Combination chemotherapy has been a primary management for cancer. Thus a drug delivery system which can administer several drugs simultaneously and control the drug release at the cancer site is desired. Here we synthesized hyperbranched poly(amine-ester) (HPAE) macromers with different degrees of terminal C C modification to make injectable hydrogels as a multi-drug delivery system. The aqueous solutions of the macromers were fast transformed into hydrogel at body temperature with a low concentration (0.05 wt%) of ammonium persulfate (APS) but no activator for accelerating the polymerization, since the HPAE macromer with tertiary amines and APS themselves formed a redox system as initiator. Three different types of drugs, doxorubicin hydrochloride (Dox), 5-fluorouracil (5FU) and leucovorin calcium (LC), were used as model drugs in this experiment. This system allows locally releasing single and/or combinations of anticancer drugs simultaneously by a controllable way. Behaviors of drug release can be controlled by the drug-loading methods or/and the C C modification degree of macromers loaded with the drug molecules. The drug release period could be prolonged when the drug was loaded into the macromers with high content of C C. The HPAE macromers exhibited good biocompatibility which was evaluated in L929 and MCF7 cell lines using MTT cell proliferation assay. The swelling behavior and degradation of HPAE hydrogels in vitro were also examined. These results suggest that the HPAE hydrogels hold great potential for use as injectable systems for locally delivering single and/or multiple drugs in chemotherapy of cancer.
Xianglian Liao,Youshi Zheng,Ziguo Lin,Yi Shen,Huiyun Lin,Xiaolong Liu,Da Zhang,Buhong Li
On-demand delivery of drug to deep tumor tissues with long-term tumor retention has directly influence on therapeutic efficiency and prognosis of patients, which still remains challenge in cancer therapy. Here we introduce metallo-supramolecular nanoflowers through multi-drugs and metal coordination effect for near-infrared (NIR) or acidic-triggered multi-drugs release, long-term accumulation at tumor tissues and NIR-II fluorescence imaging-guided photo-chemotherapy. The nanoflowers (refer to ICG⊃EDOX) are constructed by (−)-epigallocatechin-3-gallate (EGCG), Cu 2+ ions, indocyanine green (ICG) and doxorubicin hydrochloride (DOX) through coordination effect, π-π stacking and hydrophobic force. Due to strong intermolecular interaction, the ICG⊃EDOX is superior stable in physiological conditions, while releases DOX/ICG on-demand upon the acidic/NIR laser irradiation. Moreover, ICG⊃EDOX could penetrate deep tumor tissues with ultralong tumor retention (>8 d) by microvesicle (MVs)-mediated intercellular interaction. Irradiated by 808 nm laser, the higher NIR-II fluorescence signal from ICG⊃EDOX in tumors can effectively guide local phototherapy, and the synergistic therapeutic efficiency of nanoflowers with completely elimination of tumors is achieved in comparison with DOX or DOX/ICG treated 4T1-bearing mice . Overall, the excellent therapeutic effect of nanoflowers may hold great promise for the clinic translation.
The cell nucleus serves as the pivotal command center of living cells, and delivering therapeutic agents directly into the nucleus can result in highly efficient anti-tumor eradication of cancer cells. However, nucleus-targeting drug delivery is very difficult due to the presence of numerous biological barriers. Here, three antitumor drugs (DNase I, ICG: indocyanine green, and THP: pirarubicin) were sequentially triggered protein self-assembly to produce a nucleus-targeting and programmed responsive multi-drugs delivery system (DIT). DIT consisted of uniform spherical particles with a size of 282 ± 7.7 nm. The acidic microenvironment of tumors and near-infrared light could successively trigger DIT for the programmed release of three drugs, enabling targeted delivery to the tumor. THP served as a nucleus-guiding molecule and a chemotherapy drug. Through THP-guided DIT, DNase I was successfully delivered to the nucleus of tumor cells and killed them by degrading their DNA. Tumor acidic microenvironment had the ability to induce DIT, leading to the aggregation of sufficient ICG in the tumor tissues. This provided an opportunity for the photothermal therapy of ICG. Hence, three drugs were cleverly combined using a simple method to achieve multi-drugs targeted delivery and highly effective combined anticancer therapy.
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