No abstract

Abstract. Schroeder A, Levins CG, Cortez C, Langer R, Anderson DG (Massachusetts Institute of Technology, Cambridge, MA, USA). Lipid-based nanotherapeutics for siRNA delivery (Review). J Intern Med 2010; 267: 9-21.RNA interference (RNAi) is a specific gene-silencing mechanism triggered by small interfering RNA (siR-NA). The application of RNAi in the clinic requires the development of safe and effective delivery systems. Inspired by progress with lipid-based systems in drug delivery, efforts have been dedicated to the development of liposomal siRNA delivery systems. Many of the lipid-based delivery vehicles self-assemble with siRNA through electrostatic interactions with charged amines, generating multi-lamellar lipoplexes with positively charged lipid bilayers separated from one another by sheets of negatively charged siRNA strands. Internalization of lipid-based siRNA delivery systems into cells typically occurs through endocytosis; accordingly, delivery requires materials that can facilitate endosomal escape. The size of the carrier is important as carriers <100 nm in diameter have been reported to have higher accumulation levels in tumours, hepatocytes and inflamed tissue, whereas larger particles tend to be taken up by Kupffer cells or other components of the reticuloendothelial system (RES). To reduce RES uptake and increase circulation time, carriers have been modified on the surface with hydrophilic materials, such as polyethyleneglycol. Herein, we review the molecular and structural parameters of lipid-based siRNA delivery systems.

Approximately eight avidin molecules are conjugated to each Ce/Tb‐doped lanthanum phosphate nanoparticle (NP) through the formation of amide bonds (see scheme). This biofunctionalization process comprises modification of the LaPO4 NPs with 6‐aminohexanoic acid (AHA) to confer colloidal stability, activation of the AHA carboxy groups by 1‐ethyl‐3‐[3‐dimethylaminopropyl]carbodiimide, and avidin conjugation.

Anticancer emulsions: Degradable, surfactant‐ free, micrometer‐ to sub‐micrometer‐sized polymer‐encapsulated emulsions loaded with lipophilic drugs (doxorubicin and 5‐fluorouracil) are prepared. In vitro drug‐release studies demonstrate controlled release under redox conditions and incubation with human colorectal cancer cells triggers cell death with greater efficiency (≈106 fold) than the free drug.

Analogous to an assembly line, we employed a modular design for the high-throughput study of 1,536 structurally distinct nanoparticles with cationic cores and variable shells. This enabled elucidation of complexation, internalization, and delivery trends that could only be learned through evaluation of a large library. Using robotic automation, epoxide-functionalized block polymers were combinatorially cross-linked with a diverse library of amines, followed by measurement of molecular weight, diameter, RNA complexation, cellular internalization, and in vitro siRNA and pDNA delivery. Analysis revealed structure-function relationships and beneficial design guidelines, including a higher reactive block weight fraction, stoichiometric equivalence between epoxides and amines, and thin hydrophilic shells. Cross-linkers optimally possessed tertiary dimethylamine or piperazine groups and potential buffering capacity. Covalent cholesterol attachment allowed for transfection in vivo to liver hepatocytes in mice. The ability to tune the chemical nature of the core and shell may afford utility of these materials in additional applications.