Novartis

The particular identification and directing of molecular therapies to cancerous cells is an optimal treatment strategy, shown to better address, contain, and/or avoid any toxicity (Madaan et al., 2014). Here, we will focus on cancer drug delivery via folic acid receptors. The overexpression of these receptors in epithelial cancer cells was discovered and used as a method of drug delivery. This method was then improved by the introduction of a dendrimer scaffold, serving as a prime example of how biomolecular engineering capitalizes on existing biological systems. Folic acid is attracted to the folate receptor, whose protein is often overexpressed up to one hundred-fold in epithelial (referring to tissue linings in organs and blood vessels) cancer cells (like those involved in breast, lung, and brain cancers), and folic acid and folate receptors form folic acid complexes. Many folic acid complexes are proficient in molecular targeting to tumors (Zhang et al., 2010). These folate receptor proteins are expressed on the regions of cells facing interstitial tissue, rather than on the interior-facing surfaces where normal expression takes place. It is precisely this proximity to blood that allows folic acid, when active as a tracking vessel, to have an astute, biomedically conducive awareness of the particularities of cancer cells (Zhang et al., 2010). Folic acid is minuscule enough to easily find its way inside tumors and is hardly expensive, so it has experienced broad popularity in biochemical recognitions and analysis and in biological tracking (Mishra et al., 2011). Protein-based toxins, liposomes enveloped in drugs, and many types of nanoparticles are some common targets of folic acid (Mishra et al., 2011).

One complication of targeting mechanisms predicated on folate molecules by themselves is that they have levels of affinity constrained by folate quantity (many are needed for adequate affinity). In more problematic scenarios, the circumscribed attraction of folate targeting materials even bounded the outputs of drug delivery to an extent dreadfully inadequate for cancer cell therapeutics (Majoros, Myc, Thomas, Mehta, & Baker, 2006).

Biomolecular engineers sought to improve this system of drug delivery by incorporating dendrimers into the system. Experimental analysis of a drug delivery device based on a polyamidoamine scaffold, branched to multiple folic acid molecules, within in vivo contexts, has made apparent the advantages of this nanostructured device transporting drugs as opposed to the folic acid molecules themselves operating individually and freely (Madaan et al., 2014). The most plausible reason for folate acid molecules working through the scaffold being more effective than those operating independently is the multiplicity and high level of attraction of the interplay taking place across the folic acid groups externally on the dendrimer (Patri, Majoros, & Baker, 2002). Dendrimer scaffolds branched to folic acid molecules were quantitatively tested in response and resulted in a strength of ligand-protein (in this case, surface folate binding proteins) binding (important for efficiency and continuity in therapeutic drug delivery) in the weakest regions of at least 2,000 times as strong as individual folic acid molecules (Kang, 2011).

Collections of such experimental data vindicate the capacity of polyamidoamine dendrimer scaffolds to function in multivalent binding systems. Quantitatively, there was a positive, linear relationship between the association constant (representing binding strength) and the number of targeting vessels involved (demonstrating its value as an explanatory variable) (Patri et al., 2002). In other words, the more the polyamidoamine dendrimers are branched, the more targeting molecules (in this case, folic acid) they contain, and the higher the affinity between the ligand and the receptor. In this way, the targeting and tracking mechanism is streamlined.

Polyamidoamine dendrimers are key to the development of expansive, multipurpose cancer-therapy nanostructured devices. It is important, then, that there are several modifications that can improve the effectiveness of these dendrimers. Adding a partial acetyl group to the dendrimer allows for the neutralization and containment of some of the negative effects caused by amino groups comprising the dendrimer. Such a measure also increases solubility (important for binding), and prevents unintended, overly broad and promiscuous detection and targeting over the course of drug transport (Majoros et al., 2006). Amino groupings without the added acetyl group can still be helpful in combining folic acid (again, important because it targets the folate receptor proteins), drugs like methotrexate, and contrast agents needed for clear imaging (Majoros et al., 2006).

