针对肿瘤微环境精确设计的智能抗肿瘤纳米药物

Using nanocarrier to deliver anti-cancer drugs has become one of the most active research areas in cancer medicine. Nanocarriers can effectively optimize the solubility, stability and pharmacokinetic properties of traditional drugs, and improve adverse effects by altering their biological distribution profiles. However, clinical evidence indicated that the "first generation" nanomedicines, where drugs were passively delivered by a nanosized carrier, were often not efficient enough against the heterogeneity and complexity of tumors. Therefore "smart" designs to synergistically improve delivery and therapeutic efficiency via the application of multiple functional elements have attracted much interest. The emerging concept of tumor microenvironment regulation has greatly advanced the development of "smart" nanotherapeutics. As therapeutic or drug delivery targets, microenvironmental components such as tumor stroma or vasculature are genetically more stable than tumor cells, and microenvironment-targeted delivery can also facilitate the bypassing of some biological barriers. Our group's research demonstrated that, rational exploitment of intrinsic material and multifunctional advantages of nanostructure-based drug carriers might prove critical for the development of novel anticancer strategies. In recent years, our group has systematically investigated both targeting and regulation strategies based on pathological characteristics of diverse microenvironmental components, achieving a series of innovative therapeutic solutions involving tumor vascular-specific embolization, tumor stromal microenvironment remodeling, or selective clearance of tumor-associated platelet through precisely designed nanotherapeutics. This report briefly reviews the representative results among them and comments on the future directions of microenvironment-modulated nanomedicines. Examples of our recent advances include: (1) Using self-assembled DNA origami nanorobots, we have developed a novel approach to safely deliver thrombin, a potent coagulant, via intravenous administration. The highly programmable supramolecular behaviors of nucleic acids allowed the protein to be accurately collocated inside the tube-shaped nanorobot without risking to be non-specifically exposed during the transport in the bloodstream. Once arrived at the tumor microenvironment, the nanorobot could be selectively "unlocked" by a tumor-specific endothelial marker via molecular recognition. This approach for the first time transformed thrombin, a protein that was previously thought unsuitable for intravenous injection to a biosafe and effective agent for tumor-specific blood vessel occlusion. (2) A multifunctional nanostructure has been developed to re-model the tumor stroma for enhanced chemotherapy. Depleting the dense and fibrotic tumor stroma reportedly enhanced intratumoral drug penetration but in some cases might disrupt tissue homeostasis leading to tumor progression or metastasis. Using a polymeric nanoparticle that selectively reversed its surface charge in the slightly acidic tumor microenvironment, we effectively delivered anti-fibrotic and stromal cell-inhibiting drugs into tumor stromal cells through tumor-triggered cellular uptake. This nanotherapeutic was shown to significantly induce quiescence of stromal cells, reducing their extracellular matrix production and pro-tumor signaling to enhance the efficacy of co-administrated chemotherapy. (3) A novel strategy to enhance nanoparticle delivery across the vascular endothelial barrier has been proposed via localized depletion of platelets, whose presence and activation in the tumor microenvironment helped to maintain the endothelial integrity of tumor vasculature. Co-delivery of anti-platelet antibodies with chemotherapeutic drug through a nanoparticle system capable of enzyme-responsive, multiple-step drug release effectively induced endothelial damage in tumor tissues, leading to enhanced extravasation of the nanoparticleencapsulated chemotherapeutic. (4) Using a tumor-targeted chitosan nanoparticle to co-deliver thrombin and doxorubicin we have achieved further improved anti-tumor efficacy of vascular occlusion therapy. While rim cells in tumor tissues were often less sensitive to anti-vascular treatments, the co-administration of chemotherapeutic drug allowed us to more efficiently eradicate these cells and prevent recurrence, demonstrating the potential of multifunctional nanotherapeutics in overcoming tumor heterogeneity. In summary, our work has demonstrated that based on specific pathological characteristics of different types of tumors, it is possible to precisely construct multifunctional nanocarriers for drug delivery and microenvironment modulation to achieve optimal efficacy. The next generation of "smart" nanotherapeutics will certainly aim at more programmable material design and more sophisticated in vivo actions, and our effort will continuously be dedicated to understanding the tumor microenvironment in order to enable personalized microenvironment-targeted nanomedicine.