Self-assembly nanoparticles for the delivery of bisphosphonates into tumors.
Bisphosphonates (BPs) are molecules able to induce apoptosis in several cancer cell lines. However, their short half-life and the rapid uptake and accumulation within bone, limit its use as antitumor agent for extra-skeletal malignancies. Here we proposed a new delivery system to avoid BP accumulation into the bone, thus improving extra-skeletal bioavailability. In this work, we used the zoledronic acid (ZOL), a third generation bisphosphonate, able to induce apoptosis at micromolar concentration. We developed ZOL-containing self-assembly PEGylated nanoparticles (NPs) based on ZOL complexes with calcium phosphate NPs (CaPZ NPs) and cationic liposomes. PEGylation was achieved by two different strategies. CaPZ NPs were covered with PEGylated liposomes (pre-PLCaPZ NPs); alternatively, CaPZ NPs were previously mixed with cationic liposomes and then PEGylated by post-insertion method (post-PLCaPZ NPs). The NPs were fully characterized in terms of mean diameter and size distribution, morphology, ZOL loading, antiproliferative effect on different cell lines. Pre-PLCaPZ NPs showed the best technological characteristics, with a narrow size distribution and a high ZOL loading. Moreover, on different cancer cell lines, these NPs enhanced the antiproliferative effect of ZOL. Finally, in an animal model of prostate cancer, a significant reduction of tumor growth was achieved with pre-PLCaPZ NPs, while the tumor was unaffected by ZOL in solution.
Department of Pharmaceutical and Toxicological Chemistry, Università degli Studi di Napoli Federico II, Naples, Italy.
G
G
Salzano
M
M
Marra
M
M
Porru
S
S
Zappavigna
A
A
Abbruzzese
M I
MI
La Rotonda
C
C
Leonetti
M
M
Caraglia
G
G
De Rosa
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002130:Calcium Phosphates / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004339:Drug Compounding; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013499:Surface Properties; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D002130:Calcium Phosphates; D004164:Diphosphonates; D007093:Imidazoles; D008081:Liposomes; D011092:Polyethylene Glycols; D000077211:Zoledronic Acid; C020243:calcium phosphate