Journal
MOLECULAR PHARMACEUTICS
Volume 13, Issue 4, Pages 1217-1228Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.5b00670
Keywords
alendronate; prostate cancer; bisphosphonates; cell penetrating peptides; self-assembling nanoparticles
Funding
- Royal Pharmaceutical Society of Great Britain
- EPSRC [EP/H031065/1]
- Engineering and Physical Sciences Research Council [EP/I016104/1, EP/H031065/1] Funding Source: researchfish
- EPSRC [EP/I016104/1, EP/H031065/1] Funding Source: UKRI
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Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles. We hypothesized that complexation with RALA could similarly be used. to conceal a BP's hydroxyapatite affinity, and to enhance bioavailability, thereby improving anticancer efficacy. Incubation of RALA with alendronate, etidronate, risedronate, or zoledronate provoked spontaneous electrostatic formation of cationic nanoparticles that did not exceed 100 nm in diameter and that were stable over a range of temperatures and for up to 6 h. The nanoparticles demonstrated a pH responsiveness, possibly indicative of a conformational change, that could facilitate release of the BP cargo in the endosomal environment. RALA/BP nanoparticles were more potent anticancer agents than their free BP counterparts in assays investigating the viability of PC3 prostate cancer and MDA-MB-231 breast cancer cells. Moreover, RALA complexation potentiated the tumor growth delay activity of alendronate in a PC3 xenograft model of prostate cancer. Taken together, these findings further validate the use of BPs as repurposed anticancer agents.
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