Advances in the Application of Injectable Thermosensitive Hydrogel Systems for Cancer Therapy.

Systemic administration of anticancer therapeutic agents remains a crucial strategy for clinical cancer therapy. However, poor drug accumulation at tumor sites and severe side effects to normal tissues induced by off-target effects lower their therapeutic efficiency and limit their deep application in clinical settings. How to overcome these issues has continuously raised concerns. Reportedly, injectable thermosensitive hydrogels are good carriers for local drug delivery systems, demonstrating a flowable and injectable sol state at room temperature, easily loading therapeutic agents with large loading contents. Under normal body temperature, these hydrogels are stimulated to undergo a phase transition to an immobile gel state, which serves as a drug reservoir at local injection sites. After intratumoral or peritumoral injection, the localized hydrogel reservoir shows a slow and sustained drug release behavior, and can also targeted deliver therapeutic agents to cancer cells instead of normal cells, improving the therapeutic efficiency and reducing systemic side effects. This review summarizes the development of injectable thermosensitive hydrogel systems, reviews the research application advances of these systems in different therapy strategies for cancer, discusses the present issues and awaits their future in clinical applications.

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.

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.

Synthesis and Application of a Novel Gene Delivery Vector for Non-Small-Cell Lung Cancer Therapy.

Human Wnt inhibitory factor-1 (hWIF-1), as an anti-oncogene, holds great promise for non-small-cell lung cancer (NSCLC) therapy. However, the clinical application of hWIF-1 in cancer therapy is limited by elimination and degradation of free hWIF-1 in vivo. Therefore, it is necessary to develop safe and effective gene delivery vectors for hWIF-1 delivery in vivo. In this paper, we synthesized a novel polyethylenimine (PEI) derivative PEI-SP5-2 (PES) based on branched PEI1800 and NSCLC-targeting peptide SP5-2 to deliver hWIF-1 for NSCLC therapy. PES had excellent gene delivery capacity, and the transfection efficiency reached 50.02% ± 4.75% in A549 cell lines when the weight ratio of PES/gene was 100. Besides, the PES/gene particles were monodispersed, and the hydrodynamic diameter and zeta potential were 47.55 nm and 24.9 mV, respectively. In addition, PES/hWIF-1 complexes could inhibit the tumor growth in vitro and in vivo when it was used for non-small-cell lung cancer therapy. We concluded that PES would be promising as a novel gene delivery vector, and PES/hWIF-1 complexes inhibited the tumor growth and showed potential for non-small-cell lung cancer therapy.

Suberoylanilide hydroxamic acid reversed cognitive and synaptic plasticity impairments induced by sevoflurane exposure in adult mice.

Although it has been shown that sevoflurane exposure could impair the cognitive function, there are few effective treatments to prevent this disorder. Suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylase, plays an important role in hippocampal memory formation, which has been proven to enhance memory. As such, we explored whether SAHA could improve the memory impairment induced by sevoflurane in adult mice. In the present study, adult male C57BL/6 mice were exposed to 3% sevoflurane for 6 h, and then the cognitive impairment in Morris water maze was found at 24 h after anesthesia. Moreover, an impairment in long-term potentiation was also detected in the isolated hippocampal slices. SAHA administrated intraperitoneally 2 h before anesthesia improved cognitive and synaptic plasticity impairments. SAHA also significantly reversed the decreases in Ac-H3, brain-derived neurotrophic factor, tropomyosin-related kinase B, and p-cAMP response element-binding expressions induced by sevoflurane exposure, and reduced the level of apoptosis-related protein cleaved caspase-3. We concluded that cognitive and synaptic plasticity impairments induced by sevoflurane exposure could be reversed by normalizing the histone acetylation state. The effect is related to inhibiting cell apoptosis and activating the brain-derived neurotrophic factor/tropomyosin-related kinase B/cAMP response element-binding signaling pathway in the hippocampus.

Biodegradable self-assembled MPEG-PCL micelles for hydrophobic oridonin delivery in vitro.

The great potential of oridonin (ORI) for clinical application in cancer therapy is greatly limited due to its poor water-solubility. The purpose of this study was to increase the water solubility of oridonin using monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone) (MPEG-PCL) as drug carrier. The ORI-loaded MPEG-PCL micelles were prepared by thin film hydration method. The obtained ORI-micelles could be lyophilized into powder form, which could be re-dissolved in water to form homogeneous solution. This study showed that ORI was successfully incorporated in the core-shell structure of MPEG-PCL micelles and maintained its anticancer activity. The average particle size was 25.55 +/- 0.10 nm and the mean zeta potential was -4.71 +/- 0.05 mV. The actual drug loading and encapsulation efficiency were 7.99 +/- 0.03% and 99.51 +/- 0.34%, respectively. ORI could be released from MPEG-PCL micelles in a sustained manner in vitro. The permeation profiles of ORI from ORI-micelles and ORI water saturated solution through excised mouse skin demonstrated that ORI-micelles showed much better transdermal penetration performance than ORI water saturated solution. The prepared ORI-micelles have great potential for both direct intravascular administration and being further developed as a transdermal drug delivery system in cancer chemotherapy.