Drug delivery is an area of research on the border of pharmaceutical science and medicinal chemistry. My experience of drug delivery is mainly concerned with using polymers to devise new ways of getting approved drugs into the human body. For example, a drug used in chemotherapy may well have extensive side effects when administered to a patient by intra venous infusion, yet conjugating it to a polymer and providing some kind of targeting mechanism may reduce the side effects by only releasing the active drug molecule in the target tissue. Targetting mechanisms may be either active, attaching a molecule that will bind to another molecule only found in the target tissue, or passive, exploting the enhanced permability and retention effect (EPR). The EPR effect is simply that particles within a certain size will accumulate in tumor tissue to a greater extent than in normal tissue[1].
I’m interested in dendrimers for drug delivery because they have precisely defined size and structure and therefore overcome some of the issues with other polymeric architecture. Dendrimers are very time consuming to synthesise, requiring very high yielding reactions and many steps to obtain molecules in the size range 10 – 50 nm. A way to work around this is to use a polyhedral oligomeric silisesquioxane (POSS) core which is a small cubic molecule comprising 8 silicon atoms at each corner of the cube, linked by 12 oxygen. A functional group (H, propylamine etc) exists at each corner and can be used to synthesise the dendrimer from. Note: these molecules are extremely beautiful with high symmetry and snowflake like structure.
Adapted from [2] Kaneshiro et al. Molecular Pharmaceutics, 2007 (4) 759, drawn by KJHaxton.
This molecule has the POSS core in the centre, and poly (L-lysine) branches radiating from each of the 8 corners. You may recognise the POSS core from the header image on this blog. The periphery of the molecule has primary amine terminal groups. Kaneshiro and coworkers used this dendrimer for gene delivery [2] and also for delivery of the chemotherapy agent doxorubicin [3]. The dendrimer-drug conjugate was targetted to tumor cells via short RGD peptide sequence.
A more recent paper using POSS cores and poly (amino acid) dendrimers was published by Yuan et al. [4]. This time, a poly (L-glutamic acid) dendrimer with a POSS core was prepared and used for drug delivery of doxorubicin, this time using biotin as a targeting group. These dendrimer-drug conjugates were found to be around 30 nm in size and should be nearly spherical in shape (globular). Interestingly, the doxorubicin was conjugated via a pH sensitive hydrazone bond. This is important because little drug was released through cleaveage of this bond at pH 7.4, the pH found in the blood stream, but extensive drug release was measured at pH 5.0, the pH found around tumor tissue. The combination of low release in the blood stream and both an active and passive targeting mechanism increase the chances of the dose being distributed preferentially into the tumor tissues.
My interest in this work is mainly due to the synthesis of complex and beautiful molecules that have a useful function. These papers caught my eye because I’m interested in organic-inorganic hybrid materials and have worked with the POSS core. These papers describe the synthesis, characterisation and preliminary drug release and in vitro studies, assessing these dendrimers as drug delivery vehicles. The drawbacks of using a dendrimer system, even with a POSS core, is the complex synthetic route required to make the molecule and conjugate the drug and targeting system to it. These papers represent the initial steps in a very long program of research that could involve intensive cell culture (in vitro) studies, many animal studies (in vivo) before anything like a human trial of these systems could take place. The evidence presented in these papers suggests that these are potentially very useful systems, but to realise that potential is a very long and very expensive path indeed.
Refs:
[1] Maeda H (2001). The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Advances in enzyme regulation, 41, 189-207 PMID: 11384745
[2] Kaneshiro, T., Wang, X., & Lu, Z. (2007). Synthesis, Characterization, and Gene Delivery of Poly-
-lysine Octa(3-aminopropyl)silsesquioxane Dendrimers: Nanoglobular Drug Carriers with Precisely Defined Molecular Architectures
Molecular Pharmaceutics, 4 (5), 759-768 DOI: 10.1021/mp070036z
[3] Kaneshiro, T., & Lu, Z. (2009). Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier Biomaterials, 30 (29), 5660-5666 DOI: 10.1016/j.biomaterials.2009.06.026
[4] Yuan, H., Luo, K., Lai, Y., Pu, Y., He, B., Wang, G., Wu, Y., & Gu, Z. (2010). A Novel Poly( -glutamic acid) Dendrimer Based Drug Delivery System with Both pH-Sensitive and Targeting Functions Molecular Pharmaceutics, 7 (4), 953-962 DOI: 10.1021/mp1000923
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