171: Nanoparticle Therapy in Lung Cancer

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.

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.

Micelles

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

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.

Besides enabling the improved delivery of established chemotherapeutics such as paclitaxel, doxorubicin, and camptothecin (CPT), NP drug delivery is also being explored for use in delivering newly developed drugs that are limited by solubility. For example, Agashe et al.¹⁸ recently reported a novel curcuminoid, CLEFMA, as a potent antiproliferation agent that induces autophagic cell death in lung cancer cells. CLEFMA is a highly hydrophobic compound, and therefore a drug-in-cyclodextrin-in-liposome formulation was developed. This formulation demonstrated more potent antiproliferative activity in vitro in lung adenocarcinoma H441 cells than naturally occurring curcumin, while having no effect on the proliferation of healthy lung fibroblasts. Additionally, tumor volume in nude rats bearing xenograft H441 tumors was significantly reduced following treatment with CLEFMA liposomes as compared to liposome-only controls.¹⁸

Nanoparticle Bound Conjugates

As an alternative to physical encapsulation of paclitaxel within a particle, the drug may also be formulated with a protein for protein-stabilized NP delivery. The most successful example of this approach is NP albumin bound (nab)-paclitaxel, also known as Abraxane^®. This is the most recent NP drug delivery system to be approved for clinical use by the FDA. Abraxane is a protein-stabilized paclitaxel suspension created by subjecting paclitaxel to high-pressure homogenization in the presence of human serum albumin, resulting in a colloidal suspension of paclitaxel NPs. This formulation provides the ability to administer paclitaxel without the use of Cremophor EL, allowing quicker administration and higher maximum tolerated doses while reducing adverse events. Preclinical studies with Abraxane have shown improved tumor penetration, higher plasma clearance, and a larger volume of distribution compared to conventional paclitaxel. In addition, results from NSCLC Phase I/II trials with weekly IV Abraxane therapy have indicated that nab-paclitaxel was well tolerated and demonstrated encouraging single-agent activity.¹⁹ Recently Phase III clinical trials in NSCLC using Abraxane as a first-line treatment in combination with carboplatin demonstrated that Abraxane allowed administration of a higher total paclitaxel dose with a significant improvement in overall response rate compared to conventional paclitaxel.²⁰

Polymeric Nanospheres

Due to its hydrophobic nature, paclitaxel has also been encapsulated within polymeric NPs to enhance delivery while minimizing complications secondary to issues with drug solubility. Polymeric NPs tend to be more stable than other carriers, such as liposomes and micelles, and their delivery properties can be adjusted by manipulating the structure and composition of the polymer used to prepare the particles. This flexibility suggests that polymeric NPs may be a favorable means to delivery chemotherapeutic agents in a postoperative setting. Several natural and synthetic polymers have been investigated for the preparation of polymeric NPs, including chitosan, methacrylic acid copolymers, and polycaprolactone, but poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) are the most widely studied due to availability, biocompatibility, and FDA-approved status.

PLGA systems are simple to synthesize, can be functionalized for tumor targeting, and have been explored for the delivery of many agents, including anticancer drugs. Despite promising in vivo results in small animal models and the appeal of PLGA as a biocompatible FDA-approved polymer, PLGA NPs have at least one significant limitation—particles afford rapid “burst” release of the encapsulated drug (>50% release in 10–48 hours) regardless of NP location. Drug release before NPs reach the tumor may therefore reduce the benefit of using a localized drug delivery system.²⁴ Furthermore, a recent study suggests that PLGA NPs are not readily taken up by cells and thus deliver their payload by extracellular drug release and/or direct drug transfer to contacting cells.²⁴

To improve the relatively low tumor-targeting efficiency of bare PLGA NPs, several studies have focused on modifying the surface of these NPs. For example, surfaces of paclitaxel-loaded PLGA NPs surface modified with covalently bound wheat germ agglutinin (WGA) were found to have superior antiproliferation activity against A549 human NSCLC cells in vitro compared with conventional formulations of paclitaxel. The increased efficacy was attributed to a more efficient intracellular accumulation of paclitaxel via WGA-receptor mediated uptake. A single intratumoral injection of these NPs was also shown to inhibit growth of A549 tumor nodules in mice over a period of 25 days and tumor volume shrank to baseline within 2 days.²⁵ Similarly, other investigators have utilized chitosan modification to enhance lung specificity or tumor targeting.

