The
ability to activate drugs only at desired locations avoiding
systemic immunosuppression and other dose limiting toxicities is highly
desirable. Here we present a new approach, named local drug activation,
that uses bioorthogonal chemistry to concentrate and activate systemic
small molecules at a location of choice. This method is independent
of endogenous cellular or environmental markers and only depends on
the presence of a preimplanted biomaterial near a desired site (e.g.,
tumor). We demonstrate the clear therapeutic benefit with minimal
side effects of this approach in mice over systemic therapy using
a doxorubicin pro-drug against xenograft tumors of a type of soft
tissue sarcoma (HT1080).
While systemic immuno-oncology therapies have shown remarkable success, only a limited subset of patients benefit from them. The Click Activated Protodrugs Against Cancer (CAPAC) platform is a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. The CAPAC Platform is agnostic to tumor characteristics that can vary across patients and hence applicable to several types of tumors. The benefits of SQ3370 (lead candidate of CAPAC) are described to achieve systemic anti-tumor responses in mice bearing two tumors. SQ3370 consists of a biopolymer, injected in a single lesion, followed by systemic doses of an attenuated protodrug of doxorubicin (Dox). SQ3370 is well-tolerated at 5.9-times the maximum dose of conventional Dox, increased survival by 63% and induces a systemic anti-tumor response against injected and non-injected lesions. The sustained anti-tumor response also correlates with immune activation measured at both lesions. SQ3370 can potentially benefit patients with micro-metastatic lesions.
The Click Activated Protodrugs Against Cancer (CAPAC) platform uses click chemistry to activate cytotoxic drugs directly at a target site with minimal toxicity, overcoming limitations of conventional chemotherapy and traditional targeted therapies.
Systemic administration
of antibiotics can cause severe side-effects
such as liver and kidney toxicity, destruction of healthy gut bacteria,
as well as multidrug resistance. Here, we present a bio-orthogonal
chemistry-based strategy toward local prodrug concentration and activation.
The strategy is based on the inverse electron-demand Diels–Alder
chemistry between trans-cyclooctene and tetrazine
and involves a biomaterial that can concentrate and activate multiple
doses of systemic antibiotic therapy prodrugs at a local site. We
demonstrate that a biomaterial, consisting of alginate hydrogel modified
with tetrazine, is efficient at activating multiple doses of prodrugs
of vancomycin and daptomycin in vitro as well as in vivo. These results support a drug delivery process that
is independent of endogenous environmental markers. This approach
is expected to improve therapeutic efficacy with decreased side-effects
of antibiotics against bacterial infections. The platform has a wide
scope of possible applications such as wound healing, and cancer and
immunotherapy.
Specific and targeted delivery of medical therapies continues to be a challenge for the optimal treatment of multiple medical conditions. Technological advances permit physicians to target most sites of the body. However, after the intervention, physicians rely on systemic medications that need frequent dosing and may have noxious side effects. A novel system combining the temporal flexibility of systemic drug delivery and the spatial control of injectable biomaterials would improve the spatiotemporal control of medical therapies. Here we present an implantable biomaterial that harnesses in vivo click chemistry to enhance the delivery of suitable small molecules by an order of magnitude. The results demonstrate a simple and modular method to modify a biomaterial with small molecules in vitro and present an example of a polysaccharide modified hours after in vivo implantation. This approach provides the ability to precisely control the moment when biochemical and/or physical signals may appear in an implanted biomaterial. This is the first step towards the construction of a biomaterial that enhances the spatial location of systemic small molecules via in vivo chemical delivery.
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