Sequentially Site‐Specific Delivery of Apoptotic Protein and Tumor‐Suppressor Gene for Combination Cancer Therapy

Nanocarrier‐mediated codelivery of multiple anticancer drugs is a potential strategy for enhanced efficacy of combination cancer treatment by unifying differential pharmacokinetic properties and maintaining an optimal ratio of drug cargoes. However, a programmable codelivery system is highly desired to deliver different therapeutics to their specific sites of action to pursue maximized combinational effect. Herein a liposome‐based nanoassembly (p53/C‐rNC/L‐FA) is developed for intracellular site‐specific delivery of an apoptotic protein cytochrome c (CytoC) and a plasmid DNA encoding tumor‐suppressing p53 protein (p53 DNA). p53/C‐rNC/L‐FA consists of an acid‐activated fusogenic liposomal membrane shell modified with folic acid (L‐FA) and a DNA/protein complex core assembled by the p53 DNA, protamine and CytoC‐encapsulated redox‐responsive nanocapsule (C‐rNC). Intratumoral and intraendosomal acidities promote membrane fusion between liposome and biomembrane, resulting in release of the encapsulated p53/C‐rNC complex into the cytoplasm. The cytoplasmic reduction causes degradation of C‐rNC with release of CytoC that induces tumor cell apoptosis. The p53 DNA is transported into the nucleus by the aid of the cationic protamine and thus generates expression of the p53 protein that enhances apoptosis combined with CytoC. p53/C‐rNC/L‐FA is demonstrated to significantly induce tumor cell apoptosis and inhibit tumor growth in the orthotopic breast tumor mouse model.     

Self‐Assembly of an Amphiphilic Janus Camptothecin–Floxuridine Conjugate into Liposome‐Like Nanocapsules for More Efficacious Combination Chemotherapy in Cancer

The combination of camptothecin (CPT) and fluoropyrimidine derivatives acts synergistically at a 1:1 molar ratio. Practically, the greatest challenge is the development of a single liposomal formulation that can both encapsulate and maintain this drug combination at an exact 1:1 ratio to achieve coordinated pharmacokinetics. Consequently, a new type of liposome‐like nanocapsule (NC) is developed from a highly symmetric Janus camptothecin–floxuridine conjugate (JCFC) amphiphile, which is synthesized by coupling two hydrophobic CPT molecules and two hydrophilic floxuridine (FUDR) molecules to multivalent pentaerythritol via a hydrolyzable ester linkage. JCFC NCs possess remarkably high drug‐loading contents, and no premature release because of the highly stable co‐delivery of the drug combination without the need for any carrier. It is shown that JCFC NCs consistently provide synergy and avoid antagonism in a broad panel of tumor cell lines. In vivo delivery of JCFC NCs leads to longer blood retention half‐life, higher tumorous accumulation and cellular uptake of drugs, and greatly enhanced efficacy in murine tumor models compared to CPT, FUDR, and CPT + FUDR. This liposomal strategy can be extended to other hydrophilic and hydrophobic anticancer drugs that are coupled to pentaerythritol to self‐assemble into nanocapsules for drug self‐delivery, pointing to potential clinical translation in near future.     

Powell–Sabin B‐splines and unstructured standard T‐splines for the solution of the Kirchhoff–Love plate theory exploiting Bézier extraction

The equations that govern Kirchhoff–Love plate theory are solved using quadratic Powell–Sabin B‐splines and unstructured standard T‐splines. Bézier extraction is exploited to make the formulation computationally efficient. Because quadratic Powell–Sabin B‐splines result in ‐continuous shape functions, they are of sufficiently high continuity to capture Kirchhoff–Love plate theory when cast in a weak form. Unlike non‐uniform rational B‐splines (NURBS), which are commonly used in isogeometric analysis, Powell–Sabin B‐splines do not necessarily capture the geometry exactly. However, the fact that they are defined on triangles instead of on quadrilaterals increases their flexibility in meshing and can make them competitive with respect to NURBS, as no bending strip method for joined NURBS patches is needed. This paper further illustrates how unstructured T‐splines can be modified such that they are ‐continuous around extraordinary points, and that the blending functions fulfil the partition of unity property. The performance of quadratic NURBS, unstructured T‐splines, Powell–Sabin B‐splines and NURBS‐to‐NURPS (non‐uniform rational Powell–Sabin B‐splines, which are obtained by a transformation from a NURBS patch) is compared in a study of a circular plate. Copyright © 2015 John Wiley & Sons, Ltd.