Methotrexate, a drug commonly conjugated to folic acid (which has long been suspected of being able to neutralize some of the harmful side effects of methotrexate, as a “folate antagonist”) is a chemotherapeutic drug often applied to forms of cancer (Thomas et al., 2005) and arthritis (Weinblatt, 2013). The DNA replication of cancerous cells that enables the overexpression of folate receptors relies on the dihydrofolate reductase enzyme, which is blocked by methotrexate. Folic acid binds to these overexpressed receptors, and the dendrimer delivers methotrexate to those cells. It is in this way that the overexpressed receptor-expressing cancer cells are killed (Zhang et al., 2010). Thereby, the folic acid-methotrexate device is adept in accurately tracking and degrading these cancer cells through their relationship with excessively expressed, yet fully-formed, folate receptor proteins (Quintana et al., 2002).

Here, Quintana et al. summarize their work on the folic acid receptor drug delivery system:

The cellular uptake and cytotoxicity of an engineered multifunctional dendritic nanodevice containing folic acid (FA) as the targeting molecule, methotrexate (MTX) as the chemotherapeutic drug, and fluorescein (FI) as the detecting agent were studied in vitro.
Methods: The device is based on an ethylenediamine core polyamidoamine dendrimer of generation 5. Folic acid, fluorescein, and methotrexate were covalently attached to the surface to provide targeting, imaging, and intracellular drug delivery capabilities. Molecular modeling determined the optimal dendrimer surface modification for the function of the device and suggested a surface modification that improved targeting. Results: Three nanodevices were synthesized. Experimental targeting data in KB cells [a tumor cell] confirmed the modeling predictions of specific and highly selective binding. Targeted delivery improved the cytotoxic response of the cells to methotrexate 100-fold over free drug.
Conclusions: These results demonstrate the ability to design and produce polymer- based nanodevices for the intracellular targeting of drugs, imaging agents, and other materials (Quintana et al., 2002)

This multifunctional dendrimer-based device can be abbreviated as G5-FI-FA-MTX. The G5-FI-FA-MTX conjugated product activated molecular pathways that lead to the inhibition of cell growth in KB tumor cells, because the capacity of G5-FI-FA-MTX nanodevices to detect, target, and finally repress the proliferation of cancerous cells directly derive from their folic acid component’s affinity to overexpressed folate receptor proteins (Zhang et al., 2010).

Drugs primarily useful for cancer therapy traditionally are dangerous due to a lack of precision in toxicity. However, precise polymer-predicated targeting techniques tailored to cancer cells can bridge many of these biomolecular inadequacies (Madaan et al., 2014).

When fabricated to completion, these nanodevices are deeply effective, transporting chemotherapeutic drugs to specifically selected cancer cells. Manufacturing these devices at larger material scales and ensuring real-life clinical familiarity should follow.

Dendrimers are nanostructures, and drug delivery often encompasses the conceptual space of nanoengineering. A dexterity in working with transport systems inside of cells as well as with imaging methodologies for mapping the cellular uptake of the given transported biomaterials would allow nanodevices to carry out multi-purposed processes.

Polymers can be structurally altered in order to integrate biomaterials applicable to targeting endeavors. Sending the polymer directly to the tumor brings therapeutic drugs with the facility to destroy the tumor cells. As these combinations of polymers and cancer therapy drugs are made more accurate and specific in tracking cancerous cells and become embedded in more complex systems of device manufacture, toxicity is minimized and the most restorative characteristics of the drugs are highlighted (Madaan et al., 2014).

Polymeric drug conjugates have several advantages over free drugs, especially since they face decreased drug resistance (Patri et al., 2002). Several synthetic and natural polymers of this sort have been tested in the past decade for targeting tumor cells (Kang, 2011).

Ideally, drug delivery mechanisms specifically geared for tumor cells necessitate an apparatus advanced enough to contain a variety of functionally central parts, like therapeutic drugs and fluorescent sensors (Majoros et al., 2006). Polyamidoamine dendrimers can build such transport systems because of their well-defined branches, themselves containing (either within interior void space or by covalent bonding on their surface) a plethora of biomolecules (Zhang et al., 2010). And thinking beyond these particular tactics for drug delivery, dendrimers have been utilized for their carrying qualities in a wide spectrum of medical capacities, whether they are agents for delivering drugs, sharpening imaging, or outlining radioactive molecules (Abbasi et al., 2014).

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