Towards clinical translation of ligand-functionalized liposomes in targeted cancer therapy: Challenges and opportunities

Abstract

The development of therapeutic resistance to targeted anticancer therapies remains a significant clinical problem, with intratumoral heterogeneity playing a key role. In this context, improving the therapeutic outcome through simultaneous targeting of multiple tumor cell subtypes within a heterogeneous tumor is a promising approach. Liposomes have emerged as useful drug carriers that can reduce systemic toxicity and increase drug delivery to the tumor site. While clinically used liposomal drug formulations show marked therapeutic advantages over free drug formulations, ligand-functionalized liposomes that can target multiple tumor cell subtypes may further improve the therapeutic efficacy by facilitating drug delivery to a broader population of tumor cells making up the heterogeneous tumor tissue. Ligand-directed liposomes enable the so-called active targeting of cell receptors via surface-attached ligands that direct drug uptake into tumor cells or tumor-associated stromal cells, and so can increase the selectivity of drug delivery. Despite promising preclinical results demonstrating improved targeting and anti-tumor effects of ligand-directed liposomes, there has been limited translation of this approach to the clinic. Key challenges for translation include the lack of established methods to scale up production and comprehensively characterize ligand-functionalized liposome formulations, as well as the inadequate recapitulation of in vivo tumors in the preclinical models currently used to evaluate their performance. Herein, we discuss the utility of recent ligand-directed liposome approaches, with a focus on dual-ligand liposomes, for the treatment of solid tumors and examine the drawbacks limiting their progression to clinical adoption.

Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids

“…To enhance tumour-specific imaging and drug delivery, targeted probes can be engineered through the conjugation of ligands that recognize receptor-like molecules, which are either highly expressed in cancer cells or enriched in the tumour microenvironment 2 . Although promising, this approach is limited 4,5 by the rarity of molecules that are expressed in cancer cells but not in normal tissues 6,7 and, therefore, cargo agents can also accumulate in normal organs. Furthermore, cancers are typically heterogeneous across tissues and within tumours and are therefore unlikely to be successfully targeted using a single ligand 6,7 .…”

“…Although promising, this approach is limited 4,5 by the rarity of molecules that are expressed in cancer cells but not in normal tissues 6,7 and, therefore, cargo agents can also accumulate in normal organs. Furthermore, cancers are typically heterogeneous across tissues and within tumours and are therefore unlikely to be successfully targeted using a single ligand 6,7 . The ligand-receptor approach is particularly limited for the imaging of brain tumours and the delivery of drugs to them owing to the blood-brain barrier (BBB) [8][9][10] .…”

Autocatalytic Delivery of Brain Tumor–Targeting, Size‐Shrinkable Nanoparticles for Treatment of Breast Cancer Brain Metastases

“…To improve drug delivery to tumors, a common approach has been engineering nanocarriers through conjugation of ligands that recognize “receptor” molecules expressed on cancer cells, such as hyaluronic acid (HA),6 TAT,7 iRGD,8 polysorbate 80,1b and chlorotoxin,9 which have been tested for BCBMs. Despite their potential, this approach has shown to be limited by various factors, including the lack of molecules that is specifically expressed on the surface of all cancer cells but not normal tissues 10. As a result, the efficiency of ligand‐mediated targeted delivery has been limited to 0.7% without significant improvement 11.…”

The Impact of New Targeting Methods in the Cancer Therapy

“…Liposomes represent the most important nanoparticles with wide applications in cancer therapy. They are composed of two double layers of lipid surrounding an aqueous matrix and having a large particle size to ensure accumulation in the cancer tissue [23,25,26]. This unique composition gives liposomes the capability to carry different types of molecules with different chemical nature.…”