Study On Functional Collaborated Complex Micelle As Anti-tumor Drug Delivery Nanocarrier

Nanoparticles self-assembled from polymers have attracted intensive interest in biomedical application as drug delivery nanocarriers in cancer therapy. Benefitting from multi-functionality, controllable modification and other advantages of polymer materials, polymer-based drug delivery systems obtained continuous research and development, which facilitated the advances in clinic trials of novel nano-medicine. The in vivo barriers for systemic administered nanoparticles (NPs) include the transport via blood to the tumor extracellular matrix, binding to the cell membrane, cellular internalization, and intracellular delivery. Taking into account of the multiple physiological and biological barriers, ideal nanocarriers following systemic administration should possess the properties of (i) prolonged circulation in plasma,(ii) increased tumor accumulation,(iii) enhanced cellular uptake, and (iv) sufficient intracellular drug release. In order to develop novel efficient drug delivery system, in this paper, our research started from the investigation of nanoparticles with prolonged blood circulation and systematically studied the in vivo biodistribution of different micelles. Then, based on the optimization of rational property, we developed a novel multifunctional collaborated nanocarrier with self-regulated property to overcome the barriers in drug delivery.The effect of surface heterogeneity on the in vivo biodistribution was investigated firstly in this work. A series of mixed shell micelles (MSMs) with approximately the same size, charge and core composition but with varied hydrophilic/hydrophobic ratios in the shell was fabricated through spontaneously self-assembly of block copolymers poly(ethylene glycol)-block-poly(L-lysine)(PEG-b-PLys) and poly(N-isopropylacrylamide)-block-poly(aspartic acid)(PNIPAM-b-PAsp) in aqueous medium. The in vivo biodistribution was systematically investigated through in vivo tracking of the125I-labeled MSMs determined by Gamma counter. We found that the MSMs with proper surface microphase separation showed highly improved biodistribution behaviors with reduced accumulation in liver and spleen and prolonged blood circulation. Meanwhile, with similar strategy of self-assembly, we fabricated a series of polyion complex (PIC) micelles PEGylated with similar major physicochemical properties including size, size distribution, shape, surface charge, and core composition, but with different ratios of PEG2k and PEG550. The plasma protein adsorption, murine macrophage uptake, and in vivo biodistribution with iodine-125as the tracer were systematically studied to elucidate the impact of PEGylation patterns on the biodistribution of micelles. We demonstrated that the PEGylated micelles with short hydrophilic PEG chains mixed on the surface were cleared quickly by the RES, and the single PEG2k PEGylated micelles could efficiently prolong the blood circulation time and increase their deposition in tumor sites. This study extended the understanding of the PEGylation strategy to further advance the development of ideal nanocarriers for drug delivery and imaging applications.Based on our previous work on the in vivo biodistribution, we developed a new self-regulated delivery system based on the controlled self-assembly of mixed shell micelle to overcome the conflict between prolonged blood circulation and enhanced cellular uptake, and finally promote the efficacy of cancer therapy. The mixed shell micelle was fabricated through the self-assembly of poly(ethylene glycol)-block-poly(ε-caprolactone)(PEG-b-PCL) and poly(ε-caprolactone)-block-poly(β-amino ester)-c(RGDfK)(PCL-b-PAE-c(RGDfK)) in water. The c(RGDfK) decorated mixed shell micelle (RMSM) consisted of a hydrophobic PCL core, a mixed shell of PEG, PAE and PAE-c(RGDfK). The heterogeneous surface structure endowed the micelle with prolonged blood circulation. To avoid the accelerated clearance from blood circulation caused by the surface exposed targeting group c(RGDfK), here, c(RGDfK) was conjugated to the hydrophobic PAE and hidden in the shell of PEG at pH7.4. At tumor pH, charge conversion occurred and c(RGDfK) stretched out of the shell, leading to facilitated cellular internalization according to the HepG2cell uptake experiments. With the self-regulated multifunctional collaborated properties of enhanced cellular uptake and prolonged blood circulation, successful inhibition of tumor growth was achieved from the demonstration in a tumor-bearing mice model. This delivery strategy provided a simple and versatile approach to overcome the obstacles in drug delivery system. We anticipate this kind of shell responsive mixed micelles can serve as anticancer drug carriers in future clinical trials.