Targeted drug delivery strategies for precision medicines

Abstract

Progress in the field of precision medicine has changed the landscape of cancer therapy. Precision medicine is propelled by technologies that enable molecular profiling, genomic analysis, and optimized drug design to tailor treatments for individual patients. Although precision medicines have resulted in some clinical successes, the use of many potential therapeutics has been hindered by pharmacological issues, including toxicities and drug resistance. Drug delivery materials and approaches have now advanced to a point where they can enable the modulation of a drug's pharmacological parameters without compromising the desired effect on molecular targets. Specifically, they can modulate a drug's pharmacokinetics, stability, absorption, and exposure to tumours and healthy tissues, and facilitate the administration of synergistic drug combinations. This Review highlights recent progress in precision therapeutics and drug delivery, and identifies opportunities for strategies to improve the therapeutic index of cancer drugs, and consequently, clinical outcomes.

Figure 1.. Major side effects of kinase inhibitors.

Kinase inhibitors, like all systemically administered therapies, can cause a wide variety of side effects. Nanomedicine may be used to prevent side effects such as neurotoxicities, hematological issues, skin rashes, hypertension, liver dysfunction, musculoskeletal problems, GI syndromes, and cardiovascular issues.

Figure 2.. Pharmacologic properties of kinase inhibitors.

Absorption (a) half-life in the blood (b), plasma protein binding (c), and recommended daily dosage (d). The data were collected from online sources including DrugBank.ca, U.S. Food and Drug Administration pharmacology and toxicology reports, and European Medicines Agency reports.

Figure 3.. Nanoscale delivery approaches for high-loading small molecule cargoes.

Drug nanocrystals or nanoaggregates can be formed with the aid of stabilizers/excipients. Liposomal drug vehicles can encapsulate drugs in the bilayer of the micelle and/or as drug crystals in the interior. Polymeric micelles are composed of amphiphilic polymers that typically enclose the drug in the core. Protein-based nanodelivery systems can incorporate drug in hydrophobic regions of proteins and/or between multiple protein components. Dendrimers can be designed to covalently attach the drug or encapsulate it between substructures. Silica or other solid nanoparticles can incorporate/attach drugs within/onto a porous/solid matrix. Drug loading is reported in mass (drug)/mass (total).

Figure 4.. Routes and Targets in the Tumor Microenvironment.

Nanomedicine can be used to deliver drugs to the tumor site [right] and avoid penetration of normal tissue [left]. Passive targeting allows for appropriately sized nanoparticles to take advantage of the enhanced permeability and retention (EPR) effect that increases entry and retention due to leaky vasculature of some tumor types. Active targeting, made possible by receptor-binding moieties on the surface of the nanocarriers, can be used to improve specificity and penetration of tumors via transcytosis across endothelial cells or direct binding to receptors upregulated on cancer cells or other cell types in the tumor microenvironment (i.e. fibroblasts, tumor-associated macrophages).

Figure 5.. Organ targeting with drug delivery systems.

Nanotechnologies designed for targeted delivery to specific tissues.

Figure 6.. Proposed patient selection and clinical correlate measurements for a precision drug nanomedicine trial.

Left side: patient selection via (top) histology, molecular imaging, and sequencing of tumor for tumor diagnosis and to determine eligibility of the patient for the precision drug cargo. (Bottom) measurements to determine likelihood of uptake of the nanoparticle into the patient’s tumors via histology, molecular imaging, and (when possible) imaging of a radiolabeled version of the nanoparticle. Left side: During the trial (right), patients will be monitored for toxicity/efficacy as in conventional clinical trials. Correlative measurements of tumor histology, imaging, and blood enable maximum information to be gained to determine indicators of which patients may best respond to the nanomedicine.