Thermosensitive Injectable Hydrogel for Simultaneous Intraperitoneal Delivery of Doxorubicin and Prevention of Peritoneal Adhesion

Abstract

To improve intraperitoneal chemotherapy and to prevent postsurgical peritoneal adhesion, we aimed to develop a drug delivery strategy for controlled release of a chemotherapeutic drug from the intraperitoneally injected thermosensitive poly(N-isopropylacrylamide)-based hydrogel (HACPN), which is also endowed with peritoneal anti-adhesion properties. Anticancer drug doxorubicin (DOX) was loaded into the hydrogel (HACPN-DOX) to investigate the chemotherapeutic and adhesion barrier effects in vivo. A burst release followed by sustained release of DOX from HACPN-DOX was found due to gradual degradation of the hydrogel. Cell culture studies demonstrated the cytotoxicity of released DOX toward CT-26 mouse colon carcinoma cells in vitro. Using peritoneal carcinomatosis animal model in BALB/c mice with intraperitoneally injected CT-26 cells, animals treated with HACPN-DOX revealed the best antitumor efficacy judging from tumor weight and volume, survival rate, and bioluminescence signal intensity when compared with treatment with free DOX at the same drug dosage. HACPN (or HACPN-DOX) also significantly reduced the risk of postoperative peritoneal adhesion, which was generated by sidewall defect-cecum abrasion in tumor-bearing BALB/c mice, from gross and histology analyses. This study could create a paradigm to combine controlled drug release with barrier function in a single drug-loaded injectable hydrogel to enhance the intraperitoneal chemotherapeutic efficacy while simultaneously preventing postsurgical adhesion.

Thermo-Sensitive Nanomaterials: Recent Advance in Synthesis and Biomedical Applications

“…Several natural polymers that demonstrate thermally sensitive properties have been used for the synthesis of hydrogels such as polysaccharides (cellulose, chitosan and xiloglucan) [ 123 , 124 , 125 ] and proteins (gelatin) [ 126 ]. Different polymers such as poly(ethylene glycol)-poly(3-caprolactone)-poly(ethylene glycol) [ 127 ], poly n -isopropylacrylamide/polyacrylic acid (PNIPAm/PAA) [ 128 ], poly( d , l -lactide)-block poly(ethylene glycol)-block-poly( d , l -lactide) (PDLLA-PEG-PDLLA) [ 129 ], poly(ethylene oxide)- b -poly(propylene oxide)- b -poly(ethylene oxide) (PEO-PPO-PEO) [ 130 ], and PNIPAm-based hydrogels have also been reported in drug delivery [ 131 , 132 , 133 ] (see Table 1 ).…”

<p>Poly(N-Isopropyl-Acrylamide)/Poly(γ-Glutamic Acid) Thermo-Sensitive Hydrogels Loaded with Superoxide Dismutase for Wound Dressing Application</p>

“…18 A family of thermosensitive hydrogels based on N-isopropylacrylamide (NIPAM) macromer by Chen et al was synthesized for drug delivery. 19 So a PNIPAM-based thermo-sensitive hydrogel could be loaded with SOD for clinical injection in situ. But PNIPAM as synthetic polymers could induce minimal inflammatory reaction and decrease biocompatibility.…”

Biomaterials to Prevent Post-Operative Adhesion

“…Recently, a thermosensitive hydrogel was developed to apply an anti-adhesion barrier, even in surgery, using the minimally invasive method. Thermosensitive anti-adhesion barriers have the advantage that they can be applied to surgical sites through injection because they are liquid at room temperature and gel at body temperature [ 27 , 32 , 146 , 147 ].…”