Paclitaxel-loaded iron platinum stealth immunomicelles are potent MRI imaging agents that prevent prostate cancer growth in a PSMA-dependent manner.
METHODS
Problems with the clinical management of prostate cancer include the lack of both specific detection and efficient therapeutic intervention. We report the encapsulation of superparamagnetic iron platinum nanoparticles (SIPPs) and paclitaxel in a mixture of polyethyleneglycolated, fluorescent, and biotin-functionalized phospholipids to create multifunctional SIPP-PTX micelles (SPMs) that were conjugated to an antibody against prostate-specific membrane antigen (PSMA) for the specific targeting, magnetic resonance imaging (MRI), and treatment of human prostate cancer xenografts in mice.


RESULTS
SPMs were 45.4 ± 24.9 nm in diameter and composed of 160.7 ± 22.9 μg/mL iron, 247.0 ± 33.4 μg/mL platinum, and 702.6 ± 206.0 μg/mL paclitaxel. Drug release measurements showed that, at 37°C, half of the paclitaxel was released in 30.2 hours in serum and two times faster in saline. Binding assays suggested that PSMA-targeted SPMs specifically bound to C4-2 human prostate cancer cells in vitro and released paclitaxel into the cells. In vitro, paclitaxel was 2.2 and 1.6 times more cytotoxic than SPMs to C4-2 cells at 24 and 48 hours of incubation, respectively. After 72 hours of incubation, paclitaxel and SPMs were equally cytotoxic. SPMs had MRI transverse relaxivities of 389 ± 15.5 Hz/mM iron, and SIPP micelles with and without drug caused MRI contrast enhancement in vivo.


CONCLUSIONS
Only PSMA-targeted SPMs and paclitaxel significantly prevented growth of C4-2 prostate cancer xenografts in nude mice. Furthermore, mice injected with PSMA-targeted SPMs showed significantly more paclitaxel and platinum in tumors, compared with nontargeted SPM-injected and paclitaxel-injected mice.
Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA. rmtaylor@salud.unm.edu
Robert M
RM
Taylor
Laurel O
LO
Sillerud
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D043425:Glutamate Carboxypeptidase II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007501:Iron / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008279:Magnetic Resonance Imaging / Q000295:instrumentation; D058185:Magnetite Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D017239:Paclitaxel / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010316:Particle Size; D010984:Platinum / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D000954:Antigens, Surface; D000972:Antineoplastic Agents, Phytogenic; D003287:Contrast Media; D018796:Immunoconjugates; D058185:Magnetite Nanoparticles; D008823:Micelles; D010984:Platinum; D007501:Iron; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017239:Paclitaxel