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Posted: Sep 22, 2006

Pros and cons of biodegradable nanoparticle drug delivery systems to the lung

(Nanowerk Spotlight) Particulate nanocarriers have been praised for their advantageous drug delivery properties in the lung, such as avoidance of macrophage clearance mechanisms and long residence times. However, instilled non-biodegradable polystyrene nanospheres with small diameters and thus large surface areas have been shown to induce pulmonary inflammation. New evidence suggests that biodegradable polymeric nanoparticles designed for pulmonary drug delivery may not induce the same inflammatory response as non-biodegradable polystyrene particles of comparable size.
“Nanomedicines” are all the rage. Especially in the area of drug delivery to the lung, nano-sized drug carriers promise many advantages over conventional inhalation products. These carriers may be loaded with drugs and formulated so that they may reach specific areas of the lung. Once at their target site, they may be designed to deliver their payload over a controlled period of time, thus reducing the frequency with which a patient may have to inhale their medicine.
For example, patients prescribed inhalable forms of prostacyclins to treat pulmonary hypertension may have to inhale their medicine up to 12 times daily (during the day), because of the short half-life of the drug. Overnight they are forced resort to other measures, such as infusion pumps, to provide the necessary dilation of their lung arteries. With a suitable controlled release preparation, the patient may ideally only have to inhale mornings and evenings to receive their therapeutic dose.
Several strategies may be used to control the release rate of the drug, but by far the most popular method in the scientific literature is to package the drug in a nanoparticle composed of biodegradable polymers. The release rate is then controlled by the polymer properties and the lung environment.
The main attraction of using sub-micron sized particles in lung delivery, particularly those under 260 nm in size, is the observation that such small particles tend to escape the detection systems of alveolar macrophages and remain in the lung long enough to release their contents in a controlled manner (for more details see "Trojan particles: Large porous carriers of nanoparticles for drug delivery" and "Delivery of biotherapeutics by inhalation aerosol.").
During the time our labs were experimenting with a new class of polymers for lung delivery, we discovered a study by environmental toxicologists describing the inflammatory effects of particle surface area in the lung ("Size-Dependent Proinflammatory Effects of Ultrafine Polystyrene Particles: A Role for Surface Area and Oxidative Stress in the Enhanced Activity of Ultrafines"). They used polymeric particles, albeit of a non-biodegradable nature (polystyrene), to show that supposedly “inert” materials could cause lung inflammation if a high enough surface area were presented to the lungs.
Their findings were primarily meant to showcase the danger of airborne “ultrafines” (particles generally <100 nm in diameter) in air pollution, yet these results presented a very different dilemma to us. We asked ourselves whether the “nanomedicines” we were creating may have the undesirable side effect of causing lung inflammation.
The main idea behind our study ("Investigation of the proinflammatory potential of biodegradable nanoparticle drug delivery systems in the lung", published in the August 15, 2006 issue of Toxicology and Applied Pharmacology) was, therefore, was to examine whether some of the new inhalable “nanomedicines” based on biodegradable polymeric systems being could potentially lead to lung inflammation.
This type of study, carried out in the same manner as environmental toxicology studies, had not yet been undertaken with a pharmaceutical formulation. What we found was that we were able to confirm the findings of Brown et al. with regard to the pro-inflammatory effect of non-biodegrable polystyrene particles in the lung; this effect increasing with a decrease in particle diameter and thus an increase in particle surface area. In contrast, biodegradable particles of the same size and surface area, but made from our new polymer and a standard biodegradable polymer, did not show the same pro-inflammatory effect, suggesting that the properties of “inert” materials may also play an important role in triggering lung inflammation.
The studies carried out to date were only very preliminary in nature. A systemic investigation of each individual polymeric “nanocarrier” remains to be carried out. Questions such as the role of material hydrophobicity, the role of surface charge, the role of a semi-gel state vs. a solid surface on pulmonary inflammation still need to be addressed. Also, before a verdict on the safety of such drug carriers in the lung may be reached, further intensive toxicological studies are required. Are such polymeric drug delivery vehicles safe after multiple doses? Are they safe for chronic use?
With the growing utilization of nanotechnology in all fields, not only biotechnology, awareness of potential toxicological issues is increasing. We hope our study will provide a small contribution towards increasing our understanding of this valuable technology along with its usefulness.
By Dr. Lea Ann Dailey, KCL

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