Heparan sulfate targeting strategy for enhancing liposomal drug accumulation and facilitating deep distribution in tumors

Abstract

Nanoparticles (NPs), such as liposomes, effectively evade the severe toxicity of unexpected accumulation and passively shuttle drugs into tumor tissues by enhanced permeability and retention. In the case of non-small cell lung cancer and pancreatic ductal adenocarcinoma, cancer-associated fibroblasts promote the aggregation of a gel-like extracellular matrix that forms a physical barrier in the desmoplastic stroma of the tumor. These stroma are composed of protein networks and glycosaminoglycans (GAGs) that greatly compromise tumor-penetrating performance, leading to insufficient extravasation and tissue penetration of NPs. Moreover, the presence of heparan sulfate (HS) and related proteoglycans on the cell surface and tumor extracellular matrix may serve as molecular targets for NP-mediated drug delivery. Here, a GAG-binding peptide (GBP) with high affinity for HS and high cell-penetrating activity was used to develop an HS-targeting delivery system. Specifically, liposomal doxorubicin (L-DOX) was modified by post-insertion with the GBP. We show that the in vitro uptake of L-DOX in A549 lung adenocarcinoma cells increased by GBP modification. Cellular uptake of GBP-modified L-DOX (L-DOX-GBP) was diminished in the presence of extracellular HS but not in the presence of other GAGs, indicating that the interaction with HS is critical for the cell surface binding of L-DOX-GBP. The cytotoxicity of doxorubicin positively correlated with the molecular composition of GBP. Moreover, GBP modification improved the in vivo distribution and anticancer efficiency of L-DOX, with enhanced desmoplastic targeting and extensive distribution. Taken together, GBP modification may greatly improve the tissue distribution and delivery efficiency of NPs against HS-abundant desmoplastic stroma-associated neoplasm.

Key Design Features of Lipid Nanoparticles and Electrostatic Charge-Based Lipid Nanoparticle Targeting

“…The low pH combined with the presence of a negatively charged ECM provides a good targeting lever to develop electrostatic charge-based targeting of LNPs to target cells. Cationic liposomes have been envisioned as a desirable delivery system that can target GAGs [111,112]. Charged-based removal of the PEG coating for tumor targeting largely uses two key approaches: (i) PEG removal by employing a pH-sensitive linker in a PEG-lipid and (ii) concentration of PEG in domains on the LNP surface, thereby leaving a large part of LNPs exposed to target cell surfaces.…”

A Small Sugar Molecule with Huge Potential in Targeted Cancer Therapy

“…Due to factors specific to the tumor microenvironment, controlled release of the drug from such carriers is possible [ 35 ]. An interesting solution is also the use of polysaccharides, such as alginate [ 36 ], hyaluronic acid [ 37 ], heparin (sulfate) [ 38 , 39 ], carrageenan [ 40 ], dextran [ 41 ], chitin, or chitosan [ 42 ], to create drug-delivery nanoparticles. These compounds are characterized by biocompatibility and often also turn out to be bioactive [ 43 ].…”

Cascade Drug Delivery through Tumor Barriers of Pancreatic Cancer via Ultrasound in Combination with Functional Microbubbles

“…However, the drug delivery efficacy was still disappointed due to the limited EPR effect caused by the poor blood perfusion and the abnormal vascular structure of pancreatic cancer. − In addition, the high interstitial fluid pressure induced by the desmoplastic stroma in pancreatic cancer formed a formidable physical barrier to prevent the DDS from penetrating into a deep tumor despite the extravasation of DDS from blood vessels by the EPR effect. − Furthermore, the cellular membrane could also impede the entrance of the drug after interstitial transport to compromise the drug efficacy because most chemotherapeutics work only in tumor cells . Previous studies mainly developed a single-ligand-decorated DDS for targeting either pancreatic cancer cells or stroma, which were not able to overcome multiple barriers of pancreatic cancer. , Therefore, there is an urgent need to develop a multi-targeting DDS with enhanced penetration and cellular uptake ability to improve the drug delivery and therapeutic efficacy for pancreatic cancer.…”

“…7 Previous studies mainly developed a single-ligand-decorated DDS for targeting either pancreatic cancer cells or stroma, which were not able to overcome multiple barriers of pancreatic cancer. 11,12 Therefore, there is an urgent need to develop a multi-targeting DDS with enhanced penetration and cellular uptake ability to improve the drug delivery and therapeutic efficacy for pancreatic cancer.…”