Acid-sensitive linkers for drug delivery

#The invention is in general directed to acid-sensitive linkers, and methods of use thereof, such as, for example, in drug delivery methods.

#Chemotherapy has made a significant impact on the longevity and quality of life of those affected by cancer. The influence a drug may have on the outcome of cancer treatments, however, is highly dependent on the ability of the therapeutic to selectively and effectively kill targeted malignant cells while leaving normal cells untouched. Addressing this challenge has been a central focus for the discovery of new therapeutics that can alter specific biological processes that are critical to the survival of cancer cells. New methods of administering drugs (i.e., orally, systemically, or loco-regionally) also plays a critical role in the development of new treatment strategies for effective management of cancer. [10-16] Although a number of small molecules are known to have potent cytotoxicity towards cancer cells, relatively few anticancer agents are used clinically due, in part, to low therapeutic windows for drug efficacy compared to drug-related toxicity.[17] Drug delivery systems (DDSs) have, therefore, attracted wide attention in cancer research due to their potential to significantly reduce the toxicity of anticancer agents in normal healthy tissues, while making it possible to control the concentration and location of active drugs released in the body over long periods of time.[18] DDSs may also be used to increase the potency of drugs by increasing their accumulation at targeted tissues compared to administration of equitoxic levels of free drugs in solution.[19, 20]

#DDSs have already been shown to play a critical role in the development of effective therapeutic strategies against several forms of cancer.[21] Nanoparticle carriers, for instance, are useful as systemically-administered delivery vessels for cancer therapeutics to solid tumors[22-26] due to their enhanced permeability from leaky blood vessels in tumor tissues compared to blood vessels in healthy tissues.[27-29]

#FIG. 1 depicts a proposed mechanism for the hydrolysis of N-alkoxyalkylimidazoles in aqueous acidic solutions. RDS=rate determining step.

#FIG. 2 depicts a linear Hammett correlation for the hydrolysis of compounds 1-4 in 0.5 M MES buffered D2O (pD=5.5) at 37° C., where R=n-butyl (Bu), H, Br, and NO2.

#FIG. 3 depicts an example of a general procedure for the synthesis of N-ethoxybenzylimidazoles 1-8 from the corresponding benzaldehydes.

#It has been found that N-linked imidazoles may be used as tunable acid-sensitive linkers. These linkers undergo hydrolysis in aqueous acidic solutions at physiological temperature, upon protonation of the imidazole group. The difference in the protonated state of certain N-linked imidazoles in acidic pH environments (for example, pH 5.5) compared to normal, physiological pH (for example pH 7.4; pKa of imidazolium ions have been reported to be between 5 and 7 (Bruice, T. C., and Schmir, G. L., J. Am. Chem. Soc. 1958, 80:148-156)) this difference may be useful for initiating the rapid release of molecules, for example drugs, linked to imidazole-containing delivery vessels when exposed to tumor-like environments.

#Thus, in a first embodiment of the invention is a compound having the formula

#wherein R1 is selected from the group consisting of H, Br, NO2, Butyl, OMe, CN, methyl, carboxy, methyl carboxylate, a drug delivery vessel, a therapeutic, and an imaging agent; R2 is selected from the group consisting of H, NO2, Butyl, OMe, CN, Histidine, histamine, a drug delivery vessel, a therapeutic, and an imaging agent; R3 is selected from the group consisting of H, NO2, Butyl, OMe, CN, a drug delivery vessel, a therapeutic, and an imaging agent, or one of R2 and R3 is selected from the group consisting of Br, 2-aminoethyl, acetate, and N-(prop-2-ynyl)acetamide and one of R2 and R3 is H; R4 is selected from the group consisting of OCH2CH3 and OCH3 R5 is selected from the group consisting of methyl, H, and