Another chemotherapeutic agent commonly used in the treatment of lung cancer is CPT, a natural plant alkaloid, which has shown a broad spectrum of antitumor activity against a range of solid tumors. The effective delivery of CPT to tumor targets presents a challenge however, due to the drug's insolubility in water, structural instability, and high toxicity to healthy tissue cells. Because of these toxic side effects, CPT needs to be administered frequently in limited doses to achieve the desired drug efficacy. NPs have therefore been explored as a means to provide sustained release of controlled amounts of CPT over a prolonged period. One example of a CPT-loaded polymer formulation is 100 to 300 nm particles synthesized from highly hydrophobic, biodegradable poly(ω-pentadecalactone-co-butylene-co-succinate) (PPBS) copolyesters.²⁶ In vivo studies using a 7-day established subcutaneous LLC tumor model demonstrated that PPBS NPs loaded with 12% to 22% CPT showed increased cellular uptake, higher cytotoxicity against murine Lewis lung carcinoma cells in vitro and better antitumor efficacy in vivo.²⁶

A new area of investigation is the use of NP drug delivery for the prevention of lung cancer recurrence. Local recurrence of lung cancer following lobectomy for Stage I patients occurs in 7% to 9% of patients.²⁷ However, many patients with lung cancer have poor pulmonary function due to age and/or the effects of smoking, therefore surgical removal of a significant amount of lung tissue is not a clinically viable option for these patients. Consequently, these patients often undergo a more limited wedge resection with the trade-off being higher locoregional tumor recurrence. The recurrence rate for such patients is nearly three times higher than in patients undergoing lobectomy.²⁷ Therefore, a drug delivery system capable of preventing recurrence at the tumor–tissue interface would potentially extend the benefit of surgical therapy with improved clinical outcomes to patients previously deemed unacceptable candidates for lobectomy.

Recently, pH-responsive paclitaxel-loaded NPs, prepared using methacrylate-based polymers, have been developed for local application at the surgical resection margin to reduce the rate of cancer recurrence.²⁸ These NPs are designed to focus chemotherapy delivery within tumor cells through a unique mechanism. Upon endocytosis by the tumor cell, exposure of the NP to the acidic pH of the endosome results in cleavage of a pH-responsive “protecting group” which triggers NP expansion and subsequent intracellular drug release (Fig. 171-3). These paclitaxel-loaded expansile nanoparticles (Pax-eNP) have been shown to prevent the initial in vivo tumor growth of Lewis lung carcinoma in mice, whereas more conventional paclitaxel-loaded nonexpansile NPs, empty expansile NPs, or even a 10-fold higher dose of paclitaxel alone did not.²⁸ Subsequent studies with a more robust and clinically relevant model of tumor recurrence after surgical resection, have shown that local delivery of Pax-eNP immediately after resection of established tumors prevented local recurrence.²⁹ In these studies, subcutaneous Lewis lung carcinoma implants were excised when tumor volume reached 300 mm, and animals were treated with a 300 µg dose of either IV paclitaxel or as a local injection of pax-eNP. A single dose of pax-eNP placed within the tumor bed at the time of surgical resection delayed tumor recurrence and modestly prolonged survival compared to the current clinical formulation of the paclitaxel in Cremophor EL/ethanol.²⁹

Due to their unique properties, NPs have the potential for application in a wide range of fields, and are being increasingly used as a means of drug delivery. Specifically, NPs are being developed to address many of the difficulties encountered when administering therapeutic compounds. Their use for anticancer drug delivery is especially of interest as NPs can improve delivery of the chemotherapeutic agents to cancer cells while minimizing toxicity to healthy tissues.

Current research on NP therapy in cancer encompasses a variety of approaches differing in NP material composition, method of delivery, type of therapeutic drug delivered, and the specific disease target. Many of the NP formulations being studied today show improved efficacy over conventional treatments or equivalent efficacy with reduced incidence of side effects. However, continued development of NP systems for the delivery of chemotherapeutics will provide ways of maximizing the benefits derived from current and future therapeutic compounds, with the ultimate goal of advancing adjuvant cancer therapy, decreasing tumor recurrence and improving the lives of lung cancer patients.

New improved methods of delivering effective drugs to the site of the tumor are critical to future advances in lung cancer care. This chapter reviews the promise of a wide variety of NP drug delivery systems.