrast agents was investigated by monitoring their T2 relaxation time with concentration. Cytotoxicity of these nanoparticles was also studied. The results of these studies are presented.
Chronic wounds are characterized by impaired healing and uncontrolled inflammation, which comprom... more Chronic wounds are characterized by impaired healing and uncontrolled inflammation, which compromise the protective role of the immune system and may lead to bacterial infection. Upregulation of miR‐223 microRNAs (miRNAs) shows driving of the polarization of macrophages toward the anti‐inflammatory (M2) phenotype, which could aid in the acceleration of wound healing. However, local‐targeted delivery of microRNAs is still challenging, due to their low stability. Here, adhesive hydrogels containing miR‐223 5p mimic (miR‐223*) loaded hyaluronic acid nanoparticles are developed to control tissue macrophages polarization during wound healing processes. In vitro upregulation of miR‐223* in J774A.1 macrophages demonstrates increased expression of the anti‐inflammatory gene Arg‐1 and a decrease in proinflammatory markers, including TNF‐α, IL‐1β, and IL‐6. The therapeutic potential of miR‐223* loaded adhesive hydrogels is also evaluated in vivo. The adhesive hydrogels could adhere to and cov...
The development of new vaccine adjuvants represents a key approach to improvingi the immune respo... more The development of new vaccine adjuvants represents a key approach to improvingi the immune responses to recombinant vaccine antigens. Emulsion adjuvants, such as AS03 and MF59, in combination with influenza vaccines, have allowed antigen dose sparing, greater breadth of responses and fewer immunizations. It has been demonstrated previously that emulsion adjuvants can be prepared using a simple, low-shear process of self-emulsification (SE). The role of alpha tocopherol as an immune potentiator in emulsion adjuvants is clear from the success of AS03 in pandemic responses, both to influenza and COVID-19. Although it was a significant formulation challenge to include alpha tocopherol in an emulsion prepared by a low-shear process, the resultant self-emulsifying adjuvant system (SE-AS) showed a comparable effect to the established AS03 when used with a quadrivalent influenza vaccine (QIV). In this paper, we first optimized the SE-AS with alpha tocopherol to create SE-AS44, which allowe...
Epidermal growth factor (EGF) is required for various regulations of skin tissue, including wound... more Epidermal growth factor (EGF) is required for various regulations of skin tissue, including wound healing; however, it has limited stability due to the physicochemical conditions of the wound milieu.
Despite wide recognition as a disease of pandemic proportions, effective treatments for nonalcoho... more Despite wide recognition as a disease of pandemic proportions, effective treatments for nonalcoholic fatty liver disease (NAFLD) remain elusive. Most of the current clinical programs aim to reduce hepatic fat accumulation and, thus, prevent downstream inflammation and fibrosis. To date, this therapeutic approach has helped identify a potential disconnect between steatosis reduction and disease resolution. Mounting preclinical evidence indicates liver inflammation may play a major role in steatosis development and fibrosis but has not garnered the same clinical representation. This may be owing to deficiencies in standard therapeutic modalities that limit their application in NAFLD. RNA interference (RNAi) is an attractive approach to targeting liver inflammation owing to its clinical safety profile, target specificity, and limited biodistribution. In this study, we characterize a simple cholesterol-short-interfering RNA (siRNA) conjugate system targeting Tnf mRNA in liver macrophages for the treatment of NAFLD. First, we observed delivery and anti-inflammatory activity in an acute liver inflammation model. In a follow-up murine NAFLD model, we observed total prevention of nearly all hallmarks of this disease: steatosis, inflammation, and fibrosis. This simple conjugate siRNA delivery system may be the first to show RNAi activity in liver macrophages and provide evidence for a novel therapeutic approach to inflammation in NAFLD.
Upon systemic administration, nanoparticles encounter serum proteins in the biological system res... more Upon systemic administration, nanoparticles encounter serum proteins in the biological system resulting in the formation of "protein corona" on the surface. Increased understanding of the relationship between nanoparticles' "chemical identity" and "biological identity" can contribute to improved clinical translation. Recent studies of protein corona composition on nanoparticles, including from our group, suggest that a strategic choice of materials can influence the types of protein adsorbed from plasma and lead to improved delivery efficiency. This mini-review reflects on the fundamental knowledge of nanoparticle protein corona and highlights the recent applications of protein corona on nanoparticles' systemic circulation, cell, and tissue-specific delivery. Important considerations on the safety and efficacy aspects pertaining to the exploration of nanoparticle protein corona's targeting effect are also summarized. Finally, the future perspectives of protein corona research are discussed.
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Papers by Mansoor Amiji