In a recent review published in Natures Signal Transduction and Targeted Therapy Journal, a group of authors explored current and future strategies in the design of tumor tissue-, cell-, and organelle-targeted cancer nanomedicines, emphasizing the latest advances in hierarchical targeting technologies to maximize therapeutic efficacy while minimizing off-target toxicity.
Study: Nanomedicine in cancer therapy. Image Credit: fizkes/Shutterstock.com
Background
Cancer is a leading global killer, with 19.3 million new cases and nearly 10 million deaths in 2020. As lifestyle and environmental factors change, cancer incidents will likely surge in the next two decades. Traditional treatments, including surgery and chemotherapy, are limited, especially for advanced cases.
Although promising, immunotherapies offer limited patient response and can produce severe side effects. Consequently, there’s a strong push for tumor-specific drug delivery systems.
Cancer nanomedicine research has expanded over the past 30 years, introducing nanoparticle-based therapies.
Over 15 cancer nanomedicines are approved worldwide, with more in trials. These nanomedicines aim for accurate drug delivery to tumor sites, minimizing side effects and maximizing therapeutic efficacy. However, designing a universally effective nanocarrier remains challenging due to varying requirements at different targeting stages.
Tumor tissue targeting strategies
The enhanced permeability and retention (EPR) effect was discovered by Matsumura and Maeda in 1986, emphasizing the principle of nanoparticles entering tumor tissues due to abnormal blood vessels.
For effective EPR targeting, nanoparticles should be 50-150 nm in size with a neutral or slightly negative charge. However, the EPR effect varies among tumors and patients, with factors like tumor location and stage influencing its effectiveness.
Tumor vascular targeting aims at destroying the tumor’s blood vessels. It relies on three main proteins: vascular endothelial growth factor receptor 2 (VEGFR2), alpha-v beta-3 integrins (αvβ3), and cluster of differentiation (CD105) present in tumor blood vessels.
For instance, VEGFR2-targeted nanoparticles show improved drug delivery, while integrins αvβ3 and CD105 offer other effective targeting strategies.
Cell-mediated targeting uses cells like leukocytes or stem cells as nanoparticle delivery vehicles. Given their natural tumor-targeting ability, these cells can effectively deliver therapeutic agents to tumor sites.
Locoregional delivery concentrate nanomedicines within tumors; it enhances drug delivery while minimizing side effects. Techniques like direct intratumoral injection, surgical implantation, and in situ spraying ensure prolonged drug presence in tumors.
Tumor cell targeting strategies
To target tumor cells directly, nanoparticles can be modified with ligands such as antibodies, proteins, and peptides that bind specifically to receptors on tumor cells.
Monoclonal antibodies (mAbs) have shown effectiveness in targeted tumor therapy. Additionally, antibody fragments like Fab fragments can offer better tumor penetration.
Proteins like transferrin (Tf) are exploited for targeting due to their precision. For example, Tf-infused nanoparticles can target tumor cells rich in transferrin receptors. Short amino acid chains called peptides can effectively deliver nanoparticles to tumors.
RGD Peptides, for instance, have shown significant potential in reducing tumor growth and metastasis.
Carbohydrates are biocompatible molecules that can be used as targeting agents. Examples include mannose receptors, galectins, and selectins, which offer potential in tumor-targeted therapy.
Small molecules like folic acid (FA) and biotin have shown promise in targeted tumor therapy. FA, for instance, has been effectively used in treating breast cancer.
Using membranes from cells like red blood cells (RBCs), platelets, and white blood cells (WBCs) to coat nanoparticles can enhance tumor targeting. For instance, WBC-coated nanoparticles have shown promising results in various cancer models.
Coating nanoparticles with cancer cell membranes can increase source cell uptake. These coated nanoparticles are efficient in targeting primary tumors and metastases. With their tumor tropism, stem cells have led to the development of stem cell membrane-coated nanoparticles for targeted drug delivery.
Organelle-targeting strategies
The nucleus of eukaryotic cells, containing genetic material, can also be a target for drug delivery, opening up avenues for precision treatment at a cellular level.
Different other approaches, such as mitochondrial targeting signals/sequences and mitochondria-penetrating peptides, have been used to functionalize nanocarriers for efficient drug delivery to mitochondria, resulting in improved treatment outcomes and reduced side effects in preclinical studies.
Triphenylphosphonium (TPP) is a lipophilic cation that can selectively accumulate in mitochondria due to its interactions with the negatively charged mitochondrial membrane. It has been widely used to target various small molecules and nanoparticles to mitochondria for therapeutic purposes.
Dequalinium (DQA) self-assembles into DQAsomes, which preferentially accumulate in mitochondria through electrostatic interactions. Functionalizing DQAsomes with other moieties, such as dioleoyl trimethylammonium propane (DOTAP) and dioleoyl phosphatidylethanolamine (DOPE), has been shown to enhance mitochondrial-targeted gene transfection and improve the efficacy of anticancer treatments.
MITO-Porter can facilitate cellular uptake, endosomal escape, and accumulation in mitochondria. It has been utilized to deliver therapeutics, such as gentamicin and doxorubicin, to mitochondria, leading to potent antitumor responses and improved treatment outcomes.
The endo/lysosome system is a crucial cellular compartment for sorting, degradation, and signaling. Nanoparticles have been designed to target endo/lysosomes through endocytosis, enabling spatiotemporal delivery of therapeutic cargoes.
Lysosomal sorting peptides (LSPs) have been used to guarantee nanoparticles’ final delivery to lysosomes, facilitating efficient lysosomal targeting and enhanced anticancer efficacy.
Sequential implementation of multistage tumor-targeting approaches
Advancements in tumor-targeted nano-drug delivery systems have been made, but fixed physicochemical properties hinder optimal targeting at different tumor stages. Stimuli-responsive strategies, using endogenous or exogenous stimuli, enable dynamic integration of multistage tumor targeting.
This achieves high tumor accumulation, deep penetration, cellular internalization, and precise organelle localization.
Researchers have developed stimuli-responsive clustered nanoparticles, iCluster, that shrink from ~100 nm to ~5 nm in acidic tumor environments, enabling deep penetration and enhanced antitumor efficacy.
Size-shrinkable iCluster nanoparticles effectively inhibited tumor metastasis, showcasing improved survival in a mouse mammary carcinoma metastasis model. Enzymes like matrix metalloproteinase-2 (MMP-2) and hyaluronidase (Haase), highly expressed in tumors, also trigger size reduction in nanoparticles, enhancing intratumoral penetration and drug delivery.
Charge-switchable nanoparticles with anionic parts at physiological pH and a positive charge at the tumor site promote cellular internalization and enhance antitumor effects. MMPs in the tumor microenvironment can also trigger charge conversion, improving nanoparticles’ cellular interaction and uptake.
The strategy has been employed to enhance nanocarriers’ tissue-penetrating and mitochondrial-targeting capabilities.
The “de-PEGylation” strategy exposes hidden ligands by detaching polyethylene glycol corona at the tumor site, enhancing drug delivery and targeting.
A “pop-up” mechanism is used where ligands are buried in nanoparticles at physiological pH but exposed in acidic tumor environments, promoting drug delivery and cellular internalization. These strategies have shown improved therapeutic efficacy in various tumor models.
