Fabrication Of Acidic Tumor Microenvironment-responsive Polymeric Drug Vectors Through Size Design

Nanocarrier drug delivery systems (NDDS) have received tremendous attention for cancer therapy, due to their special structures, characteristics, and delivery performance. In order to make treatments with conventional chemotherapeutic agents more effectively more safety, a lot of studies have been done in the fields of NDDS by colleges, research institutions, and pharmaceutical enterprises. Accordingly, various kinds of advanced NDDS are constantly emerging with the development of nanotechnology and carrier materials. It is known that a proper design of NDDS is crucial to achieve an efficient antitumor effect. For all this, based on the effect of particle size on biological systems, we fabricated a tumor microenvironment-responsive NDDS in order to enhance the antitumor effect of chemotherapeutics. The main content of this dissertation are described as below:1. The relationship between the particle size and the delivery performance of polymeric micelles was systemically investigated. A series of MPEG-PLA copolymers of different molecular weights were synthesized and used for micelle preparation. Five sizes (30,45,60,118, and 230 nm) of micelles loading docetaxel (DTX) were developed using solid dispersion technique. These micelles differed only in size, while presented similar zeta potentials and drug loadings. Cellular uptake study indicated a decreased uptake for bigger (230 nm) micelles. Micelles of 118 nm had markedly longer blood circulation half-life than smaller or larger micelles. Penetration studies performed in both multicellular tumor spheroids and tumor xenografts revealed that micelles with diameters as small as 30 nm possessed a significantly higher penetration ability. With increasing size, particle accumulation in tumor and kidneys was dramatically reduced, whereas a highly increased spleen uptake was shown. Moreover, the size effect of DTX-PM on antitumor activity was evident, with all sub-60 nm micelles showing the strongest efficiency to suppress tumor growth, the 118 nm micelles leading to reduced antitumour activity, and the 230 nm micelles failing to inhibit tumor growth. These findings could serve as a guideline in the rational design of drug nanocarriers with maximized therapeutic efficacy and predictable in vivo properties, considering the importance of controlled particle size.2. We have developed a tumor-acidity-responsive size/charge-changing multistage NDDS, which was prepared from the pH-responsive amphiphilic MPEG-PLA-PAE copolymers. Due to its original large size of 100-200 nm, the nanocarrier owned prolonged circulation time in blood. Once arriving at the tumor tissue, it shrinked to a small micelle structure while the positive surface charge increased in response to the mildly acidic pH of the tumor, lowering their diffusional hindrance in the interstitial matrix and improving tumor cellular uptake. Based on this multistage approach, the nanocarrier possessed the advantages of longer blood circulation time, better intratumoral penetration ability, higher cellular uptake, and more tumor accumulation. Finally, the superior nanocarrier could remarkably enhanced the antitumor efficiency of chemotherapeutics. This multistage NDDS was evaluated through two kinds of anticancer drugs (CUR and DTX) and two kinds of tumor models (MCF-7 cells and KB cells).