A Chemical Strategy of Developing Resistance-Proof, Immune-Friendly Drugs

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Clever synthetic strategies have been used to develop highly potent drugs such as antibiotics and chemotherapeutic agents, but concurrently bacteria and cancer cells have also developed mechanisms of resistance. Such drug-resistance is proven to be devastating for patients and bewildering for the physicians. We submit the novel idea of potentiating drugs against resistant organisms and cells using simple yet reversible chemical modification. As a proof of principle, we propose to use some chemotherapeutic agents (CAs) as drugs for modification. Cancer cells develop resistance to CAs and the rarely-dividing cancer stem cells are refractory to CAs. This prompts the use of higher doses of the CAs, which results in the death of normal cells such as the immune cells, thereby exposing the patients to infections that often overpower them. Extensive studies performed by many groups including ours establish that the dietary polyphenol curcumin (CC) eliminates chemoresistance, kills cancer stem cells, and stimulates tumor-associated innate immune cells (microglia), converting them from a tumor-promoting (M2) to a tumoricidal (M1) state. However, CC per se is sparingly soluble in the aqueous body fluids and undergoes rapid degradation in vivo, which results in poor bioavailability. Capitalizing on the beneficial properties of CC, we will apply innovative, single-step chemistry to link CC to each of four prototypic CAs, Paclitaxel, Gemcitabine, Doxorubicin, and Methotrexate, through chemical bonds that would be cleaved by intracellular esterases and amidases upon entry of the adduct into cancer cells to release CA and CC. To stabilize and solubilize the adducts and enable their transit through the blood-brain barrier and other membranes, we will use our established strategy of encapsulating drugs into biocompatible chitosan-carbon dot hybrid nanogels with the capacity of smart release of adduct in the low-pH tumor micro-environment. The efficacy of the nanogel form of each adduct (named as Stomalignum) in eliminating patient-derived GBM stem cells in culture will then be compared with the cognate nanogel-encapsulated CA alone (named as Apo-Stomalignum). We expect that the Stomalignum would release CC to efficiently eliminate GBM stem cells whereas these cells should be resistant to the cognate Apo-Stomalignum. Subsequently, the anticancer efficacy of Stomalignum in vivo will be compared with that of the corresponding Apo-Stomalignum using our well-established orthotopic mouse model of GBM. We expect that each Stomalignum will be able to rescue the GBM mice at a much lower dose than required for the corresponding Apo-Stomalignum. The objective of this project is to develop a family of chemoresistance-proof, immune-friendly, new-generation, safe CAs. This project will also provide an excellent platform to train undergraduate researchers successively in three laboratories. They will synthesize each adduct, encapsulate it, and then use the Stomalignum alongside the cognate Apo-Stomalignum in biological tests for anti-cancer activity.