Cooperative Macromolecular Self-Assembly toward Polymeric Assemblies with Multiple and Bioactive Functions

ConspectusIn the past decades, polymer based nanoscale polymeric assemblies have attracted continuous interest due to their potential applications in many fields, such as nanomedicine. Many efforts have been dedicated to tailoring the three-dimensional architecture and the placement of functional groups at well-defined positions within the polymeric assemblies, aiming to augment their function. To achieve such goals, in one way, novel polymeric building blocks can be designed by controlled living polymerization methodology and advanced chemical modifications. In contrast, by focusing on the end function, others and we have been practicing strategies of cooperative self-assembly of multiple polymeric building blocks chosen from the vast library of conventional block polymers which are easily available. The advantages of such strategies lie in the simplicity of the preparation process and versatile choice of the constituent polymers in terms of their chemical structure and functionality as well as the fact that cooperative self-assembly based on supramolecular interactions offers elegant and energy-efficient bottom-up strategies. Combination of these principles has been exploited to optimize the architecture of polymeric assemblies with improved function, to impart new functionality into micelles and to realize polymeric nanocomplexes exhibiting functional integration, similar to some natural systems like artificial viruses, molecular chaperones, multiple enzyme systems, and so forth.In this Account, we shall first summarize several straightforward designing principles with which cooperative assembly of multiple polymeric building blocks can be implemented, aiming to construct polymeric nanoassemblies with hierarchal structure and enhanced functionalities. Next, examples will be discussed to demonstrate the possibility to create multifunctional nanoparticles by combination of the designing principles and judiciously choosing of the building blocks. We focus on multifunctional nanoparticles which can partially address challenges widely existing in nanomedicine such as long blood circulation, efficient cellular uptake, and controllable release of payloads. Finally, bioactive polymeric assemblies, which have certain functions closely mimicking those of some natural systems, will be used to conceive the concept of functional integration

Stabilization of Multimeric Enzymes against Heat Inactivation by Chitosan-<i>graft</i>-poly(<i>N</i>‑isopropylacrylamide) in Confined Spaces

The inactivation of multimeric enzymes is a more complicated process compared with that of monomeric enzymes. Stabilization of multimeric enzymes is regarded as a challenge with practical values in enzyme technology. Temperature-sensitive copolymer chitosan-<i>graft</i>- poly­(<i>N</i>-isopropylacrylamide) was synthesized and encapsulated with multimeric enzymes in the confined spaces constructed by the W/O microemulsion. In this way, the quaternary structures of multimeric enzymes are stabilized and the thermal stabilities of them are enhanced. The whole process was studied and discussed. This method, which works well for both glucose oxidase and catalase, can be developed as a general protection strategy for multimeric enzymes

Aggregation Behavior of the Template-Removed 5,10,15,20-Tetrakis(4-sulfonatophenyl)porphyrin Chiral Array Directed by Poly(ethylene glycol)-<i>block</i>-poly(l‑lysine)

Complexation between 5,10,15,20-tetrakis­(4-sulfonatophenyl)­porphyrin (TPPS) and poly­(ethylene glycol)-<i>block-</i>poly­(l-lysine) (PEG-<i>b</i>-PLL) was performed via electrostatic interaction. Two kinds of primary arrays of TPPS with different supramolecular chirality induced by PLL were obtained in the resultant complex by inverting the mixing procedure of the two components. These arrays could be displaced by poly­(sodium-<i>p</i>-styrenesulfonate) (PSS) from the chiral PLL template through competitive electrostatic complexation, and then PSS formed a polyion complex micelle with PEG-<i>b</i>-PLL. The template-removed TPPS arrays preserved their induced chirality and served as primary subunits for the secondary aggregation of TPPS. The morphology of the secondary aggregates was strongly dependent upon the asymmetric primary supramolecular arrangement of TPPS. The rodlike nanostructure that was ∼200 nm in length was composed of the primary arrays that showed opposite exciton chirality between the J- and H-bands. In contrast, the micrometer-sized fibrils observed were composed of the arrays with the same exciton chirality at the J- and H-bands

