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Aim: To develop delivery systems for efficient siRNA delivery to breast cancer., Methods: Poly(ethylene oxide)-block-poly(ϵ-caprolactone-grafted-spermine) (PEO-b-P(CL-g-SP)) micelles were modified with cholesterol group in their core and with RGD4C peptide on their shell. Transfection efficiency of complexed MCL-1 siRNA in MDA-MB-435 was investigated, in vitro and in vivo following intratumoral and intravenous injection., Results: Cholesteryl modification of the core significantly increased the transfection efficiency of PEO-b-P(CL-g-SP)-complexed siRNA, in vitro, but not following intratumoral or intravenous administration, in vivo. Instead, RGD4C modification of the micellar shell enhanced transfection efficiency of complexed MCL-1 siRNA in tumor upon intravenous administration., Conclusion: RGD4C-PEO-b-P(CL-g-SP) micelles, without or with cholesterol modification, can provide efficient delivery of siRNA to breast tumors following systemic administration.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a major role in the development of resistance to conventional anti-cancer drugs in many types of cancer, when constitutively activated. Inhibition of STAT3 is considered as a promising strategy for inhibition of tumor growth and overcoming the drug resistance manifested. In this study, the capability of STAT3 knockdown by lipid substituted low molecular weight (2 kDa) polyethyleneimine (PEI2) complexes of STAT3-siRNA was assessed. The efficiency of PEI/STAT3-siRNA polyplexes in the induction of STAT3 associated cell death in wild type and drug-resistant MDA-MB-435 breast cancer cells as monotherapy and upon combination with chemotherapeutic agents, doxorubicin and paclitaxel, was also investigated. Our results identified linoleic acid-substituted (PEI-LA) polymer as the most efficient carrier among different lipid substituted PEI2 for siRNA delivery, leading to most STAT3 associated loss of cell viability in MDA-MB-435 cells. STAT3-siRNA delivery by the PEI-LA polymer resulted in efficient down-regulation of STAT3 at both mRNA and protein levels. Furthermore, pre-treatment of cancer cells with STAT3-siRNA formulation increased the cytotoxic effect of doxorubicin and paclitaxel in both wild type and drug resistant MDA-MB-435 cells. The results of this study point to the potential of PEI-LA polyplexes of STAT3-siRNA as inhibitors of STAT3 expression in breast tumor cells. The results also demonstrate an improved efficacy for chemotherapeutic drugs in combination with lipid-substituted low molecular weight PEI-LA/STAT3-siRNA complexes in comparison to drug therapy alone., (© 2013 Wiley Periodicals, Inc.)

The use of nano-delivery systems formed through assembly of synthetic amphiphilic block copolymers (ABCs) in experimental medicine and pharmaceutical sciences is experiencing rapid development. This rapid development is driven by a crucial need in improving the performance of existing therapeutic agents, as well as the necessity for the development of advanced delivery systems for complex new entities such as genes, proteins and other cellular components. The flexibility in the construction of appropriate carriers for the delivery requirements of these complex new "drugs" offered by versatile polymer chemistry provides an undeniable advantage for polymer based nano-delivery systems compared to other colloids in this regard. With seven formulations already in different stages of clinical trials, polymeric micelles are in the front line of drug development among different ABC-based nano-carriers. The success in rapid advancement of polymeric micelles from bench to bedside is owed to the rational engineering of core/shell structure so that the polymeric micellar carrier can meet the requirements for optimum delivery of specific drug(s) in certain disease condition(s). The engineering efforts in this regard have mostly been aimed at providing efficient drug loading, micellar stabilization, and sustained and/or site specific drug release. The objective of this review is to provide an update on different engineering strategies employed to achieve optimum polymeric micellar formulations., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of the study was to develop a polymeric nano-carrier based on methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (MePEO-b-PCL) for the optimum solubilization and delivery of Amphotericin B (AmB). For this purpose, MePEO-b-PCL block co-polymers containing palmitoyl substituent on PCL (at a 100% substitution level) were synthesized through preparation of substituted monomer, that is, alpha-palmitoyl-epsilon-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol(-1)) using stannous octoate as catalyst. Prepared block co-polymers were characterized for their molecular weight by (1)H NMR and gel permeation chromatography, and assembled to polymeric nano-carriers. The self-assembly of synthesized MePEO-b-PPaCL to spherical particles of nanometer size range was shown by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The efficacy of nano-carriers formed from this structure (abbreviated as MePEO-b-PPaCL) in comparison to unmodified MePEO-b-PCL and those with benzyl and cholesteryl substituent on PCL (abbreviated as MePEO-b-PBCL and MePEO-b-PChCL, respectively) on the solubilization and hemolytic activity of AmB against rat red blood cells was assessed. Under identical conditions, the maximum solubilization of AmB was achieved by nano-carriers prepared from MePEO-b-PPaCL (436 microg/mL), followed by MePEO-b-PChCL (355 microg/mL), MePEO-b-PBCL (296 microg/mL) and MePEO-b-PCL (222 microg/mL). The hemolytic activity of AmB was reduced the most by its encapsulation in MePEO-b-PChCL nano-particles which showed only 7% hemolysis at 30 microg/mL AmB concentration. This was followed by MePEO-b-PCL nano-particles which illustrated 15% hemolysis, MePEO-b-PPaCL with 40% hemolysis and MePEO-b-PBCL with 60% hemolysis at 30 microg/mL AmB concentrations, respectively. In contrast Fungizone showed 90% hemolysis at 30 microg/mL AmB concentration. Based on the improved solubility and reduced hemolytic activity, the MePEO-b-PChCL nano-carriers are considered as optimum structures for AmB delivery., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

The aim of this study was to develop methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (MePEO-b-PCL) containing stearyl (St) substituents on PCL, and assess the efficacy of nanocarriers formed from this structure in comparison to unmodified MePEO-b-PCL and those with carboxyl substitutes on PCL on the solubilization and delivery of Amphotericin B (AmB). Prepared block copolymers were characterized for their molecular weight by (1)H NMR and gel permeation chromatography. The self-assembly of synthesized MePEO-b-PStCL to spherical particles of nanometer size range was shown by dynamic light scattering as well as electron and atomic force microscopy. Encapsulated AmB showed a reduction in its hemolytic activity against rat red blood cells in comparison to the commercial formulation of AmB, Fungizone.