Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenoty... more Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenotypes. It has been established that pancreatic cancers overexpressing CD44 receptors (a target of hyaluronic acid; HA) is one of the major contributors for causing MDR. Therefore, targeted killing of CD44 expressing tumor cells using HA based active targeting strategies may be beneficial for eradicating MDR-pancreatic cancers. Here, we report the synthesis of a new HA conjugate of copoly(styrene maleic acid) (HA-SMA) that could be engineered to form nanomicelles with a potent anticancer agent, 3,4-difluorobenzylidene curcumin (CDF). The anticancer activity of CDF loaded nanomicelles against MiaPaCa-2 and AsPC-1 human pancreatic cancer cells revealed dose-dependent cell killing. Results of cellular internalization further confirmed better uptake of HA engineered nanomicelles in triple-marker positive (CD44+/CD133+/EpCAM+) pancreatic CSLCs compared with triple-marker negative (CD44-/CD133-/EpCAM-) counterparts. More importantly, HA-SMA-CDF exhibited superior anticancer response toward CD44+ pancreatic CSLCs. Results further confirmed that triple-marker positive cells treated with HA-SMA-CDF caused significant reduction in CD44 expression and marked inhibition of NF-κB that in-turn can mitigate their proliferative and invasive behavior. Conclusively, these results suggest that the newly developed CD44 targeted nanomicelles may have great implications in treating pancreatic cancers including the more aggressive pancreatic CSLCs.
Journal of Biomaterials Science, Polymer Edition, 2015
Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among... more Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among the various cancer types, brain tumors are most life threatening with low survival rate. Every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed. The dendrimeric approaches have a huge potential for diagnosis and treatment of brain tumor with targeting abilities of molecular cargoes to the tumor sites and the efficiency of crossing the blood brain barrier and penetration to brain after systemic administration. The various generations of dendrimers have been designed as novel targeted drug delivery tools for new therapies including sustained drug release, gene therapy, and antiangiogenic activities. At present era, various types of dendrimers like PAMAM, PPI, and PLL dendrimers validated them as milestones for the treatment and diagnosis of brain tumor as well as other cancers. This review highlights the recent research, opportunities, advantages, and challenges involved in development of novel dendrimeric complex for the therapy of brain tumor.
Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeti... more Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 μM), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 ± 1.7%, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25% doxorubicin was released within 24 h at pH 7.4, while more than 30% release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.
In the last two decades, dendrimers have proven their capabilities in drug delivery, physical sta... more In the last two decades, dendrimers have proven their capabilities in drug delivery, physical stabilization of the drug, solubility enhancement of the poorly soluble drugs and gene delivery. Key features of dendrimers like excellent control over molecular structure, nanoscopic size, availability of multiple functional groups at the periphery and narrow polydispersity index distinguish them amongst the available polymers. Diversity of bio-actives loaded in dendrimers due to covalent and non-covalent interactions, such as hydrogen bonding and hydrophobic interaction contribute to the physical forces for binding of bioactives. The key advantage of drug loaded dendrimers is the delayed and sustained release of bioactives because of the encapsulation of the drug in the hydrophobic cavities of the dendrimer that acts as a sink to retain the drug molecules for extended duration. Because of these features researchers are particularly excited about the potential application of dendrimers as ...
In the last couple of decades antioxidant agents have entered the health market as an easy and at... more In the last couple of decades antioxidant agents have entered the health market as an easy and attractive means of managing diseases. These agents are of enormous interest for an increasingly health-concerned society, and may be particularly relevant for prophylaxis of a number of diseases i.e. arthritis, cancer, metabolic and cardiovascular diseases, osteoporosis, cataracts, brain disorders, etc. Antioxidants are also favorable to vascular healthiness and symbolize useful compounds because they are able to diminish overall cardiovascular risk by acting analogous to first line therapy or as adjuvants in case of failure or in situations where first line therapy cannot be used. Furthermore, well-designed trials are indeed needed to improve the therapeutic efficacy and health benefits of antioxidants. Numerous in vivo proof-of-concepts studies are offered to underline the feasibility of nanostructure system in order to optimizing the delivery of cardiovascular drugs. The present review...
Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenoty... more Cancer stem-like cells (CSLCs) play a pivotal role in acquiring multidrug resistant (MDR) phenotypes. It has been established that pancreatic cancers overexpressing CD44 receptors (a target of hyaluronic acid; HA) is one of the major contributors for causing MDR. Therefore, targeted killing of CD44 expressing tumor cells using HA based active targeting strategies may be beneficial for eradicating MDR-pancreatic cancers. Here, we report the synthesis of a new HA conjugate of copoly(styrene maleic acid) (HA-SMA) that could be engineered to form nanomicelles with a potent anticancer agent, 3,4-difluorobenzylidene curcumin (CDF). The anticancer activity of CDF loaded nanomicelles against MiaPaCa-2 and AsPC-1 human pancreatic cancer cells revealed dose-dependent cell killing. Results of cellular internalization further confirmed better uptake of HA engineered nanomicelles in triple-marker positive (CD44+/CD133+/EpCAM+) pancreatic CSLCs compared with triple-marker negative (CD44-/CD133-/EpCAM-) counterparts. More importantly, HA-SMA-CDF exhibited superior anticancer response toward CD44+ pancreatic CSLCs. Results further confirmed that triple-marker positive cells treated with HA-SMA-CDF caused significant reduction in CD44 expression and marked inhibition of NF-κB that in-turn can mitigate their proliferative and invasive behavior. Conclusively, these results suggest that the newly developed CD44 targeted nanomicelles may have great implications in treating pancreatic cancers including the more aggressive pancreatic CSLCs.
Journal of Biomaterials Science, Polymer Edition, 2015
Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among... more Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among the various cancer types, brain tumors are most life threatening with low survival rate. Every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed. The dendrimeric approaches have a huge potential for diagnosis and treatment of brain tumor with targeting abilities of molecular cargoes to the tumor sites and the efficiency of crossing the blood brain barrier and penetration to brain after systemic administration. The various generations of dendrimers have been designed as novel targeted drug delivery tools for new therapies including sustained drug release, gene therapy, and antiangiogenic activities. At present era, various types of dendrimers like PAMAM, PPI, and PLL dendrimers validated them as milestones for the treatment and diagnosis of brain tumor as well as other cancers. This review highlights the recent research, opportunities, advantages, and challenges involved in development of novel dendrimeric complex for the therapy of brain tumor.
Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeti... more Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 μM), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 ± 1.7%, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25% doxorubicin was released within 24 h at pH 7.4, while more than 30% release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.
In the last two decades, dendrimers have proven their capabilities in drug delivery, physical sta... more In the last two decades, dendrimers have proven their capabilities in drug delivery, physical stabilization of the drug, solubility enhancement of the poorly soluble drugs and gene delivery. Key features of dendrimers like excellent control over molecular structure, nanoscopic size, availability of multiple functional groups at the periphery and narrow polydispersity index distinguish them amongst the available polymers. Diversity of bio-actives loaded in dendrimers due to covalent and non-covalent interactions, such as hydrogen bonding and hydrophobic interaction contribute to the physical forces for binding of bioactives. The key advantage of drug loaded dendrimers is the delayed and sustained release of bioactives because of the encapsulation of the drug in the hydrophobic cavities of the dendrimer that acts as a sink to retain the drug molecules for extended duration. Because of these features researchers are particularly excited about the potential application of dendrimers as ...
In the last couple of decades antioxidant agents have entered the health market as an easy and at... more In the last couple of decades antioxidant agents have entered the health market as an easy and attractive means of managing diseases. These agents are of enormous interest for an increasingly health-concerned society, and may be particularly relevant for prophylaxis of a number of diseases i.e. arthritis, cancer, metabolic and cardiovascular diseases, osteoporosis, cataracts, brain disorders, etc. Antioxidants are also favorable to vascular healthiness and symbolize useful compounds because they are able to diminish overall cardiovascular risk by acting analogous to first line therapy or as adjuvants in case of failure or in situations where first line therapy cannot be used. Furthermore, well-designed trials are indeed needed to improve the therapeutic efficacy and health benefits of antioxidants. Numerous in vivo proof-of-concepts studies are offered to underline the feasibility of nanostructure system in order to optimizing the delivery of cardiovascular drugs. The present review...
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Papers by Arun Iyer