Chemotherapeutic drug delivery by tumoral extracellular matrix targeting

Abstract

Systemic chemotherapy is a primary strategy in the treatment of cancer, but comes with a number of limitations such as toxicity and unfavorable biodistribution. To overcome these issues, numerous targeting systems for specific delivery of chemotherapeutics to tumor cells have been designed and evaluated. Such strategies generally address subsets of tumor cells, still allowing the progressive growth of tumor cells not expressing the target. Moreover, tumor stem cells and tumor supportive cells, such as cancer associated fibroblasts and cancer associated macrophages, are left unaffected by this approach. In this review, we discuss an alternative targeting strategy aimed at delivery of anti-tumor drugs to the tumoral extracellular matrix with the potential to eliminate all cell types. The extracellular matrix of tumors is vastly different from that of healthy tissue and offers hooks for targeted drug delivery. It is concluded that matrix targeting is promising, but that clinical studies are required to evaluate translation.

Tumor microenvironment complexity and therapeutic implications at a glance

“…For example, LOX enzymes are widely used to block collagen crosslinking in various preclinical settings [130,131]. Alternatively, ECM components can be used to ensure a precise tumor drug delivery [132]. Tenascin-C, a300 kDa large glycoprotein, is overexpressed within the ECM of numerous cancer cells such as breast, colon, lung, and ovarian.…”

“…Chemotherapeutic agents can also be targeted to ECM of the tumor cells through the membrane-bound receptors such as tenascin-C [132]. In an interesting study, immune checkpoint inhibitors (antibodies) including anti-CTLA4 and anti-PD-L1 plus IL-2 were conjugated to the collagen-binding domain of the blood protein von willebrand factor (VWF) A3 domain to reduce side effects.…”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…The immune cells migrate then along the gradient of increasing rigidity and ECM-provided adhesion sites (haptotaxis), being diverted from the tumor cells (see Figure 2 for a detailed representation of various ways the ECM might affect immunotherapy). Thereby, the high density of the tumor ECM strongly determines not only distribution of immunomodulatory drugs but also infiltration of immune cells into the tumor (Hallmann et al, 2015;Raave et al, 2018). Increased hypoxia and metabolic stress that are in part a result of the poor diffusion in ECM-rich tumors lead to an upregulation of immunosuppressive factors like IL-10, CCL18, CCL22, TGFβ, and prostaglandin E2 and also VEGF-A (Wei et al, 2011;Xue and Shah, 2013;Schaaf et al, 2018).…”

Targeted Drug Delivery via the Use of ECM-Mimetic Materials

“…Employing DDS for localized therapy can improve drug efficacy by preventing the loss of therapeutic agent from the administration site, which minimizes necessary doses and maximizes potency. In addition, polymeric or liposomal carriers can be tailored to achieve sustained release of drugs at optimal therapeutic concentrations in a particular tissue (Sheikhpour et al, 2017;Cervadoro et al, 2018;Raave et al, 2018). As DDS for localized therapy, hydrophilic polymeric hydrogels (for hydrophilic drugs) or nanoparticles (for encapsulation of hydrophobic drugs) can be directly injected or applied to the tissue of interest to achieve sustained and controlled drug release to a particular site through diffusion (Kohane and Todd, 2008;Tibbitt et al, 2016).…”