Intratumoral Injection of Norcantharidin-Loaded Poly(D,L-lactide)-b-Poly(ethylene glycol)-b-Poly(D,L-lactide) Thermosensitive Hydrogel for the Treatment of Primary Hepatocellular Carcinoma

Abstract

In this study we employed self-designed PDLLA-PEG-PDLLA (PLEL) thermosensitive hydrogel to blend with norcantharidin (NCTD), a hydrophilic chemotherapeutic drug possessing curative effect on primary hepatocellular carcinoma (HCC) and adverse effects, then utilized the composite in HCC interstitial chemotherapy. PLEL copolymer was synthesized by ring-opening polymerization, NCTD-loaded PLEL hydrogel was prepared in a simple and reasonable way. The addition of NCTD had no significant effect on the temperature-dependent rheological properties of PLEL hydrogel. The pH values of NCTD-loaded gel solutions (13 wt%) and free NCTD solutions with three drug concentrations of 0.4 mg/mL, 0.8 mg/mL and 1.2 mg/mL under different storage conditions met the pH requirement of small-volume injection. There was no significant difference among the drug release behaviors of NCTD-loaded gels with drug concentrations of 0.4 mg/mL, 0.8 mg/mL and 1.2 mg/mL, they fitted first-order dynamics, exhibited significantly slower drug release than free drug solutions and the release was mainly based on drug diffusion. Drug-loaded gel solution (13 wt%) could evenly distribute throughout tumor tissue before converting into gel after being intratumorally injected and was able to significantly prolong retention time of the drug in tumor compared to free drug solution. The sustained-release performance of NCTD-loaded gel (13 wt%) was confirmed from the perspective of pharmacodynamics in vitro. The in vivo evaluation demonstrated that intratumoral injection of NCTD-loaded PLEL gel (13 wt%) was capable of improving curative effect of the drug and reducing its toxicity.

Injectable Thermosensitive Hydrogel Containing Erlotinib‐Loaded Hollow Mesoporous Silica Nanoparticles as a Localized Drug Delivery System for NSCLC Therapy

“…Amphiphilic block copolymers, PLEL were synthesized from the methoxypolyethylene glycols (mPEG) and d , l ‐lactide (LA) by the ring‐open polymerization according to the previous works. [ 23,25 ] The obtained PLEL copolymers were characterized by 1 H NMR (Varian 400 spectrometer, Varian, USA).…”

“…[21,22] In our previous work, we have successfully synthesized a biodegradable and biocompatible thermosensitive hydrogel made of the amphiphilic triblock copolymer, poly(d,l-lactide)poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA, PLEL), with the ability to self-assemble into core-shell-like micelles in water under room temperature and to transfer into physically crosslinked non-flowing gel structure at physiological conditions. [23][24][25] Due to the hydrophilic characteristics in the nature of hydrogels, the amount and homogeneity of ERT loaded into this high water content structure may be limited. Hence, in our study, hollow mesoporous silica nanoparticles (HMSNs) were adopted to encapsulate ERT for increasing drug loading and improving the solubility to solve the incompatibility of hydrophobic agents in hydrogel systems (Scheme 1).…”

“…In our previous work, we have successfully synthesized a biodegradable and biocompatible thermosensitive hydrogel made of the amphiphilic triblock copolymer, poly( d , l ‐lactide)‐poly(ethylene glycol)‐poly( d , l ‐lactide) (PDLLA‐PEG‐PDLLA, PLEL), with the ability to self‐assemble into core–shell‐like micelles in water under room temperature and to transfer into physically crosslinked non‐flowing gel structure at physiological conditions. [ 23–25 ]…”

Injectable and thermosensitive hydrogels mediating a universal macromolecular contrast agent with radiopacity for noninvasive imaging of deep tissues

“…Meanwhile, in-situ gelation also affords a perfect match for filling a complex defect. In virtue of the characteristics of facile synthesis, good biocompatibility and adjustable biodegradability, thermosensitive PEG/polyester copolymer hydrogels have suggested for various applications in biomedical fields, such as drug delivery [ 35 , [37] , [38] , [39] , [40] , [41] , [42] ], wound repair [ 43 ], tissue regeneration [ 44 , 45 ] and post-surgical anti-adhesion [ 34 , 46 ].…”

Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma

“…Hepatocellular carcinoma (HCC) is a primary liver malignancy with one of the highest mortality rates worldwide ( Jacobson et al, 2018 ; Zhou et al, 2018 ; Paludetto et al, 2019 ; Siegel et al, 2019 ). Although significant progress has been made to improve chemotherapy, transcatheter artery chemoembolization (TACE), and targeted HCC therapy, many patients still present recurrences and the development of drug resistance ( Xue et al, 2019 ; Pan et al, 2020 ; Yu et al, 2020 ). Therefore, novel targeted therapeutic approaches are required to help overcome these problems.…”