Recent progress in mitochondria-targeted drug and drug-free agents for cancer therapy

The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches

Anticancer Therapeutic Approach through Spatiotemporal Self-assembly Control of Cancerous Organelle Target Peptides

Department of Chemistryclos

The Power of Enzyme-Instructed Self-Assembly and Lysosome-targeting to overcome the Drug Resistance and Selective Cancer Cell Death

Lysosome always remains a powerful organelle and an important target for cancer therapy as cancer cells are greatly dependent on effective lysosomal function. There are very few strategies for selective targeting the lysosome of cancer cells. Here, we show lysosome targeting followed by lyso-assembly of the peptide amphiphiles as a powerful techniques for the development of selective cancer therapeutics and overcome the drug resistance. We have designed a peptide amphiphiles, which specifically target the cancer lysosome, undergoes supramolecular assembly through enzymatic cleavage governed by cathepsin B followed by lysosomal swelling. It induces the lysosomal membrane permeabilization (LMP) and damage and causes the caspase independent apoptotic death of the cancer cells through disruption of plasma membrane. Moreover, the lysosome possess high cancer selectivity and are effective towards drug resistance cancer treatment

Enzyme-instructed morphology transformation of mitochondria-targeting peptide for the selective eradication of osteosarcoma

The treatment of osteosarcoma involves an adjuvant therapy that combines surgery and chemotherapy. However, considering that children are the main victims of osteosarcoma, replacing such a harsh treatment with a soft but powerful method that ensures a complete cure while having no adverse effects is highly desirable. To achieve this aim, we have developed a supramolecular therapeutic strategy based on morphology-transformable mitochondria-targeting peptides for the eradication of osteosarcoma with enhanced selectivity and reduced side effects. A newly designed micelle-forming amphiphilic peptide, L-Mito-FFYp, consisting of a phosphate substrate for the biomarker enzyme of osteosarcoma alkaline phosphatase (ALP), disassembles in response to the ALP enzyme in the cell membrane to generate positively charged L-Mito-FFY molecules, which diffuse inside the targeted cell and self-assemble to form nanostructures specifically inside the mitochondria to induce cell apoptosis

Self-assembly inside cellular organelles: Aspects of functions and various strategies for cancer therapy

Self-assembly generates three-dimensional architectures through the non-covalent interactions of building blocks of various sizes, ranging from nanometers to micrometers, and the assembled structures may have new functions that the building blocks do not have. Cell self-assembly has attracted considerable attention in cancer treatment because it can overcome the side effects of conventional chemotherapy and the low therapeutic effect on drug-resistant cells. In addition, the trigger in the building block reacts with the specific environment of the cancer, such as pH, ions, redox reactions, enzymes, or receptors, facilitating cancer-targeted therapy. However, the precise control of self-assembly for the construction of nanostructures is difficult in harsh intracellular environments. To overcome this challenge, various researchers have investigated intracellular self-assembly. In particular, the self-assembly in cellular organelles is of great interest. Compared with self-assembly in the cytoplasm of cells, organelle-targeting self-assembly has the advantage of being able to self-assemble without side effects under more stable conditions with a relatively low concentration of building blocks. In this mini-review, we discuss the latest research on self-assembly inside or near organelles for cancer treatment

Surface protein-retractive and redox-degradable mesoporous organosilica nanoparticles for enhanced cancer therapy

Targeted delivery along with controlled drug release is considered crucial in development of a drug delivery system (DDS) for efficient cancer treatment. In this paper, we present a strategy to obtain such a DDS by utilizing disulfide-incorporated mesoporous organosilica nanoparticles (MONs), which were engineered to minimize the surface interactions with proteins for better targeting and therapeutic performance. That is, after MONs were loaded with a chemodrug doxorubicin (DOX) through the inner pores, their outer surface was treated for conjugation to the glutathione-S-transferase (GST)-fused cell-specific affibody (Afb) (GST-Afb). These particles exhibited prompt responsivity to the SS bond-dissociating glutathione (GSH), which resulted in considerable degradation of the initial particle morphology and DOX release. As the protein adsorption to the MON surface appeared largely reduced, their targeting ability with GSH-stimulated therapeutic activities was demonstrated in vitro by employing two kinds of the GST-Afb protein, which target human cancer cells with the surface membrane receptor, HER2 or EGFR. Compared with unmodified control particles, the presented results show that our system can significantly enhance cancer-therapeutic outcomes of the loaded drug, offering a promising way of designing a more efficacious DDS

Spatiotemporal Self-Assembly of Peptides Dictates Cancer-Selective Toxicity

The intracellular or pericellular self-assembly of amphiphilic peptides is emerging as a potent cancer therapeutic strategy. Achieving the self-assembly of amphiphilic peptides inside a cell or cellular organelle is challenging due to the complex cellular environment, which consists of many amphiphilic biomolecules that may alter the self-assembling propensity of the synthetic peptides. Herein, we show that the hydrophobic-hydrophilic balance of the amphiphilic peptides determines the self-assembling propensity, thereby controlling the fate of the cell. A series of peptides were designed to target and self-assemble inside the mitochondria of cancer cells. The hydrophobicity of the peptides was tuned by varying their N-terminus capping. The analysis showed that the largest hydrophobic peptide was self-assembled before reaching the mitochondria and showed no selectivity toward cancer cells, whereas hydrophilic peptides could not self-assemble inside the mitochondria. Optimum balance between hydrophobicity and hydrophilicity is a critical factor for achieving self-assembly inside the mitochondria, thereby providing greater selectivity against cancer cells

Antibody plug-and-playable nanoparticles as a facile and versatile platform for targeted drug delivery

For effective drug delivery using nanoparticles, antibody can be beneficially utilized thanks to its high binding affinity to the target site. However, a conventional method to conjugate antibody to nanoparticles involves a multi-step synthetic process, which can damage the antibody's intrinsic target-recognition nature. Herein, a facile approach is reported to construct a versatile targeted delivery platform, to which any desired antibodies are allowed to directly bind, by coating the nanoparticle surface with a functional fusion protein consisting of glutathione-S-transferase (GST) and the antibody-binding domain (ABD) called Z domain. The antibody-plugged nanoparticle exhibits high structural stability in biological environments and cell-specific targeting behaviors, significantly enhancing drug delivery efficiency both in vitro and in vivo for diverse therapeutic applications

Intra-Lysosomal Peptide Assembly for the High Selectivity Index against Cancer

Lysosomes remain powerful organellesand important targetsforcancer therapy because cancer cell proliferation is greatly dependenton effective lysosomal function. Recent studies have shown that lysosomalmembrane permeabilization induces cell death and is an effective wayto treat cancer by bypassing the classical caspase-dependent apoptoticpathway. However, most lysosome-targeted anticancer drugs have verylow selectivity for cancer cells. Here, we show intra-lysosomal self-assemblyof a peptide amphiphile as a powerful technique to overcome this problem.We designed a peptide amphiphile that localizes in the cancer lysosomeand undergoes cathepsin B enzyme-instructed supramolecular assembly.This localized assembly induces lysosomal swelling, membrane permeabilization,and damage to the lysosome, which eventually causes caspase-independentapoptotic death of cancer cells without conventional chemotherapeuticdrugs. It has specific anticancer effects and is effective againstdrug-resistant cancers. Moreover, this peptide amphiphile exhibitshigh tumor targeting when attached to a tumor-targeting ligand andcauses significant inhibition of tumor growth both in cancer and drug-resistantcancer xenograft models