Tumor Microenvironment-Responsive Nanoparticles For Drug Delivery

A series of complex biological barriers considerably prevent nanomedicine from reaching its targets in sufficient concentration and thus severely limit its clinical therapeutic benefits,including the blood barriers,tumor microenvironment barriers and intratumoral cell barriers.The characteristics of nanomedicine have an important influence at different drug delivery stage,which in turn affects the overall efficiency of drug delivery and cancer treatment.A feasible strategy is to formulate the nanocarriers in response to the microenvironment and tune their properties to adapt to each individual environment for robust and effective delivery.In this dissertation,we focus on the performance of nanocarriers regulated by the tumor acid microenvironment,including surface charge,size,etc.,and further study the biological effects at the tumor site,such as the tumor penetration,cell internalization,transportation,anti-tumor responses and anti-metastasis effects,etc.The main content of this dissertation is described in three parts as below:1.We developed a tumor-acidity-activated ultrafast charge-conversional nanocarrier UCC-NP3/Pt.The carboxyl groups of PCEA block can efficiently load cisplatin,while the PAEMA block formed the hydrophobic core at the physiological pH values.Once accumulated in the tumor tissues,the tumor acidity ensured rapid protonation of tertiary amine groups of PAEMA block,resulting in the ultrafast charge conversion within 10 s.Such ultrafast charge-conversional effect more efficiently enhanced tumor cell internalization of nanocarriers,thus achieving targeted drug delivery,which in turn exhibited superior anticancer efficacy even in the cisplatin-resistant model.2.We uncovered that improved perfusion in primary tumor facilitates nanoparticle translocation to lymph nodes for inhibiting tumor metastasis.On the basis of our finding that an iCluster platform which undergoes size reduction at tumor site markedly improved particle perfusion in the interstitium of primary tumor,we further revealed in the current study that such tumor-specific size transition promoted particle intravasation into tumor lymphatics and migration into lymph nodes.Quantitative analysis indicated that the drug deposition in lymph nodes after iCluster treatment was significantly higher in the presence of primary tumor in comparison with that after primary tumor resection.Early intervention of metastatic breast tumor with iCluster chemotherapy and subsequent surgical resection of the primary tumor resulted in significantly extending animal survival.Additionally,in the more clinically relevant late metastatic model,iCluster inhibited the metastatic colonies to the lungs,and extended animal survival time.3.By utilizing the iCluster delivery strategy that maintaining larger sizes during blood circulation,whereas releasing small particle cargos at tumor site,we construct G3-,G5-,and G7-iCluster with similar initial size and zeta potential.They showed comparable initial tumor deposition due to their similarity in pharmacokinetics,and then diff erent size of PAMAM were released locally within the tumor tissue.Our results indicated a subtle change in size evidently affects their intratumor activities.G5?iCluster outperformed G3-iCluster and G7-iCluster in the treatment efficacy in an orthotopic pancreatic tumor model.The mechanistic study revealed that G3-PAMAM showed reduced particle retention in tumor tissue due to its small size and weak cell internalization,while G7-PAMAM was much less penetrative because of its relatively large size and strong particle-cell interaction.In contrast,G5-PAMAM exhibited balanced tumor penetration,cell internalization,and tumor retention.Our finding highlights the striking influence of subtle size difference in the intratumor performance of ultrasmall NPs.