Development and testing of nanoparticles delivery for P7C3 small molecule using injury models

• Published in: Molecular and cellular biochemistry 2024-09, Vol.479 (9), p.2429-2445
• Main Authors: Sutariya, Vijaykumar, Bhatt, Priyanka, Saini, Aren, Miller, Abraian, Badole, Sachin L., Tur, Jared, Gittinger, Mackenzie, Kim, Joung Woul, Manickam, Ravikumar, Tipparaju, Srinivas M.
• Format: Article
• Language: English
• Subjects: Animals; Aptamers; Aptamers, Nucleotide - chemistry; Aptamers, Nucleotide - pharmacology; Assaying; Biochemistry; Biomedical and Life Sciences; Cancer Research; Carboxylic acids; Cardiology; Cell Line; Cell viability; Cytotoxicity; Disease Models, Animal; Drug delivery; Effectiveness; Encapsulation; Glycolic acid; Ischemia; Life Sciences; Male; Medical Biochemistry; Mice; Molecular modelling; Myoblasts; Nanoparticle Drug Delivery System - chemistry; Nanoparticles; Nanoparticles - chemistry; NF-κB protein; Polydispersity; Polyglycolic Acid - chemistry; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry; Polylactide-co-glycolide; Polymers; Reperfusion; Skeletal muscle; Toxicity testing; Tumor necrosis factor-α; Wound healing; Wound Healing - drug effects; Zeta potential
• ISSN: 0300-8177; 1573-4919; 1573-4919
• DOI: 10.1007/s11010-023-04865-2

The use of nanoparticles (NPs) has emerged as a potential tool for safe and effective drug delivery. In the present study, we developed small molecule P7C3-based NPs and tested its efficacy and toxicity along with the tissue specific aptamer-modified P7C3 NPs. The P7C3 NPs were prepared using poly (D, L-lactic-co-glycolic acid) carboxylic acid (PLGA-COOH) polymer, were conjugated with skeletal muscle-specific RNA aptamer (A01B P7C3 NPs) and characterized for its cytotoxicity, cellular uptake, and wound healing in vitro. The A01B P7C3 NPs demonstrated an encapsulation efficiency of 30.2 ± 2.6%, with the particle size 255.9 ± 4.3 nm, polydispersity index of 0.335 ± 0.05 and zeta potential of + 10.4 ± 1.8mV. The FTIR spectrum of P7C3 NPs displayed complete encapsulation of the drug in the NPs. The P7C3 NPs and A01B P7C3 NPs displayed sustained drug release in vitro for up to 6 days and qPCR analysis confirmed A01B aptamer binding to P7C3 NPs. The C2C12 cells viability assay displayed no cytotoxic effects of all 3 formulations at 48 and 72 h. In addition, the cellular uptake of A01B P7C3 NPs in C2C12 myoblasts demonstrated higher uptake. In vitro assay mimicking wound healing showed improved wound closure with P7C3 NPs. In addition, P7C3 NPs significantly decreased TNF-α induced NF-κB activity in the C2C12/NF-κB reporter cells after 24-hour treatment. The P7C3 NPs showed 3-4-fold higher efficacy compared to P7C3 solutions in both wound-closure and inflammation assays in C2C12 cells. Furthermore, the P7C3 NPs showed 3-4-fold higher efficacy in reducing the infarct size and protected mouse hearts from ex vivo ischemia-reperfusion injury. Overall, this study demonstrates the safe and effective delivery of P7C3 NPs.