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Interleukin-2: Evaluation of Routes of Administration and Current Delivery Systems in Cancer Therapy

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ABSTRACT:

Despite the fact that different administration routes and delivery systems have been used for interleukin-2 (IL-2) delivery, little has been reported regarding the most efficient strategies used to deliver IL-2 in a nontoxic, efficient, stable and safe manner. Systemic IL-2 administration has always been associated with rapid clearance and severe toxicity as a result of its narrow therapeutic index. Loco-regional IL-2 delivery, however, is used to localize IL-2 actions and activities into the vicinity of tumors and can result in an improved therapeutic outcome with much less side effects or toxicity. The purpose of this review is to report on the different properties and aspects of IL-2, including its mechanism of action, physicochemical properties, and structure which have an impact on the activity, stability and formulation of IL-2 dosage forms and delivery systems. In addition, advantages and limitations of the currently available techniques and strategies to deliver IL-2 will also be covered. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association.

Section snippets

INTRODUCTION

Interleukin-2 (IL-2) is a cytokine messenger protein, which activates parts of the immune system. It is one of the members of the interleukins family that was discovered in early 1976.1 Although members of this family are structurally similar, IL-2 demonstrated an extraordinary unique contribution to the concept of immunotherapy as a whole and to cancer therapy in specific. IL-2 is particularly important as it regulates both inflammatory and immune responses by stimulating the growth of blood

MECHANISMS OF ACTION

Although most of the issues relating to how IL-2 exerts its effect are fairly clear, the exact cellular mechanism of action of IL-2 is still not yet fully understood. Several theories were proposed on explaining the cellular mechanism of IL-2,33, 34 however, the most acceptable theory today states that IL-2 is taken by activated CD4+ T-cells which express IL-2 specific receptors.35 Those receptors are reported to be composed of three subunits: IL-2 receptor alpha (IL-2Rα), beta (IL-2Rβ), and

PHYSICAL PROPERTIES AND STRUCTURE

The structure and the physicochemical properties of IL-2 are important aspects in understanding the function, activity and in designing the optimal therapeutic strategies and delivery systems for this cytokine. IL-2 is a member of a four-helical bundle family of proteins. It has a structure similar to that of human growth hormone and reported to have an isoelectric point (pI) of 7.9. It is susceptible to deamidation of asparagine amino acid, at position 88 of its amino acid sequence, upon its

PHARMACOKINETICS

The rate and extent at which the maximum IL-2 concentration is reached in the bloodstream depends mainly on its physicochemical properties (molecular weight, size, and degree of glycosylation), the dosage form design, and its route of administration.

As it is the case with all the other acid-sensitive protein drugs, IL-2 faces many stability and physiological challenges when given orally. This explains the reason for it being mainly given by alternative routes of administration. For most

LOCO-REGIONAL VERSUS SYSTEMIC DELIVERY

Although systemic injections (i.v., im, and i.p.) are reported to be the most commonly used routes for delivering IL-2 when used in cancer immunotherapy,31, 62 the intratumoral and loco-regional administration strategies of this cytokine has been reported to be more successful and of much effectiveness against a broad range of cancers, specifically those associated with solid tumors.81, 82 This mode of IL-2 administration provides many advantages over systemic administration. First, local IL-2

SUSTAINED (CONTINUOUS) VERSUS INTERMITTENT RELEASE

In view of the discussion above, the following questions come to mind: What is the maximum concentration required in the local microenvironment? Do we need an intermittent or continuous release of IL-2? Although, several recent studies described the application of IL-2 and the superiority of its regional delivery over its systemic administration in the treatment of different tumors,102 little has been reported regarding the most efficient and least toxic mode of delivering this cytokine to its

DELIVERY SYSTEMS AND DOSAGE FORMS: ADVANTAGES AND LIMITATIONS

Since its discovery in 1976, different delivery systems and strategies have been explored to formulate and deliver IL-2 while at the same time trying to achieve two major goals. The first is to deliver and target IL-2 specifically and safely to its site of action to maximize its therapeutic efficacy while minimizing its toxicity. The other is to overcome stability issues during the preparation of dosage forms containing this cytokine, and to help in maintaining its stability during storage of

CONCLUSIONS

The following conclusions can be drawn from this review: first, continuous and loco-regional delivery of IL-2 in the vicinity of the tumor site is a desirable mode of delivery as it closely reflects the cytokine natural release pattern and results in a more effective treatment with fewer side effects. Second, long-acting formulations such as PEGylation and protein fusion techniques, prolongs IL-2 action but do not adapt with IL-2 localization concept. Third, of the examined localized IL-2

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