A general prodrug nanohydrogel platform for reduction-triggered drug activation and treatment of taxane-resistant malignancies.

Chemotherapy has been widely used for treating the vast majority of cancer patients. Unfortunately, only a fraction of patients can respond to chemotherapies, but these patients still experience severe side effects. In this context, a wide range of nanotherapeutic platforms have been developed with the aim of improving treatment outcomes while reducing drug toxicities. Nanohydrogels are highly appealing "smart" biocompatible and biodegradable vehicles for either local or systemic delivery of bioactive compounds. Here, we developed prodrug hydrogelators that can undergo one-step distillation-precipitation polymerization to form systemically injectable nanohydrogels. The optimized nanohydrogels were capable of rapidly releasing active agents (e.g., the cytotoxic agent cabazitaxel or the PI3K molecular inhibitor PI103) in response to the reducing tumor microenvironment, while drug release was very slow in the absence of the reductive reagent glutathione. Cabazitaxel-loaded nanogels showed preferential tumor accumulation, and administration of nanogels produced durable tumor regression in a docetaxel-resistant cervical tumor xenograft-bearing mouse model. More significantly, nanogel-based therapy was proven to demonstrate a higher safety profile than solution-based free cabazitaxel. Collectively, this study provides an alternative formulation that meets the essential requirements of high stability in the blood, spontaneous drug release at diseased sites, favorable safety in vivo, and translational capacity for further investigations. STATEMENT OF SIGNIFICANCE: Chemotherapy remains a considerable challenge and only a fraction of patients can respond to chemotherapies. Here we report an intratumoral reducing agent-activatable, tumor-targeting prodrug nanogel platform for therapeutic delivery. To this end, two anticancer agents (e.g., cytotoxic cabazitaxel or PI3K molecular inhibitor PI103) are tested. Prodrug nanogels are stable in the blood but performed reduction-triggered release of chemically unmodified drug molecules in cancerous tissues. Cabazitaxel-loaded nanogels exhibit satisfactory anticancer performance in a preclinical docetaxel-resistant tumor model. This is a practical and expedient approach that combines the prodrug strategy and nanogel scaffold to re-engineer a hydrophobic and toxic anticancer drug. The approach also is broadly applicable for the formulation of other agents to improve the therapeutic index.

Tuning the efficacy of esterase-activatable prodrug nanoparticles for the treatment of colorectal malignancies.

Colorectal cancer (CRC) is one of the most common and lethal human cancers, and the clinical outcomes remain unsatisfactory because of the lack of effective and safe therapeutic regimens. Here, we describe a practical and potent delivery approach for the human topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38) against CRC. Injectable SN38-loaded nanoparticles are obtained through covalent ligation of the SN38 agent with oligo-ε-caprolactone (oligoCL) to form oligoCL-SN38 conjugates via an esterase-activatable linkage followed by encapsulation of these prodrugs in exogenous polymer matrices. Prodrug nanoparticles with adaptive features are sufficiently stable during blood circulation, while active drugs can be released in response to intracellular esterase. The administration of nanoparticle drugs results in durable tumor recession, and the efficacy is superior to that of the current standard-of-care therapy, CPT-11, in multiple mouse models of CRC, one of which is a chemically induced orthotopic CRC. Elucidation of the mechanism underlying these differing efficacies shows that nanoparticle delivery produces a substantial increase in the intratumoral concentration of the therapeutic agent relative to CPT-11, which contributes to improved antitumor efficacy. Finally, these nanoparticle drugs are potentially less toxic in animals than CPT-11, as evidenced by the low incidence of bloody diarrhea and attenuated colonic damage. Overall, these results demonstrate that precisely engineered therapeutic nanoparticles are capable of enhancing efficacy, addressing the risk of tumor recurrence, and increasing drug tolerance, thus deserving further investigation.