Cancerous pH‐responsive polycarboxybetaine‐coated lipid nanoparticle for smart delivery of siRNA against subcutaneous tumor model in mice

Abstract

Lipid nanoparticles (LNPs) have been commonly used as a vehicle for nucleic acids, such as small interfering RNA (siRNA); the surface modification of LNPs is one of the determinants of their delivery efficiency especially in systemic administration. However, the applications of siRNA‐encapsulated LNPs are limited due to a lack effective systems to deliver to solid tumors. Here, we report a smart surface modification using a charge‐switchable ethylenediamine‐based polycarboxybetaine for enhancing tumor accumulation via interaction with anionic tumorous tissue constituents due to selective switching to cationic charge in response to cancerous acidic pH. Our polycarboxybetaine‐modified LNP could enhance cellular uptake in cancerous pH, resulting in facilitated endosomal escape and gene knockdown efficiency. After systemic administration, the polycarboxybetaine‐modified LNP accomplished high tumor accumulation in SKOV3‐luc and CT 26 subcutaneous tumor models. The siPLK‐1‐encapsulated LNP thereby accomplished significant tumor growth inhibition. This study demonstrates a promising potential of the pH‐responsive polycarboxybetaine as a material for modifying the surface of LNPs for efficient nucleic acid delivery.

Specific and efficient knockdown of intracellular miRNA using partially neutralized phosphate-methylated DNA oligonucleic acid-loaded mesoporous silica nanoparticles

“…For instance, pH-sensitive ethylenediamine-based polyzwitterions exhibit a surface charge switch from neutral to positive under tumourous and endosomal pH conditions. 35,36 This property enhances tumour accumulation by facilitating improved cellular uptake and endosomal escape. 35,36 Similarly, the tertiary amine-based polymers convert to a positive charge within tumour microenvironments and exhibit comparable hydrophilicity to PEG.…”

“…35,36 This property enhances tumour accumulation by facilitating improved cellular uptake and endosomal escape. 35,36 Similarly, the tertiary amine-based polymers convert to a positive charge within tumour microenvironments and exhibit comparable hydrophilicity to PEG. 37 Additionally, pH-labile materials facilitate drug release within slightly acidic tumour microenvironments.…”

Tumor Microenvironment Responsive RNA Drug Delivery Systems: Intelligent Platforms for Sophisticated Release

“…More protonation polymers have also been Lipid polymers based on pH-mediated charge conversion have been widely used in RNA delivery systems, and their results have been well evaluated, 38−41 such as the first synthesis of pH-responsive 1,2-distearyloxy-N,N-dimethyl-3-aminopropane, 42 and the first new ethylenediamine-based polycarboxybetaine-modified cationic lipid. 43 In addition, many pHresponsive inorganic nanoparticles 44 and protein-like polymer nanorods 45 have also emerged, indicating that pH-responsive carrier systems have great potential in the field of specific RNA delivery and are worthy of exploration. Since malignancies proliferate and are prone to mutations, several factors must be considered when designing pH-responsive drug delivery systems, such as immunogenicity, drug loading and release ability, and efficient targeting.…”

pH-Responsive Biomaterials for the Treatment of Dental Caries—A Focussed and Critical Review

“…Recent examples of commonly used pH-responsive delivery vehicles used in cancer therapy are summarized in Table 2; only a few examples have been selected from of a large number of publications and discussed as a potential design reference in dentistry. Magnetic nanoparticles [141][142][143] Polymeric micelles [140,[144][145][146] Metal organic frameworks [147][148][149] Dendrimers [150,151] Carbon nanotubes [152,153] Solid lipid nanoparticles [154,155] Quantum dots [150] Nano-emulsions [156] Gold nanoparticles [157,158] Hydrogels [159][160][161] Biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) are widely used as drug delivery vehicles. To avoid the premature release of anticancer drugs in healthy tissue, Hu et al (2020) developed the tannic acid−Fe (III) complex-modified PLGA nanoparticle platform (TPLGA NPs) for the delivery and pH-responsive release of doxorubicin (DOX) [162].…”