Nanoparticles (NPs) are colloidal particles ranging in size from approximately 10 to 1000 nm in diameter and can be synthesized from a variety of materials (e.g., lipids, polymers, metals, and ceramics). Due to their unique properties, NPs have found increasing applications in medicine from drug delivery to imaging.
In the drug delivery arena, NPs are able to address many of the difficulties encountered during the administration of therapeutic compounds. The encapsulation of drugs within NPs can increase the solubility of insoluble drugs, improve pharmacokinetics through sustained release, alter biodistribution, protect sensitive drugs from low pH environments or enzymatic alteration, and, in some cases, provide targeting of the drug to the desired tissues.1 Modern drug discovery and developmental technologies have yielded a wide array of small molecule and biologic drugs for the treatment of many diseases; however the requirements for these compounds to be successfully commercialized and translated into the clinic are challenging.
Cancer Treatment with Nanoparticles
Oncology is one field of medicine where NP-mediated drug delivery systems can potentially have a significant impact since issues with solubility and pharmacokinetics have limited the clinical application of many new, potentially effective anticancer drug candidates. There are several classes of promising NP drug delivery systems, including drug nanocrystals, liposomes, micelles, dendrimers, and polymeric NPs (Fig. 171-1).2 Drug nanocrystals are simply pure drugs that have been processed down to nanometer sizes.3 The extremely small particle size increases the surface area of the drug, thereby increasing solubility. In contrast, liposomes are spherical lipid bilayers measuring a few nanometers in diameter.4 When used as a drug delivery vehicle, insoluble drugs can be transported within the hydrophobic environment of the lipid bilayer, whereas soluble drugs are contained within the internal aqueous compartment inside the liposome, thereby altering the pharmacokinetics and biodistribution of the native drug. Like liposomes, micelles are also composed of phospholipids. In aqueous solution, a micelle is formed by spontaneous self-assembly resulting in the exposure of the hydrophilic head regions to the surrounding solvent and aggregation of the hydrophobic tails at the micelle center. The core of the micelle can thereby contain small hydrophobic molecules such as therapeutic drugs, while remaining stable in aqueous solution. Dendrimers are highly branched molecules that can be used to deliver drugs via two different methods. Drugs can either be attached to the outer functional groups of the dendrimer branches, or encapsulated within the dendrimers to form a drug-dendrimer supermolecular assembly. Finally, polymeric NPs, which encapsulate drug within various polymers, tend to be more stable than liposomes and can increase the effective solubility of hydrophobic drugs. In addition, unlike liposomes, several polymeric systems appear to allow programmable, or at least controlled, drug release through the manipulation of the structure and composition of the polymer used to prepare the particles.1,5,6
Nanoparticles for the Treatment of Lung Cancer
Despite the potential survival advantage seen with adjuvant chemotherapy in patients with later stage lung cancer, the overall benefits of systemic treatment in lung cancer patients with early stage disease are often outweighed by the incidence of common systemic side effects. Two of the most common drugs used in lung cancer treatment are paclitaxel and docetaxel, which are both extremely hydrophobic and are difficult to deliver due to poor solubility. In its current clinical formulation, paclitaxel is delivered in a Cremophor EL (polyethoxylated castor oil) and ethanol mixture, which is thought to be responsible for many of the toxic side effects associated with paclitaxel treatment. Furthermore, drug distribution within the lung parenchyma is suboptimal since systemically administered chemotherapeutics may be rapidly excreted, leaving only a small percentage of the total dose locally available to prevent growth of recurrent lung tumors. For example, when paclitaxel is given as a single intravenous (IV) bolus dose, maximum drug levels are reached within 0.5 hours and only 0.5% of the total dose is delivered to the lung tissue.9 In contrast, drug-loaded NPs can potentially be targeted to the lungs or specific tissues following IV injection, oral delivery, or inhalation.10 Therefore, in an effort to improve tissue delivery, decrease side effects, and prevent drug resistance secondary to enhanced cellular efflux, several NP formulations have been proposed for use in the treatment of patients with non–small-cell lung cancer (NSCLC). The current chapter will discuss several promising experimental approaches, including micelles, liposomes, covalently modified paclitaxel conjugates, and polymeric NPs.
Zhang et al.11 have described ~20 nm paclitaxel-loaded Pluronic P123/F127 mixed micelles (PF-PTX), prepared by thin-film hydration. PF-PTX were developed to both deliver drug and to overcome multidrug resistance by inducing apoptosis through loss of mitochondrial membrane potential and subsequent ATP depletion. PF-PTX micelles contain paclitaxel within the hydrophobic core of the particle and demonstrate a nearly 70% decrease in tumor volume compared with standard paclitaxel in a human A549 lung tumor xenograft model in mice.11
Liposomes provide a hydrophobic environment within the lipid bilayer and a hydrophilic internal compartment to allow delivery of different payloads. Paclitaxel liposomes have been evaluated in a Phase I study to treat patients with malignant pleural effusions secondary to NSCLC. However, the most successful application of liposomal delivery relevant to lung cancer has been with anthracycline chemotherapeutic agents. As opposed to the hydrophobic taxanes, use of anthracyclines such as doxorubicin is not limited by solubility issues, but rather by cardiac toxicity which occurs with cumulative exposure of these agents to healthy tissues. Therefore liposomes are an appropriate candidate for anthracycline delivery since agents like doxorubicin can be readily loaded into the hydrophilic core of the liposome. The most common formulations include liposomal doxorubicin and polyethylene glycol (PEG)-ylated liposomal doxorubicin (PLD).
Liposomal doxorubicin and PLD delivery systems consist of a liposomal bilayer surrounding an aqueous core containing the drug doxorubicin HCl, with and without a PEG coating, respectively (Fig. 171-2). The hydrophilic PEG coating, serves to decrease systemic clearance of the liposome by the reticuloendothelial system, thereby delivering more drug to the desired tissues. Although efficacy did not differ significantly between liposomal and conventional formulations of doxorubicin in clinical trials of breast cancer patients, liposomal or PLD did significantly reduce the number of patients developing cardiac toxicity. Liposomal doxorubicin has also shown efficacy in patients with locally advanced or metastatic NSCLC that failed platinum-based first-line chemotherapy.16,17 The use of doxorubicin loaded liposomes is therefore a key example of how nanocarriers can improve delivery of effective chemotherapeutic agents by simply minimizing their toxicity on healthy tissues.