Bisphosphonates and cancer: what opportunities from nanotechnology?

Abstract

Bisphosphonates (BPs) are synthetic analogues of naturally occurring pyrophosphate compounds. They are used in clinical practice to inhibit bone resorption in bone metastases, osteoporosis, and Paget's disease. BPs induce apoptosis because they can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate. In addition, the nitrogen-containing BPs (N-BPs), second-generation BPs, act by inhibiting farnesyl diphosphate (FPP) synthase, a key enzyme of the mevalonate pathway. These molecules are able to induce apoptosis of a number of cancer cells in vitro. Moreover, antiangiogenic effect of BPs has also been reported. However, despite these promising properties, BPs rapidly accumulate into the bone, thus hampering their use to treat extraskeletal tumors. Nanotechnologies can represent an opportunity to limit BP accumulation into the bone, thus increasing drug level in extraskeletal sites of the body. Thus, nanocarriers encapsulating BPs can be used to target macrophages, to reduce angiogenesis, and to directly kill cancer cell. Moreover, nanocarriers can be conjugated with BPs to specifically deliver anticancer agent to bone tumors. This paper describes, in the first part, the state-of-art on the BPs, and, in the following part, the main studies in which nanotechnologies have been proposed to investigate new indications for BPs in cancer therapy.

Figure 1

Structures (a) and (b) show the basic structures of inorganic pyrophosphate and geminal bisphosphonate, respectively, where R₁ and R₂ represent different side chains for each bisphosphonate.

Figure 2

Structures of simple bisphosphonates (1st generation), N-BPs with primary, secondary, or tertiary nitrogen function in the R₂ alkyl side chain (2nd generation) and N-BPs with heterocyclic rings in the R₂ side chain (3rd generation).

Figure 3

Isoprenoids are synthesized from the mevalonate pathway that starts from reaction catalyzed by the 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (the rate-limiting reaction in cholesterol biosynthesis) which catalyzes the conversion of HMG-CoA to mevalonic acid. The pathway triggered by this reaction can lead to the synthesis of a key isoprenoid molecule, the farnesyl-pyrophosphate (Farnesyl-PP), whose formation is catalyzed by the farnesylpyrophosphate synthase (FPPS). Farnesyl-PP can be either converted by a series of reactions in cholesterol or can be transferred on target cellular proteins as Farnesyl-PP itself (reaction catalyzed by farnesyltransferase, FTase) or firstly converted in geranyl-geranyl-pyrophosphate (Geranyl-Geranyl-PP) and then transferred on cellular proteins by type I or type II geranylgeranyl-transferase (GGTase). FTase and GGTase-I catalyze the prenylation of substrates with a carboxy-terminal tetrapeptide sequence called a CAAX box, where C refers to cysteine, A refers to an aliphatic residue, and X typically refers to methionine, serine, alanine, or glutamine for FTase or to leucine for GGTase-I. Following prenylation of physiological substrates, the terminal three residues (AAX) are subsequently removed by a CAAX endoprotease, and the carboxyl group of the terminal cysteine is methyl esterified by a methyltransferase. At this moment prenyl substrates, such as Ras, are ready to be located on the inner side of the biological membranes to receive signals mediated by external factors. ZOL specifically inhibits the FPPS activity required for the synthesis of farnesyl and geranylgeranyl lipidic residues blocking prenylation of Ras that regulates the proliferation, invasive properties, and proangiogenic activity of human tumour cells.