Nanopharmacology of Liposomes Developed for Cancer Therapy

Keywords::

• efficacy
• liposomes
• marketed formulations
• safety

Although the last decade has seen unprecedented advances in cancer diagnosis and therapy, for many patients, cancer remains a chronic and debilitating disease. Cancer is the second most common disease that leads to death worldwide, and the concerns associated with conventional therapy/delivery systems initiated research into novel drug-delivery systems for suitable anticancer drugs. These drugs are well known for their serious dose-related side effects owing to their uncontrolled pharmacokinetics (mainly poor biodistribution) and lack of targeting effects in the body [1,2]. Multidrug resistance is another major problem in cancer drug delivery [2]. Therefore, novel drug delivery systems developed based on nanotechnology concepts such as liposomes can improve future cancer therapy.

Nanopharmacology of liposomes involves the use of nanoliposomes with novel pharmacological principles, such as favorable pharmacokinetics, to maximize efficacy and minimize the adverse effects of drugs, including drug delivery to targeted locations or tissues (e.g., cancer cells). Liposomes are lipid bilayer vesicles that were first prepared in the 1960s [3]. Liposomes can be seen as the simplest artificial biological cells, which have potential applications in drug delivery, gene therapy and artificial blood, as well as being used as a model of biological cell and cell membrane [4]. Liposomes are usually composed of phospholipids or cholesterol, which are used to encapsulate various active drugs. Liposomes may vary in size; most are 200 nm or smaller – these can be termed ‘nanoliposomes‘. However, there is a size limitation for liposomes. Liposomal formulation is similar to that of a small section of a circular lipid bilayer. During the formulation process, it must sacrifice its edge energy in order to overcome the bending resistance; thus, liposomes cannot be made as small as would be desired. If the circular section of bilayer is too small, it would not have enough edge energy to provide the necessary bending energy [5]. Liposomes are a promising dosage form/drug delivery system owing to their size, hydrophobic and hydrophilic character, biocompatibility, biodegradability, low toxicity and immunogenicity [6,7]. Indeed, liposome products were the first nanopharmaceuticals approved by the US FDA and are listed in the database of dosage forms with a FDA code of 852 [101]. Stealth liposomes are an emerging novel development in the technology to enhance their half-life in the bloodstream. Generally, the surfaces of these liposomes are modified with the attachment of polyethylene glycol (PEG) groups to the liposomal bilayer to avoid the opsonization process [8].

From a nanopharmacological view, by entering directly into the central compartment and distributing the drug to cancer tissues, liposomal cancer therapies represent an additional compartment model in the pharmacokinetic model. However, the tissue distribution patterns are dependent on the type of liposome formulation. Generally, the maximum amount of drug is rapidly released from liposomes into the central compartment for therapy, before the liposomes are cleared by the mononuclear phagocyte system. Surface modification of liposomes slows mononuclear phagocyte system uptake, thereby retaining drug-loaded liposomes in the plasma and enabling prolonged circulation, extravasation in tissues, preferential uptake at the endothelium and subsequent drug release in the tissue compartment [102].

Currently, various liposomes are being intensively developed as nanoformulations and have been shown to considerably reduce the toxicity of anticancer drugs with significant efficacy. The nanopharmacology and current clinical study highlights of the liposomes that have been encapsulated with anticancer drugs, such as doxorubicin, daunorubicin, cisplatin, paclitaxel and vincristine, are covered in this article.

