Formulation and antitumor activity evaluation of nanocrystalline suspensions of poorly soluble anticancer drugs.
OBJECTIVE
Determine if wet milling technology could be used to formulate water insoluble antitumor agents as stabilized nanocrystalline drug suspensions that retain biological effectiveness following intravenous injection.


METHODS
The versatility of the approach is demonstrated by evaluation of four poorly water soluble chemotherapeutic agents that exhibit diverse chemistries and mechanisms of action. The compounds selected were: piposulfan (alkylating agent), etoposide (topoisomerase II inhibitor), camptothecin (topoisomerase I inhibitor) and paclitaxel (antimitotic agent). The agents were wet milled as a 2% w/v solids suspension containing 1% w/v surfactant stabilizer using a low energy ball mill. The size, physical stability and efficacy of the nanocrystalline suspensions were evaluated.


RESULTS
The data show the feasibility of formulating poorly water soluble anticancer agents as physically stable aqueous nanocrystalline suspensions. The suspensions are physically stable and efficacious following intravenous injection.


CONCLUSIONS
Wet milling technology is a feasible approach for formulating poorly water soluble chemotherapeutic agents that may offer a number of advantages over a more classical approach.
Merisko-Liversidge
E
E
NanoSystems, Collegeville, Pennsylvania 19426, USA.
Sarpotdar
P
P
Bruno
J
J
Hajj
S
S
Wei
L
L
Peltier
N
N
Rake
J
J
Shaw
J M
JM
Pugh
S
S
Polin
L
L
Jones
J
J
Corbett
T
T
Cooper
E
E
Liversidge
G G
GG
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002627:Chemistry, Physical; D003460:Crystallization; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008809:Mice, Inbred C3H; D010316:Particle Size; D012995:Solubility; D013535:Suspensions
D000970:Antineoplastic Agents; D013535:Suspensions