Abstract
In the treatment of cancer, targeting of anticancer drugs to the tumor microenvironment is highly desirable. Not only does this imply accurate tumor targeting but also minimal drug release en route to the tumor and maximal drug release once there. Here we describe high-loading, “stealth-like” doxorubicin micelles as a pro-drug delivery system, which upon light activation, leads to burst-like doxorbicin release. Through this approach, we show precise spatiotemporal control of doxorubicin delivery to cells in vitro.
Highlights
Doxorubicin (DOX) is a potent cytotoxic drug used in the clinical treatment of many human cancers
Towards tumor targeting of DOX in vivo, it is envisaged micelles of 1, administered systemically, will first passively accumulate within the tumor microenvironment via the enhanced permeability and retention (EPR) effect whereupon drug release could be triggered by light, on demand
Given the limited tissue penetration of single photon UV light, options to apply UV light to tumors residing deep within the body include the use of fiber-optic endoscopic techniques [22] or 2-photon light activation [23]
Summary
Doxorubicin (DOX) is a potent cytotoxic drug used in the clinical treatment of many human cancers. Liposomal-DOX formulations (e.g., Myocet®, Doxil®) are used to treat a variety of malignant human cancers, including select breast and ovarian cancers, multiple myeloma and AIDS-related Kaposi’s sarcoma These liposome formulations, optimally 100 nm in size and administered systemically, are designed to passively accumulate within the tumor via the enhanced permeability and retention (EPR) effect. UUppoonn lliigghhtt aaccttiivvaattiioonn((336655nnmm,,1155––1177mmWW//ccmm22))hhoowweevveerr,, DDOOXX iinndduucceedd ccyyttoottooxxiicciittyy ccoorrrreellaatteedd,, aass eexxppeecctteedd,, wwiitthh bbootthh iinnccrreeaasseedd ccoonncceennttrraattiioonnss ooff 11 aass wweellll aass iinnccrreeaassiinngg iirrrraaddiiaattiioonn ttiimmee ((FFiigguurree 33bb)). >>5500%% cceellll ddeeaatthh..ItItisisalasolsoimimpoprotarntatntto tnoonteo,tbe,elboewloiwts iCtsMCCM(9C.2(9μ.M2 μ),Mth)e, tchyetoctyotxoictoitxyicoifty owfa1s walasos insignificant While this is likely due to the membrane impermeability of individual DOX-PEG constructs, these systems will no longer exist as nanoparticle assemblies and will likely demonstrate very different in vivo pharmacokinetic profiles (i.e., low vascular retention, rapid renal filtration) compared to 100 nm micelles of 1 [21]. PPrriioorr ttoo lliigghhtt aaccttiivvaattiioonn,, DDOOXX--rriicchh mmiicceelllleess aarree nnoott ccyyttoottooxxiicciittyy,, ddoo nnoott rreelleeaassee DDOOXX pprreemmaattuurreellyy aanndd sshhaarree nneeaarr iiddeennttiiccaall pphhyyssiiccoocchheemmiiccaall cchhaarraacctteerr ttoo tthhaatt ooff mmaarrkkeetteedd aanndd lloonngg--
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