Marketed nanoliposome formulations

Doxil^® (Sequus Pharmaceuticals, Menlo Park, CA, USA), a long-acting PEGylated liposomal product of doxorubicin, was developed with a diameter smaller than 100 nm and demonstrated significant improvements over free doxorubicin, with greater efficacy and lower cardiotoxicity. Doxil is used to treat cancer in Kaposi‘s sarcoma and multiple myeloma. The improvements are attributed to passive targeting of tumors, due to leaky tumor vasculature and enhanced permeation and retention, and to lower concentrations of free doxorubicin at healthy tissue sites. Pharmacological evidence suggests that liposomal Doxil is metabolized by leukemia cells via a different mechanism than that for free doxorubicin, which might explain the improved efficacy and lower toxicity. Furthermore, Doxil is currently undergoing clinical trials for the treatment of breast cancer [6]. Ogawara and colleagues have recently investigated the effect of PEGylated liposomal doxorubicin (Doxil) in a male mouse tumor model inoculated with either colon cancer (C26) cells or their doxorubicin-resistant (multidrug resistant) subclone, which overexpresses P-gp efflux pumps [9]. The results demonstrated that Doxil had anticancer effects on both doxorubicin-resistant and non-doxorubicin-resistant C26 cells. However, hand–foot syndrome was a dose-limiting toxic effect of Doxil. This adverse effect was not observed with the use of doxorubicin alone. A reason for this unexpected toxic effect of Doxil could be a considerable amount of drug being delivered to the skin owing to the drug‘s long circulation in the bloodstream; conversely, doxorubicin alone did not result in significant delivery to the skin, possibly owing to its short half-life in the blood. This study serves as an important finding for clinical applications of drug targeting [10].

Lipoplatin^® (Regulon Inc., Mountain View, CA, USA) is a liposomal cisplatin encapsulated within liposomes with an average diameter of 110 nm. Lipoplatin is used to treat cancer in Kaposi‘s sarcoma and multiple myeloma. Lipoplatin has substantially reduced the renal toxicity, peripheral neuropathy, ototoxicity, myelotoxicity as well as nausea, vomiting and asthenia of cisplatin in Phase I, II and III clinical studies with enhanced or similar efficacy to cisplatin [11]. Myocet^TM (Elan Pharmaceuticals Inc., One Research Way, NJ, USA), a non-PEGylated liposomal product (average diameter: 180 nm) encapsulating doxorubicin citrate, has been shown to offer a significant decrease in cardiotoxicity compared with doxorubicin in the treatment of metastatic breast cancer patients [12]. Daunoxome^® (NeXstar Pharmaceuticals, Boulder, CO, USA) is an anticancer liposomal product with a particle size range of 60–80 nm and encapsulates daunorubicin. Daunorubicin was recently marketed for the treatment of Kaposi‘s sarcoma in AIDS [6]. Lipusu^® (Luye Pharma Group Co. Ltd, Beijing, China), an anticancer liposomal product that encapsulates paclitaxel and was marketed in China in 2006 for the indications of oophoron and ovarian metastatic carcinoma [13]. Aizhen and colleagues compared the cytotoxic and anticancer effects of Lipusu with those of paclitaxel injection in the same dose, and suggested that Lipusu had similar anticancer activity in vitro and in vivo but its toxicity was lower than that of paclitaxel injection [14]. In another study, Chen and colleagues compared Lipusu with conventional paclitaxel treatments for breast cancer and non-small-cell lung cancer, and demonstrated that both therapies had similar efficacy; however, Lipusu reduced the incidence of serious hypersensitive reactions significantly compared with conventional paclitaxel [15]. Onco TCS™ (Enzon Pharmaceuticals Inc., Bridgewater, NJ, USA) is another liposomal product (diameter range: 120–130 nm) of vincristine that is awaiting approval by the FDA as a single agent for the treatment of patients with relapsed aggressive non-Hodgkin‘s lymphoma after a combination therapy [8].

Conclusion

This article discussed recent developments in the nanopharmacology and toxicology of liposomes regarding their role in emerging nanoliposomal formulations for the treatment of cancer. The marketed liposomal products have already made an impact on cancer treatment owing to their dual function: reduction of the toxicity of existing treatments and maximization of efficacy by selective targeting of tumors. Analytical approaches for liposomes are required that reflect the properties of the liposomes and the release kinetics of the encapsulated drug in tissues, in addition to plasma pharmacokinetics. Furthermore, novel drug delivery systems (e.g., stimulus responsive functions) are required to exploit the liposomal products, enabling advanced chemotherapy with higher efficacy and lower toxicity.

Acknowledgements

Madaswamy S Muthu acknowledges the Department of Science and Technology (DST), New Delhi, India, for the award of the BOYSCAST Fellowship (SR/BY/L-41/09) for young scientists in the year of 2009–2010.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.