Abstract
Most clinically approved cancer therapies are potent and toxic small molecules that are limited by severe off-target toxicities and poor tumor-specific localization. Over the past few decades, attempts have been made to load chemotherapies into liposomes, which act to deliver the therapeutic agent directly to the tumor. Although liposomal encapsulation has been shown to decrease toxicity in human patients, reliance on passive targeting via the enhanced permeability and retention (EPR) effect has left some of these issues unresolved. Recently, investigations into modifying the surface of liposomes via covalent and/or electrostatic functionalization have offered mechanisms for tumor homing and subsequently controlled chemotherapeutic delivery. A wide variety of biomolecules can be utilized to functionalize liposomes such as proteins, carbohydrates, and nucleic acids, which enable multiple directions for cancer cell localization. Importantly, when nanoparticles are modified with such molecules, care must be taken as not to inactivate or denature the ligand. Peptides, which are small proteins with <30 amino acids, have demonstrated the exceptional ability to act as ligands for transmembrane protein receptors overexpressed in many tumor phenotypes. Exploring this strategy offers a method in tumor targeting for cancers such as glioblastoma multiforme, pancreatic, lung, and breast based on the manifold of receptors overexpressed on various tumor cell populations. In this review, we offer a comprehensive summary of peptide-functionalized liposomes for receptor-targeted cancer therapy.
Highlights
Composed of a concentric hydrophobic phospholipid bilayer compartmentalizing an aqueous core from its aqueous environment, liposomes offer a plethora of controlled delivery applications for different classes of drugs
Hydrophobic drugs such as small molecule chemotherapeutics can be loaded into the lipid lamella, while hydrophilic therapies such as nucleic acids can be loaded into the aqueous core for applications such as gene editing
The results showed that tetrameric P6.1-conjugated liposomes had a 10 times greater degree of cellular binding and uptake in BT-474 compared to MDA-MB-231 cells, highlighting their targeting ability to cells with overexpressed HER2
Summary
Liposomes have been at the forefront of drug delivery research for the past few decades, following their discovery in 1965 by Alec Bangham. Since they have been delineated into categories including small unilamellar vesicles (SUVs < 100 nm), medium unilamellar vesicles (MUVs 100–250 nm), large unilamellar vesicles (LUVs > 250 nm), and giant unilamellar vesicles (GUVs)—with the majority of drug delivery studies focusing on SUVs. Composed of a concentric hydrophobic phospholipid bilayer compartmentalizing an aqueous core from its aqueous environment, liposomes offer a plethora of controlled delivery applications for different classes of drugs. In brief, hydrophobic drugs such as small molecule chemotherapeutics can be loaded into the lipid lamella, while hydrophilic therapies such as nucleic acids can be loaded into the aqueous core for applications such as gene editing. The majority of current cancer therapies rely on the systemic administration of chemotherapeutic agents that exhibit offtarget effects due to their inability to differentiate between healthy and tumor tissue—this often results in side effects like nausea and fatigue or more severely cardiotoxicity. To improve the therapeutic index. Several liposomal drug formulations have been approved by the FDA, loading chemotherapeutics such as doxorubicin (Doxil), duanorubicin (DaunoXome), cytarabine (Depocyte), vincristine (Marqibo), mifamurtide (Mepact), irinotecan (Onivyde), and daunorubicin/cytarabine (Vyxeos) (Table I).11–15 Some of these nanoparticle drug formulations take advantage of PEGylation, which is thought to act as a nanoparticle cloak to greatly enhance their circulation time and reduce immune responses.. There are several options for modifying liposomes to enable tumor targeting, as many groups have explored the use of peptides, proteins and antibodies, nucleic acids and aptamers, and carbohydrates.. There are several options for modifying liposomes to enable tumor targeting, as many groups have explored the use of peptides, proteins and antibodies, nucleic acids and aptamers, and carbohydrates.33,39–42 Each of these biomolecules offers advantages and disadvantages in applicability, such as high biocompatibility and bioactivity, as either liposome-membrane fusogens or ligands for receptor targeting.. By peptides acting as ligands with high affinities toward overexpressed cell membrane receptors, liposomes encapsulating chemotherapeutic agents can improve targeting in vitro and in vivo and act as clinically applicable therapies for improved cancer treatment (Fig. 1)
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