Inorganic nanoparticles as carriers for efficient cellular delivery

Abstract

Cellular delivery involving the transfer of various drugs and bio-active molecules (peptides, proteins and DNAs, etc.) through the cell membrane into cells has attracted increasing attention because of its importance in medicine and drug delivery. This topic has been extensively reviewed. The direct delivery of drugs and biomolecules, however, is generally inefficient and suffering from problems such as enzymic degradation of DNAs. Therefore, searching for efficient and safe transport vehicles (carriers) to delivery genes or drugs into cells has been challenging yet exciting area of research. In past decades, many carriers have been developed and investigated extensively which can be generally classified into four major groups: viral carriers, organic cationic compounds, recombinant protiens and inorganic nanoparticles. Many inorganic materials, such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide and layered double hydroxide (LDH), have been studied. Inorganic nanoparticles show low toxicity and promise for controlled delivery properties, thus presenting a new alternative to viral carriers and cationic carriers. Inorganic nanoparticles generally possess versatile properties suitable for cellular delivery, including wide availability, rich functionality, good biocompatibility, potential capability of targeted delivery (e.g. selectively destroying cancer cells but sparing normal tissues) and controlled release of carried drugs. This paper reviews the latest advances in inorganic nanoparticle applications as cellular delivery carriers and highlights some key issues in efficient cellular delivery using inorganic nanoparticles. Critical properties of inorganic nanoparticles, surface functionalisation (modification), uptake of biomolecules, the driving forces for delivery, and release of biomolecules will be reviewed systematically. Selected examples of promising inorganic nanoparticle delivery systems, including gold, fullerences and carbon nanotubes, LDH and various oxide nanoparticles in particular their applications for gene delivery will be discussed. The fundamental understanding of properties of inorganic nanoparticles in relation to cellular delivery efficiency as the most paramount issue will be highlighted.

Introduction

Cellular delivery involving the transfer of various drugs and bio-active molecules (peptides, proteins and DNAs, etc.) through the cell membrane into cells has attracted increasing attention because of its importance in medicine and drug delivery. This topic has been extensively reviewed (Heiser, 2004, Azzam and Domb, 2004, Dietz and Bahr, 2004, Langer and Peppas, 2003, Rolland, 1999, Garnett, 2004). The direct delivery of drugs and biomolecules, however, is generally inefficient and suffers from problems such as enzymic degradation of DNAs (Heiser, 2004, Garnett, 2004). Therefore, searching for efficient and safe transport vehicles (carriers) to delivery biomolecules and drugs into cells has been challenging yet exciting area of research. Virus is an excellent example in nature that transfers into the targeted cells very efficiently. It is also known for a long time that polybasic peptides like poly(lysine) highly enhance the protein uptake, and based on these, an omnipotent and marvelous carrier, i.e., Trojan Horse was designed which can carry the desired drugs, proteins or DNAs cross the cell membrane efficiently (Dietz and Bahr, 2004).

In past decades, many carriers have been developed and investigated extensively (Azzam and Domb, 2004, Garnett, 2004), and can be generally classified into four major groups: viral carriers, organic cationic compounds, recombinant proteins and inorganic nanoparticles. In viral carriers, part of original gene segment is eliminated to leave space for the gene to be inserted and delivered. Carriers consisting of cationic compounds mainly include cationic lipids, cationic polysaccharides, polycationic polymers, where the positive charges are resulted from protonation of various amino/imino groups. A particular type of DNA vectors receiving attention recently is recombinant proteins (Aris and Villlaverde, 2004). These proteins mimic the various viral properties by combining diverse peptide segments that are required for efficient gene delivery into a single molecule through protein engineering. For example, the multifunctional proteins may include polylysine segments, protamine, histones and amphipathic cationic peptides to bind DNA to form thermodynamically stable complexes. They may also contain antibodies, antibody segments for targeting cell delivery and some short peptide sequences acting as nuclear localisation signals. Although the formation of vector-DNA complexes is similar to the normal cationic compounds, protein vectors are much more biocompatible. Inorganic nanoparticles as new non-viral carriers have attracted much attention only recently. Many inorganic materials, such as calcium phosphate, gold, carbon materials, silicon oxide, iron oxide and layered double hydroxide (LDH), have been studied. The four types of carriers are briefly compared in Table 1. In summary, viral carriers are to date the most effective, but severe side effects (e.g. immune response and insertional mutagenesis) limit the successful application in cellular delivery. Cationic carriers (lipids and polymers) may avoid such problems but are often toxic to the cells. In contrast, inorganic nanoparticles show low toxicity and promise for controlled delivery properties, thus presenting a new alternative to viral carriers and cationic carriers. However, it is noted that the cellular transfer efficiency with existing inorganic nanoparticles is relatively low at this stage.

Inorganic nanoparticles generally possess versatile properties suitable for cellular delivery, including wide availability, rich functionality, good biocompatibility, potential capability of targeted delivery (e.g. selectively destroying cancer cells but sparing normal tissues) and controlled release of carried drugs. This is why increasing efforts in research and development worldwide have been devoted to various inorganic materials as novel non-viral carriers in the last decade (Ozkan, 2004, Barbe et al., 2004, Bauer et al., 2004). The present review aims to examine the latest advances in inorganic nanoparticle applications as cellular delivery carriers and highlight some of the key issues in efficient cellular delivery using inorganic nanoparticles. Critical properties of inorganic nanoparticles, surface functionalisation (modification), uptake of biomolecules, the driving forces for delivery, and release of biomolecules will be reviewed systematically in Section 2. Section 3 will present selected examples of promising inorganic nanoparticle delivery systems, including gold, fullerenes and carbon nanotubes (CNTs), LDH and various oxide nanoparticles in particular their applications for gene delivery. The fundamental understanding of properties of inorganic nanoparticles in relation to cellular delivery efficiency is the most paramount issue which will be highlighted in Section 4.

To avoid possible confusion in some terminologies, we present the following basic definitions and terminologies for the convenience of the readers. Nanoparticles generally refer to particles with diameters ranging from 1 to a few 100 nm. Functionalised inorganic nanoparticles with or without biomolecules loaded are generally described as hybrid nanoparticles, organic/inorganic nanohybrids or simply nanohybrids. In addition, carriers, vectors and agents in the content of this paper all refer to the vehicles that are used to carry drugs and biomolecules for cellular delivery.