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14 December 2009 NANO Magazine - Issue 10

Targeting drugs at the Nanoscale

Part 1

Image Credit: NANO Magazine.

In the first part of this two-part article, Richard Moore describes some of the challenges faced in delivering the right quantity of a drug to its target site in the human body and some of the ingenious ways in which nanotechnology is being applied to provide new, patient-friendly solutions. Significant challenges The delivery of drugs to the intended target site in the body in the right dose at the right time presents a number of important challenges. Drugs may often have a limited solubility, may suffer breakdown before they reach their target tissues, may suffer poor pharmacokinetics or distribution or may unintentionally damage healthy tissues. Overcoming these challenges occupies a large part of the research time in pharmaceutical development and costs a great deal of money.

Since the factors that affect drug delivery are commonly linked to biochemistry and metabolism taking place at or close to the nanoscale in the body, there has been an increasing focus on how nanotechnology might be used to overcome some of the problems associated with drug delivery and to address some of its keys aims such as:

  • maintaining drug levels within the therapeutic range;
  • achieving effective targeting to the therapeutic site;
  • increasing specificity;
  • designing delivery systems for slow release;
  • reducing the amount of drug needed and; as a consequence,
  • decreasing toxicity and side effects;
  • developing novel nanostructures that can be used in specific applications, e.g. cancer therapy, wound management, neurology, orthopaedics, ocular, etc.

New generation biotechnology-derived drugs, including those based on proteins, may present further challenges such as protecting the drug from breakdown in the body before it reached its therapeutic site (a major problem for oral delivery), problems with achieving correct dosage in the case of intravenously-administered drugs, ensuring targeted delivery to specific tissues or organs and other problems such as overcoming the blood-brain barrier for neurologically-targeted drugs.

Some benefits of nano-based drug delivery systems

There are many nanostructures that can be used as drug delivery vehicles and that, at the same time offer some significant advantages over traditional delivery mechanisms. These advantages include high stability, the possibility of transporting both hydrophilic and hydrophobic drugs, high carrying capacity due to greatly increased surface area, better bioavailability, systems that allow controlled release rates or release upon an external stimulus, and the possibility to exploit a range of patient-friendly delivery routes, e.g. oral, transdermal, inhalation.

Some examples of nanostructures being developed for drug delivery

Drug delivery systems may be based on so-called monolithic structures such as nanospheres, where the drug is adsorbed, dispersed or dissolved in the matrix of the nanoparticle or covalently attached to it; or they may be based on vesicular systems where the drug is carried in an aqueous or lipid carrier within the walls of a hollow particle. Particles may be manufactured from biocompatible and biodegradable polymers, may be metallic or semimetallic or may be based on natural substances such as gelatin, albumin, lecithin or chitosan. So-called active nano- drug delivery systems may utilise external energy sources such as ultrasound, light or magnetic fields to aid activation or release of the therapeutic payload at the target site.

Examples of nanostructures that have characteristics suitable for drug delivery requirements include the following.

Polymeric nanoparticles

Polymeric nanoparticles have several useful features: they are generally formed from polymers that have a history of biocompatibility and that are biodegradable, they are usually easily manufactured in useful quantities and they can often increase the stability of pharmaceutical compound. They are also frequently capable of being functionalised with various biomolecules enabling them to be targeted towards certain tissues or organs, e.g. in antibiotics, vaccines and anticancer therapies. Polyketal nanoparticles (formed from polymers with a ketal linkage in their backbone) have a further advantage in that they do not release acidic by-products on degradation, thereby reducing problems such as inflammation.


