Tissue‐Penetrating, Hypoxia‐Responsive Echogenic Polymersomes For Drug Delivery To Solid Tumors

Abstract

Hypoxia in solid tumors facilitates the progression of the disease, develops resistance to chemo and radiotherapy, and contributes to relapse. Due to the lack of tumor penetration, most of the reported drug carriers are unable to reach the hypoxic niches of the solid tumors. We have developed tissue-penetrating, hypoxia-responsive echogenic polymersomes to deliver anticancer drugs to solid tumors. The polymersomes are composed of a hypoxia-responsive azobenzene conjugated and a tissue penetrating peptide functionalized polylactic acid-polyethylene glycol polymer. The drug-encapsulated, hypoxia-responsive polymersomes substantially decreased the viability of pancreatic cancer cells in spheroidal cultures. Under normoxic conditions, polymersomes were echogenic at diagnostic ultrasound frequencies but lose the echogenicity under hypoxia. In-vivo imaging studies with xenograft mouse model further confirmed the ability of the polymersomes to target, penetrate, and deliver the encapsulated contents in hypoxic pancreatic tumor tissues.

Biomolecule–polymer hybrid compartments: combining the best of both worlds

“…Targeting or cell penetrating peptides, less expensive and smaller than antibodies, have been widely exploited to target polymersomes to locations of interest within cells or living organisms. For example, cyclic (RGD and NGQ), [46][47][48][49] pH sensitive fusogenic (GALA) 47 and other targeting (GE11, NLS, LinTT1, ApoE, Tet-1) [50][51][52][53][54] peptides have been mainly used to deliver smart polymer vehicles to specific cells or organelles and/or to improve their tumour penetration for therapeutic or diagnostic applications. Recently, targeting of the nuclear interior has been achieved using polymersomes functionalized with nuclear localization signal (peptide NLS), which position themselves as promising nanocarriers for drug delivery to cell nuclei.…”

“…44,47,49,52,53,56 Beyond that, the peptides can also be coupled to the block copolymers prior to vesicle formation via mixing of the nonfunctionalized polymer with a peptide-functionalized counterpart that self-assemble together to form peptide-functionalized polymersomes. 46,48,50,51,54 Nevertheless, even if this approach enables the simultaneous usage of different types of polymer, e.g. by mixing a triblock co-polymer with a peptide-functionalized diblock copolymer, several features like the use of polymers with matching lengths of hydrophilic and hydrophobic parts is crucial in order to achieve their co-self-assembly into polymersomes.…”

Dendritic Polyglycerol‐Derived Nano‐Architectures as Delivery Platforms of Gemcitabine for Pancreatic Cancer

“…Our hypothesis was based on the fact that such programmed disintegration of larger nanoparticles will provide with deeper penetration of drug‐transporting nanocarriers through the dense desmoplastic microenvironment of pancreatic cancer. We selected pH as the stimulus to trigger such controlled destabilization because for PDAC and any other form of solid tumors, pH decreases sharply in conjunction with low O 2 tension as the distance increases from blood vessels to tumor tissues . In addition, smaller nanoparticles are required to penetrate deep‐seated tumor cells and cancer‐like stem cells, many of which are difficult to reach with larger nanoparticles due to altered microvasculature present in solid tumors.…”

Overcoming Hurdles in Nanoparticle Clinical Translation: The Influence of Experimental Design and Surface Modification

“…In addition to using structural and biologically active proteins to enhance circulation, protein modifications can also improve the retention and targeting of drug-carrying nanoparticles. The use of tumor-targeting and cell-penetrating peptides to modify a nanoparticle surface has experienced a renewed surge of popularity [62,63], with the most widespread peptides being RGD, iRGD, and iNGR [64,65,66]. These peptides rely on the upregulation of specific ligand receptors (e.g., neuropilin-1) commonly found in solid tumors [65].…”

“…These peptides rely on the upregulation of specific ligand receptors (e.g., neuropilin-1) commonly found in solid tumors [65]. The use of tumor-targeting and cell-penetrating peptides for liposome and polymersome drug delivery, particularly for solid tumor cancers, is becoming an increasingly common strategy [9,66]. In addition to neuropilin-1 binding peptides, Epidermal Growth Factor Receptor binding peptides, integrin binding peptides, Vascular Endothelial Growth Factor binding peptides, guanine nucleotide exchange factor binding peptides, protein tyrosine phosphatase receptor type J binding peptides, platelet derived growth factor receptor binding peptides, and interleukin receptor binding peptides have all been targeted [62].…”