Review articleSafe approaches for camptothecin delivery: Structural analogues and nanomedicines
Introduction
Camptothecin (CPT) is a water insoluble, natural pentacyclic alkaloid isolated from the oriental tree Camptotheca accuminata by Wall et al. in 1966 [1]. CPT is well-known for its antitumor activity against a wide spectrum of human cancers [2], [3], [4], [5], [6], [7], [8]. In addition, a variety of biological activities, such as pesticidal [9], [10], antipsoriasis [11], [12], antiparasitic [13], antifungal [14], antimicrobial [15] and antiviral [16], [17] has been described for this compound. Certainly, several researchers have reported that CPT inhibits a cellular enzyme DNA topoisomerase I and induces apoptosis in various cancer cells [18], [19].
CPT is a planar pentacyclic quinoline that includes 3 rings of pyrrolo-(3,4-β)-quinoline part (A, B, and C rings), an unsaturated pyridone moiety in ring D and a α-hydroxy lactone ring (E ring), containing one chiral center with (S)-configuration (Fig. 1) [20], [21]. It is worth noting that the isomer 20(R) hydroxyl has little activity while the isomer 20(S) is between 10 and 100 fold more active [22]. Also, it is known that E-ring exists in equilibrium between the lactone form (closed ring, not water insoluble) and the carboxylate form (open ring, water soluble). In acidic pH, the lactone predominates which, according to different clinical trials and structure-activity studies, is the only therapeutic molecule.
However, at physiological pH, the lactone ring is converted into the carboxylate, much less active, which predominates at neutral and alkaline pH [23], [24].
Unfortunately, CPT presents some major limitations with regards to therapeutic application, like poor water solubility and the rapid lactone ring hydrolysis at physiological pH, which gives rise to the inactive carboxylate form [25]. In addition, CPT is extremely insoluble in organic compounds except for dimethyl sulfoxide, in which it shows moderate solubility [26]. Due to CPT insolubility in biocompatible solvents, it is very difficult to apply conventional drug administration routes, including oral, intravenous or intramuscular injection, to distribute this compound throughout the body [27]. Furthermore, there are other negatives aspects that limit the use of CPT in clinical trials: pronounced loss of activity due to lactone-ring hydrolysis, reversibility of drug-target interaction and severe toxicity, including hemorrhagic cystitis and myelotoxicity [28]. All these drawbacks have precluded its clinical application, making necessary to develop alternative compounds and structures for CPT use in humans.
In an effort to improve CPT solubility and pharmacokinetics structural derivatives as topotecan and irinotecan have been developed [29], [30] (see Table 1). Unfortunately, as it will be reported later on, CPT quinoline structure modification usually brings out a dramatic drop of cytotoxic activity, which results one order or even lower than pristine drug, strongly limiting the therapeutic use.
To overcome these issues two strategies have been pointed out for safety and efficient CPT delivery to target cells: i) structural analogues, in which the CPT molecule is chemically modified for increased solubility and stability in biological fluids; and ii) nanomedicines, wherein CPT is incorporated by physico-chemical methods to nanoparticles which act as stable carriers for drug delivery. In this review, we summarize the most advanced and recent achievements in the design, synthesis and development of CPT analogues and nanomedicines, including the most relevant formulations currently under clinical use.
Section snippets
Camptothecin analogues
Since the discovery of CPT and the associated therapeutic limitations, huge scientific efforts are being made to improve the pharmacokinetics, drug resistance, clinical efficacy, and toxicity profiles of the original molecule, by introducing organic ligands [31], [32], [33], [34], [35], [36].
Nanoparticles as drug delivery systems for camptothecin
Many types of nanovehicles have been developed for CPT delivery, and these drug delivery systems (DDSs) may be classified in several ways, according to their chemical nature, structure, composition, morphology, etc. Herein, we present a systematic classification of CPT nanocarriers according to their chemical nature in organic, inorganic and hybrid materials, presenting different properties and behaviors [72], [73], [74], [75]. These novel nanoplatforms have been designed to solve most of the
Stimuli responsive systems
These are currently the most representative DDSs in Nanomedicine. The main characteristic is their ability to deliver a therapeutic agent into the target cells with no previous release. This is due to the accurate control of the release process through a specific intracellular stimulus, which minimizes undesired side effects. Stimuli-responsive nanocarriers can be classified in endogenous or exogenous, depending on the stimulus which activates the drug release mechanism. Examples of endogenous
Clinical testing
One of the most disputable arguments again nanomedicines is that, despite the strong publication statistics over the last decade, very few drugs have reached the commercial market yet [79]. Although it is accepted that nanocarriers improve solubility, efficacy and biodistribution, while decreasing adverse side effects of very cytotoxic drugs as CPT, strict regulations concerning their use in human beings have hampered, so far, a quicker translation of these therapeutic platforms into the
Conclusion and future directions
CPT is one of the most active molecules for cancer treatment, but its particular limitations as poor solubility, lack of stability of the lactone ring and strong toxicity, have encouraged the development of different delivery forms in order to achieve a safe approach. Here, it is a fact that current cancer treatment cannot be tackled as the administration of a single therapeutic molecule but, instead, the new target is personalized medicine, which selects the appropriate drug combination and
Acknowledgements
Financial support of the Spanish Ministry of Economy and Competitiveness (projects MAT2012-39290-C02-02 and SEV-2012-0267) is gratefully acknowledged. Dr. E.M. Rivero thanks the Cursol Foundation for a post-doctoral scholarship. Prof. Eduardo Fernández and Dr. Ibane Abasolo are acknowledged for the useful discussion.
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