Progress and challenges towards targeted delivery of cancer therapeutics

Abstract

Targeted delivery approaches for cancer therapeutics have shown a steep rise over the past few decades. However, compared to the plethora of successful pre-clinical studies, only 15 passively targeted nanocarriers (NCs) have been approved for clinical use and none of the actively targeted NCs have advanced past clinical trials. Herein, we review the principles behind targeted delivery approaches to determine potential reasons for their limited clinical translation and success. We propose criteria and considerations that must be taken into account for the development of novel actively targeted NCs. We also highlight the possible directions for the development of successful tumor targeting strategies.

Fig. 1

Schematic illustration of main physiological barriers faced by passive and active targeted NCs. a NCs face endothelial barriers in the process of their extravasation into the tumor tissue; illustration of the blood–brain barrier as an example. b Uptake of NCs by the target cells and their escape from the endo-lysosomal system into the cytotosl are the major cellular barriers. c Hepatic Kupffer cells as an example of mononuclear phagocytic system (MPS), which results in the clearence of systemically administered NCs, reducing their half-life and effective dose

Fig. 2

The impact of nano–bio interactions on the systemically administrated NCs. a During systemic circulation, targeted NCs get coated with serum proteins and opsonins, which impacts the targeting efficiency and many other properties of NCs, including b particle size, c pharmacokinetics, d release profiles, e tissue penetration, f cellular uptake and intrecellular trafficking and g biodistribution (ID injected dose)

Fig. 3

Schematic illustration of the proposed workflow in the development of actively targeted NCs

Fig. 4

Challenges to clinical translation of stimuli-responsive NCs. Controlled-switch NCs designed to prevent premature drug release face challenges associated with the type of stimulus on which they are based. Other than that, additional design challenges for the NCs themeselves include scalability, sensitivity, and response to the stimulus, biocompatibility, and toxicity

Fig. 5

Biological and technical barriers to the success of local drug delivery. Local administration is a promising strategy for targeted drug delivery in certain cancers. However, there are still some cancer-specific biological and technical barriers that need to be overcome by the clinical success of this approach