Featured Article: Chemotherapeutic delivery using pH-responsive, affinity-based release

Abstract

Impact statementDoxorubicin (DOX) is especially cytotoxic to the heart, liver, kidneys, and healthy tissues surrounding the tumor microenvironment. This systemic toxicity can be partially addressed by local, tumor-specific drug delivery systems. While pH-sensitive DOX delivery systems have been developed by several other groups, many lack a prolonged and consistent release profile required to successfully treat heterogeneous tumors. Our system of a chemically modified form of DOX combined with an affinity-based cyclodextrin delivery system is capable of delivering DOX for 87 days while maintaining its the drug cytotoxicity. This finding is particularly relevant to improving cancer treatments because it enables regulated local delivery of DOX specifically to tumor tissue and allows the drug to be continuously delivered over a therapeutically relevant amount of time. AbstractDoxorubicin is a chemotherapeutic drug typically administered systemically which frequently leads to cardiac and hepatic toxicities. Local delivery to a tumor has a chance to mitigate some of these toxicities and can further be mitigated by including a means of tumor-specific drug release. Our laboratory has explored the use of molecular interactions to control the rate of drug release beyond that capable of diffusion alone. To this system, we added an additional affinity group (adamantane) to doxorubicin through a pH-sensitive hydrazone bond. The result was a modified doxorubicin which had an even higher affinity to our drug delivery polymer, and virtually no release in normal conditions, but showed accelerated release of drug in tumor-like low pH. Further, we show that adamantanemodified doxorubicin (adamantane-doxorubicin) and cleaved adamantane-doxorubicin showed equivalent capacity to kill human U-87 glioblastoma cells in vitro as unmodified doxorubicin. Taken together, these data demonstrate our ability to load high levels of modified chemotherapeutic drugs into our affinity-based delivery platform and deliver these drugs almost exclusively in the acidic microenvironments, such as those surrounding the tumor tissue via pH-cleavable bond while minimizing drug delivery in neutral pH tissue, with the ultimate goal of reducing systemic through better local delivery.

Surface sulfonamide modification of poly(N‐isopropylacrylamide)‐based block copolymer micelles to alter pH and temperature responsive properties for controlled intracellular uptake

“…In the case of tumor microenvironments, the slightly acidic tumor conditions are attributed to the elevated metabolism and proliferation of tumor cells. Another method used to achieve site‐specific delivery of drugs in mildly acidic conditions involves the incorporation of an acid‐labile hydrazone bond in the backbone of the drug …”

“…Another method used to achieve site-specific delivery of drugs in mildly acidic conditions involves the incorporation of an acid-labile hydrazone bond in the backbone of the drug. 12,27,29,31,34 Building upon the success of thermoresponsive and pHresponsive delivery systems, some groups have combined these two stimuli to develop dual-stimuli responsive delivery systems. [11][12][13][14][15][16][17] The benefit of such dual-responsive delivery systems is that the stimuli synergistically work together to modulate drug release.…”

Injectable liquid polymers extend the delivery of corticosteroids for the treatment of osteoarthritis

“…[22,23] Our polymers may allow for the exploration of formulations with new rheological properties while sustaining release of relevant pharmacological agents or have the release triggered by an endogenous or exogenous stimuli. [35] Similar work has been done in the design of small conjugates for environmental water treatment and found preferential loading of active pharmaceutical ingredients from certain crosslinkers over others. [36,37] This preferential loading may be a factor of molecular recognition provided by the cyclodextrin to crosslinker combination or alternatively, by an alteration of the thermodynamic parameters that drive the complexation behavior.…”

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

“…Moreover, the identification of key descriptors and the use of predictive software could lead to new chemistries for extending drug delivery. Beyond using the traditional adamantane-CD bond for improved drug delivery [46,50], recent work has shown that molecular tethering of multiple drug molecules can improve interactions with CD-based polymers [51]. Specifically, the delivery window for rapamycin, traditionally a quickly-diffusing and relatively insoluble drug, was tripled to 65 days of release in a "dimeric" formulation versus the standard drug molecules, while maintaining antifibrotic activity [51].…”