Section II: Critical Review

The assessment is a critical review of a paper published by Robert Langer, the father of controlled drug delivery, is one of the Institute Professors, MIT’s highest honour faculty member. He was also the youngest person ever to be elected to all three American science academies (Gura, 2014). His moto is to ‘do great science to create things that could change the world’. The title of the paper is - From the point of view of a drug, it's a long trip.

When a drug is administered into a body, it must survive until it reaches its target site at effective dose by dealing with various obstacles; such as the effect of pH, enzymes, membrane barrier, drug-drug interaction, etc. Langer points out that, patients do not prefer injections several times a week. However, if high dosages are administered, even though the half-life of the drug is extended in the blood circulation, the sudden high concentration could be toxic and cause unwanted effects.

Overall, the paper gave a very brief review of drug delivery, together with illustrations that explains the process of drug delivery, allow readers to understand technologies that were being researched on multiple non-invasive drug delivery systems, including its hurdles and solutions. Oral, transdermal, inhalation, transfection and ‘smart’ devices are introduced to possibly release drugs into the bloodstream in a controlled manner, providing a basic knowledge on drug delivery to understand related papers. However, it does not include the hurdles after the drug enters the bloodstream.

Throughout the years, there were many medical breakthroughs that improves delivery in higher efficiency and lower toxicity. In ‘Breaching the wall’, bioadhesives entrap active ingredients that could attach on mucous linings and enhance penetration through the membrane, providing longer time for drug absorption. But, active ingredients were released rapidly before the penetration, so a second dose would be required. In 2015, Zhang et al. introduced a smart pH responsive device that could remain stable within the stomach for 5 – 7 days, next, degraded when passing through the neutral intestines. Once surrounding pH lowered, the capsule swells and form a ring that has a larger diameter than the pylorus, which prevents the device from entering the neutral environment that would cause degradation. (Figure 1) (Leonardi, 2015).

Figure 1. Zhang holds a swelled ring shaped device (left) that can be folded into a swallowable capsule (right) (Leonardi, 2015).

Transdermal delivery allows drug access to bloodstream without encountering into low pH or hydrolytic enzymes. Even though it has an impermeable skin barrier, Joseph Kost finds improved transdermal permeability of proteins by using ultrasound to temporarily disrupting the stratum corneum. However, only low frequency ultrasound was used because high frequency could not pop the formed bubbles. The intensity and duration of treatment is very limited due to the risk of thermal side effects (Schoellhammer et al., 2012). Therefore, the utilisation of two different ultrasound frequency was proposed, where high frequency responsible in forming additional bubbles that are popped by low frequency ultrasound, that are capable of uniformly increase absorption in several folds according to the molecular weight of drug (Trafton, 2012).

The hurdles on drug delivery are not limited to pH, membrane barriers, skin, etc. Also, the stability in the bloodstream, rate of drug release from the complex, ability to target site of action, capability to enter the cells, endocytosis and degradation by macrophage, etc (Mitragotri et al., 2014). One of the biggest challenge was the aggregation of protein-based drugs in the bloodstream due to the presence of plasma protein, and rapid elimination of molecules smaller than 60kDa via renal filtration. Encapsulating protein/gene with polyethylene glycol (PEG), was shown to protect cargo from aggregation to achieve prolonged circulation, form larger and uniform nanoparticles that resist uptake of macrophages and enhance deep penetration into problematic tissues. Furthermore, the control of burst release of drugs is crucial to extend duration of drug circulation and avoid sudden high concentration of drugs in the plasma, which could be toxic (Mitragotri, 2014).

Figure 2. Schematic representation of nanocarriers delivering drugs to tumours via different mechanisms (Peer et al., 2007).

Once the drug can circulate in the blood stably, the next hurdle is the pin point targeting of abnormal cells. Tumour tissues, where the endothelium is relatively poorly formed, promotes enhanced permeation-retention (EPR) effect that allows extravasation of nanoparticles into the solid tumour via passive tissue targeting; followed by the active cellular targeting of nanoparticles. Drugs are designed to couple with ligand, receptor or proteins to promote interaction on the cellular surface to mediate internalisation (Peer et al., 2007). For example, monoantibodies coupled drugs are Rituxan, Herceptin and Avastin (Peer et al., 2007). However, some proteins may target non-cancerous cells and cause lethal effects. For example, the non-specific binding of BR96-doxorubicin shows desired targeting effects on mouse, but not on dogs and humans, causing the termination of clinical trials in the phase II of the study (Peer et al., 2007).

Besides that, protein degradation can occur intra and extracellularly. Mitragotri (2014) finds that by fusing the Fc region of IgG to the drug, can extend the half-life of the drug via Fc receptor recycling pathway; where bound peptides undergo exocytosis while the unbound peptides will be degraded. It is clinically used for drug delivery, for example, Enbrel (Amgen).

Figure 3. FcRn recycling mechanism.

Generally, the binding affinity is proportional to the targeting efficacy. However, not in the case of solid tumours because binding affinity is too strong that it decreases the penetration of nanoparticles due to ‘binding-site barrier’.

Another approach for targeted drug delivery is to inject polymer solutions made of elastin-like polypeptide (ELP) that solidifies in situ at body temperature, known as reverse thermal gelling system. Langer (2013) reveals that, no pores are formed on polymer matrix in the absence of biomolecule, which is impossible to incorporate biomolecules in within. However, under the presence of biomolecules, the polymer matrix form pores that perfectly fit the biomolecule at any size. The tightly constricted pores hold on the biomolecule that allows diffusion that is slow enough for control release (Langer, 2013).

The cells have electron dense surface that would repel negatively charged substances. The most efficient, commercially available non-viral polycationic vector, polyethylenimine (PEI) is known to be the gold standard for transfection efficiency, is toxic due to the high percentage of protonable amine groups on the polymer; where efficiency and toxicity are proportional to its molecular weight (Wen et al., 2009). Thus, higher MW PEI were prepared by conjugating low MW PEI with biodegradable backbone. For instance, polyglutamic acids derivatives, disulphide bonds and diselenide bonds (Wen et al, 2009; Kang et al, 2010), taking the advantage that abnormal cells have relatively higher concentration of glutathione (GSH) that selectively degrade polymer for rapid drug release (Chang et al, 2014). In contrast, healthy cells that do not have sufficient GSH would not release drug before it undergoes exocytosis. Besides that, polyaminoesters (PAE) are very popular in the application of drug delivery that it has a protonable amine group as well as an ester that promotes hydrolytic degradation.

All in all, it is a very long journey for a drug to reach its target site and to carry out therapeutic effects. There is no certain best nanocarrier or delivery system for drug delivery because different routes should have different parameters that would affect the biodistribution and targeting. Future research should focus on extracellular targeting to overcome membrane permeability and intracellular delivery.

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