Secretory
phospholipase A(2) (
sPLA(2)) cleave
phospholipids at sn-2
ester bonds, releasing
lysophospholipids and
fatty acids, and are over expressed in several pathologies, including
inflammation,
arthritis,
sepsis and breast and
prostate cancers. Herein we evaluated the therapeutic activity of
liposomes engineered to be responsive to different
sPLA(2)
isoforms compared to clinically used long-circulating (pegylated) sterically stabilized
liposomes (SSL) in vitro and in vivo, and assessed differences in roles of
sPLA(2) in the mechanism of uptake and delivery of these nanoparticles. Exposing
sPLA(2) responsive
liposomes (SPRL) to
sPLA(2) increased the release of intraluminal entrapped contents in a time-dependent manner that was inhibited by the
sPLA(2) inhibitor LY3117273. Treatment of
prostate cancer cells with
doxorubicin encapsulated in SSL and SPRL resulted in cytotoxicity in LNCaP, DU-145 and PC-3 cells lines comparable to free
drug. Interestingly, cytotoxicity was not altered by
sPLA(2) inhibition. Tracking of
drug and
liposome delivery using fluorescence microscopy and flow cytometry, we demonstrated that
drug uptake was
liposome-dependent, as encapsulation of
doxorubicin in SPRL resulted in 1.5 to 2-fold greater intracellular
drug levels compared to SSL.
Liposome uptake was cell-dependent and did not correlate to
doxorubicin uptake; however,
doxorubicin uptake was generally greatest in PC-3 cells, followed by DU-145 cells and then LNCaP cells. In almost all cases, uptake of one of our formulations, SPRL-E, was greater than SSL. The therapeutic activity of SPRL in vivo was demonstrated using a mouse xenograft model of human
prostate cancer, which showed that
doxorubicin entrapped within SPRL decreased
tumor growth compared to SSL, suggesting that SPRL are more effective at slowing
tumor growth than a SSL formulation similar to the FDA approved DOXIL™. Collectively, these data show the therapeutic activity of SPRL compared to SSL, yield insights into the mechanisms of action of these nanoparticles and suggest that SPRL could be useful for treatment of other pathologies that over express
sPLA(2).