There is significant clinical interest in synthetic hemostats that can be used in transfusion med... more There is significant clinical interest in synthetic hemostats that can be used in transfusion medicine for management of bleeding complications. To this end, a promising strategy is to design particulate systems with surface functionalities that allow platelet-mimetic biochemical interactions that render hemostatically important cell-cell and cell-matrix interactions. Specifically, platelets render hemostasis by marginating to the injured vascular wall from flowing blood, undergoing adhesion and activation at the injury site by binding to von Willebrand Factor (vWF) and collagen, and subsequently promoting the activation and aggregation of other neighboring platelets at this site. Inspired by these mechanisms, we have fabricated a platelet like nanoparticle (PLN) capable of performing hemostatic functions similar to their natural counterpart. Here, we will discuss the design, synthesis and applications of PLNs, fabricated via layer-by-layer (LbL) assembly, that combine both key biop...
Journal of controlled release : official journal of the Controlled Release Society, Jan 25, 2015
Combinations of topoisomerase inhibitors I and II have been found to synergistically inhibit canc... more Combinations of topoisomerase inhibitors I and II have been found to synergistically inhibit cancer cell growth in vitro, yet clinical studies of these types of combinations have not progressed beyond phase II trials. The results of clinical combinations of topoisomerase (top) I and II inhibitors typically fall within one of two categories: little to no improvement in therapeutic efficacy, or augmented toxicity compared to the single drug counterparts. Hence, despite the promising activity of top I and II inhibitor combinations in vitro, their clinical applicability has not been realized. Here, we report the use of polymer-drug conjugates as a means to co-deliver synergistic doses of top I and II inhibitors camptothecin (CPT) and doxorubicin (DOX) to tumors in vivo in a 4T1 breast cancer model. At specific molar ratios, DOX and CPT were found to be among the most synergistic combinations reported to date, with combination indices between 0.01 and 0.1. The identified optimal ratios w...
Journal of controlled release : official journal of the Controlled Release Society, Jan 10, 2015
Skin penetrating peptides (SPPs) have garnered wide attention in recent years and emerged as a si... more Skin penetrating peptides (SPPs) have garnered wide attention in recent years and emerged as a simple and effective noninvasive strategy for macromolecule delivery into the skin. Although SPPs have demonstrated their potential in enhancing skin delivery, they are still evolving as a new class of skin penetration enhancers. Detailed studies elucidating their mechanisms of action are still lacking. Using five SPPs (SPACE peptide, TD-1, polyarginine, a dermis-localizing peptide and a skin penetrating linear peptide) and a model hydrophobic macromolecule (Cyclosporine A, CsA), herein we provide a mechanistic understanding of SPPs. To evaluate the mechanism and safety of SPPs, their effects on skin lipids, proteins and keratinocyte cells were evaluated. Three SPPs (SPACE, Polyarginine and TD-1) significantly enhanced CsA penetration into the skin. SPPs did not alter the skin lipid barrier as measured by skin resistance, transepidermal water loss (TEWL) and Fourier transform infrared (FTI...
There is significant clinical interest in synthetic hemostats that can be used in transfusion med... more There is significant clinical interest in synthetic hemostats that can be used in transfusion medicine for management of bleeding complications. To this end, a promising strategy is to design particulate systems with surface functionalities that allow platelet-mimetic biochemical interactions that render hemostatically important cell-cell and cell-matrix interactions. Specifically, platelets render hemostasis by marginating to the injured vascular wall from flowing blood, undergoing adhesion and activation at the injury site by binding to von Willebrand Factor (vWF) and collagen, and subsequently promoting the activation and aggregation of other neighboring platelets at this site. Inspired by these mechanisms, we have fabricated a platelet like nanoparticle (PLN) capable of performing hemostatic functions similar to their natural counterpart. Here, we will discuss the design, synthesis and applications of PLNs, fabricated via layer-by-layer (LbL) assembly, that combine both key biop...
Journal of controlled release : official journal of the Controlled Release Society, Jan 25, 2015
Combinations of topoisomerase inhibitors I and II have been found to synergistically inhibit canc... more Combinations of topoisomerase inhibitors I and II have been found to synergistically inhibit cancer cell growth in vitro, yet clinical studies of these types of combinations have not progressed beyond phase II trials. The results of clinical combinations of topoisomerase (top) I and II inhibitors typically fall within one of two categories: little to no improvement in therapeutic efficacy, or augmented toxicity compared to the single drug counterparts. Hence, despite the promising activity of top I and II inhibitor combinations in vitro, their clinical applicability has not been realized. Here, we report the use of polymer-drug conjugates as a means to co-deliver synergistic doses of top I and II inhibitors camptothecin (CPT) and doxorubicin (DOX) to tumors in vivo in a 4T1 breast cancer model. At specific molar ratios, DOX and CPT were found to be among the most synergistic combinations reported to date, with combination indices between 0.01 and 0.1. The identified optimal ratios w...
Journal of controlled release : official journal of the Controlled Release Society, Jan 10, 2015
Skin penetrating peptides (SPPs) have garnered wide attention in recent years and emerged as a si... more Skin penetrating peptides (SPPs) have garnered wide attention in recent years and emerged as a simple and effective noninvasive strategy for macromolecule delivery into the skin. Although SPPs have demonstrated their potential in enhancing skin delivery, they are still evolving as a new class of skin penetration enhancers. Detailed studies elucidating their mechanisms of action are still lacking. Using five SPPs (SPACE peptide, TD-1, polyarginine, a dermis-localizing peptide and a skin penetrating linear peptide) and a model hydrophobic macromolecule (Cyclosporine A, CsA), herein we provide a mechanistic understanding of SPPs. To evaluate the mechanism and safety of SPPs, their effects on skin lipids, proteins and keratinocyte cells were evaluated. Three SPPs (SPACE, Polyarginine and TD-1) significantly enhanced CsA penetration into the skin. SPPs did not alter the skin lipid barrier as measured by skin resistance, transepidermal water loss (TEWL) and Fourier transform infrared (FTI...
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