Drug delivery and release systems for targeted tumor therapy

Abstract

Most toxic agents currently used for chemotherapy show a narrow therapeutic window, because of their inability to distinguish between healthy and cancer cells. Targeted drug delivery offers the possibility to overcome this issue by selectively addressing structures on the surface of cancer cells, therefore reducing undesired side effects. In this broad field, peptide-drug conjugates linked by intracellular cleavable structures have evolved as highly promising agents. They can specifically deliver toxophores to tumor cells by targeting distinct receptors overexpressed in cancer. In this review, we focus on these compounds and describe important factors to develop a highly efficient peptide-drug conjugate. The necessary properties of tumor-targeting peptides are described, and the different options for cleavable linkers used to connect toxic agents and peptides are discussed, and synthetic considerations for the introduction of these structures are reported. Furthermore, recent examples and current developments of peptide-drug conjugates are critically evaluated with a special focus on the applied linker structures and their future use in cancer therapy.

Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology

“…Aside from direct inhibition of NPY signaling with selective receptor antagonists, the high and universal expression of its surface receptors provides an opportunity for targeting neuroblastoma and Ewing sarcoma cells with ligands carrying radionuclides and chemotherapeutics in imaging and therapeutic applications, as previously proposed (Bohme and Beck-Sickinger, 2015). A similar strategy using the catecholamine analog, metaiodobenzylguanidin, has been successfully employed for monitoring neuroblastoma and is currently in clinical trials for its treatment (Maris, 2010; Yanik et al, 2015).…”

Covalent nano delivery systems for selective imaging and treatment of brain tumors

“…Linkers have been developed that are cleaved in response to exposure to chemistries or enzymatic activities typically found at the site of delivery [34]. Examples include pH-responsive hydrolytic cleavage of activated ester or hydrazides, and the reductive cleavage of disulfide bonds by glutathione in the cytoplasm of recipient cells [4, 35]. Consensus peptide linkers have been introduced that are susceptible to cleavage by specific peptidases such as metalloproteinases MMP-2 or MMP-9 [36], and cathepsins in lysosomes [37, 38].…”

“…An example is the 3’-thiopropylamido group of AON that does not adversely affect annealing with the target mRNA. Examples of complete chemotherapeutic drug reconstitution are pH-responsive hydrolysis of 2’-carboxylic acid esters of paclitaxel and docetaxel or of hydrazone derivatives of doxorubicin, summarized in [35]. Examples of incomplete removal of linker components include the cleavage of linker peptides by lysosomal cathepsin B in the case of doxorubicin [38, 123] or reductive cleavage of disulfide linker by the cytoplasmic glutathione in the case of AON [11, 12].…”

“…Examples of incomplete removal of linker components include the cleavage of linker peptides by lysosomal cathepsin B in the case of doxorubicin [38, 123] or reductive cleavage of disulfide linker by the cytoplasmic glutathione in the case of AON [11, 12]. Cleavable linkers have been recently reviewed [35]. …”

99mTc‐labeled NGR‐chlorambucil conjugate, 99mTc‐HYNIC‐CLB‐c(NGR) for targeted chemotherapy and molecular imaging

“…The high‐dose administration of drugs during conventional chemotherapy is responsible for systemic toxicity and various other side effects. Drugs conjugated with the targeting vectors like antibodies and peptides can serve as conduits for site‐specific delivery and thus overcome the problem of nonspecific accumulation of drugs in normal tissues . The tumor vasculature (tumor homing) targeting arginine‐glycine‐aspartic acid (RGD) and asparagine‐glycine‐arginine (NGR) peptides has been explored and identified as effective drug carriers .…”