Nanomedicine in cancer therapy

Abstract

Cancer remains a highly lethal disease in the world. Currently, either conventional cancer therapies or modern immunotherapies are non-tumor-targeted therapeutic approaches that cannot accurately distinguish malignant cells from healthy ones, giving rise to multiple undesired side effects. Recent advances in nanotechnology, accompanied by our growing understanding of cancer biology and nano-bio interactions, have led to the development of a series of nanocarriers, which aim to improve the therapeutic efficacy while reducing off-target toxicity of the encapsulated anticancer agents through tumor tissue-, cell-, or organelle-specific targeting. However, the vast majority of nanocarriers do not possess hierarchical targeting capability, and their therapeutic indices are often compromised by either poor tumor accumulation, inefficient cellular internalization, or inaccurate subcellular localization. This Review outlines current and prospective strategies in the design of tumor tissue-, cell-, and organelle-targeted cancer nanomedicines, and highlights the latest progress in hierarchical targeting technologies that can dynamically integrate these three different stages of static tumor targeting to maximize therapeutic outcomes. Finally, we briefly discuss the current challenges and future opportunities for the clinical translation of cancer nanomedicines.

Fig. 1

Historical timeline of key events in the field of cancer nanomedicine. DQAsomes dequalinium-based liposome-like vesicles, EPR enhanced permeability and retention, FDA US Food and Drug Administration, MITO-Porter octaarginine (R8)-modified liposomes composed of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and sphingomyelin, mRNA messenger RNA, NP nanoparticle, PRISM Profiling relative inhibition simultaneously in mixtures, siRNA small interfering RNA

Fig. 2

Schematic illustration of EPR-dependent and -independent strategies for tumor tissue-targeted nanoparticle delivery

Fig. 3

Schematic illustration of tumor cell targeting strategies and different cellular internalization pathways. Nanoparticles that are functionalized with targeting ligands (e.g., antibodies and antibody fragments, nucleic acids aptamers, protein, peptides, and small molecules) can specifically bind to tumor-specific antigens or receptors expressed on the plasma membrane and enter tumor cells via clathrin-mediated endocytosis or other pathways, depending on their size, shape, charge, and surface modifications. Alternatively, nanoparticles can be coated with plasma membranes derived from cancer cells, blood cells, or stem cells to achieve homotypic tumor targeting by taking advantage of the self-recognition and self-adherence capabilities of source cells, and can be taken up by tumor cells through membrane fusion

Fig. 4

Schematic illustration of nanoparticle intracellular delivery and strategies for organelle-specific targeting. After internalization by tumor cells, nanocarriers are typically trapped in endosomes that eventually fuse with lysosomes. Nanocargos that are functionalized with organelle-specific targeting moieties will be released from the carriers and escape from the endo/lysosomal system in response to intrinsic or extrinsic stimuli. Finally, they will be specifically delivered to the nucleus, mitochondria, lysosomes, endoplasmic reticulum, or Golgi apparatus. C₆ Six-cysteine peptide, Dex Dexamethasone, FAL Pardaxin peptide, KDEL ER retrieval signal Lys–Asp–Glu–Leu, KLA (KLAKLAK)₂ peptide, LSP Lysosomal sorting peptide, MPP Mitochondria-penetrating peptide, MTS Mitochondrial targeting signal/sequence, NLS nuclear localization signal, PAsp poly(aspartic acid), Vit-E vitamin E, CS Chondroitin sulfate, S-S Szeto-Schiller peptide; TAT Trans-activating transcriptional activator, TCPP-T^ER ER-targeting photosensitizer 4,4′,4″,4′″-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(2-((4-methylphenyl)sulfonamido)ethyl)-benzamide, TPP Triphenylphosphonium

Fig. 5

Maximizing therapeutic benefits of cancer nanomedicine through the stimuli-triggered dynamic integration of multistage tumor targeting. Either endogenous (changes in pH, redox gradients, enzyme or ATP concentrations) or exogenous (variations in temperature, magnetic fields, ultrasound, or light intensities) stimuli can be utilized to trigger nanoparticle size reduction, charge conversion, as well as ligand exposure, and therefore can dynamically integrate tumor tissue-, cell- and organelle-specific targeting to sequentially achieve high tumor accumulation, deep tumor penetration, efficient cellular internalization, and accurate organelle localization