Ceramide and N,N,N-Trimethylphytosphingosine-Iodide (TMP-I)-Based Lipid Nanoparticles for Cancer Therapy.
OBJECTIVE
To evaluate the anti-tumor effect of ceramide or trimethylphytosphingosine-iodide (TMP-I) containing solid lipid nanoparticles (SLNs) prepared using trymyristin, phosphatidylcholine (PC), and Pluronic P85 (P85) for intravenous delivery of docetaxel.


METHODS
Docetaxel-loaded SLNs using ceramide or TMP-I at 3.22% (w/w) with a mean diameter of 89-137 nm were successfully prepared by high pressure homogenization. The prepared nanoparticles were characterized by particle size, zeta potential, drug content, and TEM analysis. Cellular uptake and cytotoxicity were studied using adriamycin-resistant breast cancer (MCF-7/ADR) cells. The optimized formulation's dissolution profile, pharmacokinetics, and antitumor effect in mice tumor model were compared with that of control (Taxotere(®)).


RESULTS
The drug release rate of docetaxel from SLNs was lower than that of control (Taxotere(®)). The prepared SLNs showed higher cellular uptake of docetaxel compared to that of Taxotere(®) in MCF-7/ADR cell lines, which was further confirmed by the confocal laser scanning microscopy (CLSM) study using coumarin 6 (C6). Prepared SLNs exhibited significantly increased antitumor efficacy, compared to Taxotere(®), in MCF-7/ADR cells. In vivo pharmacokinetic study in rats (at 10 mg/kg dose) showed that the SLNs significantly reduced in vivo clearance of drug than Taxotere(®). Interestingly, ceramide and TMP-I SLNs efficiently inhibited the tumor growth compared to Taxotere(®) in MCF-7/ADR tumor xenografted mouse model.


CONCLUSIONS
This work showed that TMP-I and ceramide SLNs not only significantly enhanced systemic exposure of drug, but also increased antitumor efficacy compared to Taxotere(®) and control SLN.
College of Pharmacy, Hanyang University, Ansan, 426-791, Republic of Korea. prabagarb@gmail.com.|School of Medicine, Stony Brook University, HSC, Stony Brook, NY, 11794, USA. prabagarb@gmail.com.
Prabagar
http://orcid.org/0000-0003-0221-0207
P
Balakrishnan
Institute of Nano Science and Technology, Hanyang University, Seoul, 133-791, Republic of Korea.
Chung Kil
CK
Song
Department of Bio-Chemical Engineering, Graduate School, Dongseo University, Busan, 617-716, Republic of Korea.
Alexander
A
Jahn
College of Pharmacy, Kangwon National University, Chuncheon, 200-701, Republic of Korea. hjcho@kangwon.ac.kr.
Hyun-Jong
HJ
Cho
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002518:Ceramides / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D000077143:Docetaxel; D005079:Excipients; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy*; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry; D011060:Poloxalene; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002518:Ceramides; D003692:Delayed-Action Preparations; D005079:Excipients; C577077:N,N,N-trimethylphytosphingosine; D010713:Phosphatidylcholines; D000644:Quaternary Ammonium Compounds; D043823:Taxoids; C422648:pluronic block copolymer p85; D000077143:Docetaxel; D011060:Poloxalene; D013110:Sphingosine
ceramide; enhanced antitumor activity; multidrug resistance; reduced in vivo clearance; solid lipid nanoparticles; trimethylphytosphingosine-iodide