Controlled Release of Ionic Drugs from Complex Micelles with Charged Channels

Oral administration of ionic drugs generally encounters with significant fluctuation in plasma concentration due to the large variation of pH value in the gastrointestinal tract and the pH-dependent solubility of ionic drugs. Polymeric complex micelles with charged channels on the surface provided us with an effective way to reduce the difference in the drug release rate upon change in pH value. The complex micelles were prepared by self-assembly of PCL-<i>b</i>-PAsp and PCL-<i>b</i>-PNIPAM in water at room temperature with PCL as the core and PAsp/PNIPAM as the mixed shell. With an increase in temperature, PNIPAM collapsed and enclosed the PCL core, while PAsp penetrated through the PNIPAM shell, leading to the formation of negatively charged PAsp channels on the micelle surface. Release behavior of ionic drugs from the complex micelles was remarkably different from that of usual core–shell micelles where diffusion and solubility of drugs played a key role. Specifically, it was mainly dependent on the conformation of the PAsp chains and the electrostatic interaction between PAsp and drugs, which could partially counteract the influence of pH-dependent diffusion and solubility of drugs. As a result, the variation of drug release rate with pH value was suppressed, which was favorable for acquiring relatively steady plasma drug concentration

In Vivo Biodistribution of Mixed Shell Micelles with Tunable Hydrophilic/Hydrophobic Surface

The miserable targeting performance of nanocarriers for cancer therapy arises largely from the rapid clearance from blood circulation and the major accumulation in the organs of the reticuloendothelial system (RES), leading to inefficient enhanced permeability and retention (EPR) effect after intravenous injection (i.v.). Herein, we reported an efficient method to prolong the blood circulation of nanoparticles and decrease their deposition in liver and spleen. In this work, we fabricated 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 through spontaneously self-assembly of block copolymers poly­(ethylene glycol)-<i>block</i>-poly­(l-lysine) (PEG-<i>b</i>-PLys) and poly­(<i>N</i>-isopropylacrylamide)-<i>block</i>-poly­(aspartic acid) (PNIPAM-<i>b</i>-PAsp) in aqueous medium. The effect of the surface heterogeneity on the in vivo biodistribution was systematically investigated through in vivo tracking of the ¹²⁵I-labeled MSMs determined by Gamma counter. Compared with single PEGylated micelles, some MSMs were proved to be significantly efficient with more than 3 times lower accumulation in liver and spleen and about 6 times higher concentration in blood at 1 h after i.v.. The results provide us a novel strategy for future development of long-circulating nanocarriers for efficient cancer therapy

Phenylboronic Acid-Based Complex Micelles with Enhanced Glucose-Responsiveness at Physiological pH by Complexation with Glycopolymer

Polymeric nanoparticles with glucose-responsiveness under physiological conditions are of great interests in developing drug delivery system for the treatment of diabetes. Herein, glucose-responsive complex micelles were prepared by self-assembly of a phenylboronic acid-contained block copolymer PEG-<i>b</i>-P­(AA-<i>co</i>-APBA) and a glycopolymer P­(AA-<i>co</i>-AGA) based on the covalent complexation between phenylboronic acid and glycosyl. The formation of the complex micelles with a P­(AA-<i>co</i>-APBA)/P­(AA-<i>co</i>-AGA) core and a PEG shell was confirmed by HNMR analysis. The glucose-responsiveness of the complex micelles was investigated by monitoring the light scattering intensity and the fluorescence (ARS) of the micelle solutions. The complex micelles displayed an enhanced glucose-responsiveness compared to the simple PEG-<i>b</i>-P­(AA-<i>co</i>-APBA) micelles and the sensitivity of the complex micelles to glucose increased with the decrease of the amount of P­(AA-<i>co</i>-AGA) in the compositions. The cytotoxicity of the polymers and the complex micelles was also evaluated by MTT assay. This kind of complex micelles may be an excellent candidate for insulin delivery and may find application in the treatment of diabetes

Self-Regulated Multifunctional Collaboration of Targeted Nanocarriers for Enhanced Tumor Therapy

Exploring ideal nanocarriers for drug delivery systems has encountered unavoidable hurdles, especially the conflict between enhanced cellular uptake and prolonged blood circulation, which have determined the final efficacy of cancer therapy. Here, based on controlled self-assembly, surface structure variation in response to external environment was constructed toward overcoming the conflict. A novel micelle with mixed shell of hydrophilic poly­(ethylene glycol) PEG and pH responsive hydrophobic poly­(β-amino ester) (PAE) was designed through the self-assembly of diblock amphiphilic copolymers. 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 pH 7.4. At tumor pH, charge conversion occurred, and c­(RGDfK) stretched out of the shell, leading to facilitated cellular internalization according to the HepG2 cell uptake experiments. Meanwhile, the heterogeneous surface structure endowed the micelle with prolonged blood circulation. 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 novel nanocarrier could be a promising candidate in future clinical experiments