Targeted Drug Delivery

Targeted drug delivery is sending drug to only the parts of the body that truly need it. If you can deliver drugs for cancer treatment directly to the target organ, you can improve the effectiveness of those drugs in treating the cancer and reduce the amount of drug that you need to use. Targeted drug delivery is one of the great medical challenges of our time because it will allow us to more effectively and efficiently treat all kinds of diseases. Targeted drug delivery is intended to improve on the many challenges of conventional drug delivery, which include [3]:

Limited aqueous solubility
Fast clearance
Low bioavailability (i.e. the amount of drug that enters the body and can actively effect the desired result)
Poor biodistribution
Low intracellular permeability

But what are the difficulties in targeted drug delivery today? What is holding us back from sending glaucoma drugs directly to the anterior chamber, or sending cancer medications directly to the tumor?

I have quickly surveyed several review articles about various drug delivery methods to see what I can find out. Targeted drug delivery today is being used to deliver many different chemical compounds, including proteins, immune stimulants, chemotherapy drugs, liposomes, nanoparticles and imaging agents [1]. Here are some requirements for targeted drug delivery, some advantages and interesting concepts, and key challenges that researchers have touched upon in their work:

Requirements for Targeted Drug Delivery

Deliver the drug molecules to the right cells without harming healthy tissue [1]. If we can safely deliver drugs to only the target tissues, we can deliver higher doses which might be more effective than current dose levels which are kept lower to avoid reaching toxicity levels for healthy tissues. [1]
Have a means of binding to the target cells [1]. Hilgenbrink et al used folate conjugates (chemicals containing a folic acid molecule) to bind to cell receptors designed to receive folates. [1] Drugs can also be targeted at specific enzymes for specific processes in the body. [1]
The method must be small and nimble enough to make its way through the body to the target area [1]. Proteins, for instance, are very large so they may have difficulty entering solid tissue regions. [1]
Be compatible with the patient's biology; certain drug therapies like protein drugs can stimulate an immune response if the proteins are foreign to the host [1].
The drug must not interrupt normal biological processes [1].
The drug delivery method should be easy to build and customize with different chemicals and functional groups [1].
The delivery method should probably be water soluble; it depends on the application, but chances are that water solubility will assist with the mobility of the delivery format [1].
The delivery method should not interfere with the drug itself [1].
It is useful to see how the drug delivery therapy is progressing in real time using MRI or other methods [2].
Non-toxicity [3]
Non-immunogenicity (i.e. the drug delivery method must not trigger an immune response) [3]
Biocompatibility [3]
Biodegradability [3]

Advantages/Cool Ideas

Targeted drug delivery can leverage existing immune responses in the body [1]. Hilgenbrink et al provided an example of folate-hapten conjugates used in an animal study [1]. The conjugates bond to the target cancerous tissues and coat them in haptens, which the animals had already been inoculated against [1]. The animals' immune responses attacked the haptens and the target tissues they were bonded to [1]. The researchers also found that this method created an immunity memory in the animals, so when new cancerous tissues developed the immune system responded to them in the same way even though no additional folate-hapten conjugates had been introduced [1].
Liposomes can be used to deliver either hydrophobic or hydrophilic drugs by storing the drugs in either their lipid bilayers or aqueous compartments [1], [2]. They can also carry large quantities of drug [1].
Fernando et al describe Temperature Dependent Liposome drug delivery, where high intensity focused ultrasound (HIFU) is used to heat a precise region of the body and release drugs that are stored in the aqueous compartments of liposomes that have been injected into the body [2]. Thus drug is only released into the target region, and MRI machines can be used to assist in targeting the HIFU beam by thermally mapping the body [2].
Nanoparticles are another means of targeted drug delivery. They can carry large loads of drug, usually on their surfaces [1]. Nanoparticles tend to be so large that they have difficulty penetrating solid tissue [1].
Iron nanoparticles can be used to enhance MRI imaging [1].
Other types of nanoparticles include biodegradable micelles and thermoresponsive microgels [1]. These particles enter the target cell and the local environment can cause them to degrade or melt, releasing the drug stored in their interiors [1].
A variation on targeted drug delivery is targeted delivery of molecules that aid in imaging and analysis. Similar delivery methods can be used to carry contrast agents or ferromagnetic particles to target tissues to help detection methods identify those tissues within the body [1].
Nanoparticles made of materials that absorb light well (such as gold) can also be injected to the human body and used in combination with laser ablation therapy to eliminate tumor tissue [2].
The drug delivery method could be perpetually present in the host system, and additional drug can be added to the host [3]. The drug molecules will bind with receptor sites on the drug delivery units and then be carried to the target tissue [3].

Key Challenges

It can be difficult to ensure the delivery method is only taken up by the target tissue. Hilgenbrink et al described a liposome application where the liposome's protective layer, which was supposed to prevent it from being absorbed by the wrong tissues, also prevented the liposome from attaching itself to the target tissue [1]. The researchers had to adjust the size and shape of the protective layer and the chains of binding molecules to optimize the liposome's ability to bond to the target tissue [1].
Releasing the drug can also be a challenge if the delivery method is very stable and consequently releases the drug slowly or inefficiently [1].

[1] Hilgenbrink, A. R. and Low, P. S. (2005), Folate receptor‐mediated drug targeting: From therapeutics to diagnostics. J. Pharm. Sci., 94: 2135-2146. doi:10.1002/jps.20457

[2] Fernando, R., Downs, J., Maples, D. et al. Pharm Res (2013) 30: 2709. https://doi.org/10.1007/s11095-013-1110-8

[3] Yousefpour, P. and Chilkoti, A. (2014), Co‐opting biology to deliver drugs. Biotechnol. Bioeng., 111: 1699-1716. doi:10.1002/bit.25307