Dendrimers (from Greek, dendron, tree) are unimolecular, well-defined, micellar, symmetrical, branched, monodisperse macromolecules. They comprise multiple, perfectly-branched monomers emanating radially from a central core and are manufactured in a stepwise process resulting in structures with an exact molecular weight. If the peripheral groups are hydrophilic, the dendrimer will be water-soluble although such a structure can have internal hydrophobic groups allowing it, at the same time, to carry a hydrophobic drug. They can be readily functionalised with a variety of drugs, imaging agents and ligands and are able to enter cells rapidy so as to transport and deliver substances inside the cell. Synthesis, however, is time-consuming and has a relatively low yield compared with other forms of nanostructure.

Hyperbranched polymers

Hyperbranched polymers are also globular, highly-branched macromolecules but lack the highly-organised, symmetrical structure of a dendrimer. Chemically they are polydisperse, dendritic macromolecules that possess some of the properties of both dendrimers and linear polymers. They are imperfectly branched and have an average (rather than precise) number of terminal functional groups. They have a low viscosity and good solubility. Hyperbranched polymers are prepared in a single polymerization step and are therefore generally more cost effective than dendrimers and will often deliver some of the advantages of dendrimers at a much lower cost.


Nanoshells comprise a spherical core of silica or other materials, surrounded by a coating a few nanometres in thickness. Typically the coating comprises a metal such as gold, which is biocompatible, or silver.

Nanoshells possess a property called plasmon resonance, whereby light of particular frequencies causes oscillations of electrons at the surface, thus greatly concentrating the intensity of the light. The plasmon resonance can readily be tuned to a wide range of specific frequencies, from the near ultraviolet to the mid-infra-red, simply by controlling the relative thickness of the core and shell layers of the nanoshell. This range spans the near infrared, a region where absorption in tissue is minimal and penetration is optimal. Nanoshells have demonstrated usefulness in several medical applications including biosensing and light-triggered drug delivery and cancer thermoablation therapy.

Colloidal gold nanoparticles

Colloidal gold has been used for many years for the treatment of rheumatoid arthritis, as well as multiple sclerosis, neurodegenerative conditions such as Alzheimer’s Disease and various cancers. More recently colloidal gold nanoparticles have been further functionalised by PEGylation (attachment of polyethylene glycol chains) to mask the particles from immune system recognition and subsequent uptake in the liver and spleen, and by attachment of tumour necrosis factor (TNF) targeting biomolecules to bind to receptors on cancer cell surfaces. The functionalised nanoparticles can enter the tumour through its “leaky” neovasculature, but are too large to leave the blood circulation through normal vasculature thereby accumulating in the tumour.


Nanocrystals are aggregates formed from clusters of hundreds to tens of thousands of atoms. They are typically between10nm and 100nm in diameter and frequently exhibit physical and chemical properties somewhere between smaller molecules and bulk materials. Their surface area is very large in relation to their volume and growth and form can often be well controlled. Properties such as melting temperature, charge conductivity, dissolution and band gap (energy gap) can be modified also by varying the size and surface area of the nanocrystal. Surfaces may be functionalised using targeting biomolecules and hybrid crystals of different materials with varying properties may be fabricated. Nanocrystal delivery systems have now been commercialised and offer advantages such as large decreases in dosage volumes, increases in tolerated doses and major improvements in the bioavailability of certain drugs.


Nanoliposomes are nanoscale vesicular structures with a single or multilayered lipid bilayer. They usually comprise an aqueous drug-carrying core surrounded by a hydrophobic bilipid layer but can also be engineered to carry both hydrophilic and hydrophobic molecules. They may be manufactured in a range of sizes, e.g. to favour phagocytosis thereby releasing the carried drug, and their surfaces may be functionalised with antibodies, antigens, vitamins or other functional biomolecules to promote endocytosis by other cell types or delivery to specific tissues or other targets, e.g. tumours, as well as with polyethylene glycol (PEGylation) to help them avoid breakdown by the immune system. Nanoliposomes are of particular interest in transporting and targeting chemotherapeutic agents to cancers where their small size allows them to leak into tumours and target cancer cells through the tumour’s typical “leaky” vasculature.

Source: NANO Magazine - Issue 10 /...

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