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

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

Self-Assembling Peptide of d‑Amino Acids Boosts Selectivity and Antitumor Efficacy of 10-Hydroxycamptothecin

d-peptides, which consist of d-amino acids and can resist the hydrolysis catalyzed by endogenous peptidases, are one of the promising candidates for construction of peptide materials with enhanced biostability in vivo. In this paper, we report on a self-assembling supramolecular nanostructure of d-amino acid-based peptide Nap-G^DF^DF^DYGRGD (d-fiber, ^DF meant d-phenylalanine, ^DY meant d-tyrosine), which were used as carriers for 10-hydroxycamptothecin (HCPT). Transmission electron microscopy observations demonstrated the filamentous morphology of the HCPT-loaded peptides (d-fiber-HCPT). The better selectivity and antitumor activity of d-fiber-HCPT than l-fiber-HCPT were found in the in vitro and in vivo antitumor studies. These results highlight that this model d-fiber system holds great promise as vehicles of hydrophobic drugs for cancer therapy

Dynamic Biostability, Biodistribution, and Toxicity of l/d‑Peptide-Based Supramolecular Nanofibers

Self-assembling peptide nanofibers (including naturally l-amino acid–based and unnaturally d-amino acid–based ones) have been widely utilized in biomedical research. However, there has been no systematic study on their in vivo stability, distribution, and toxicity. Herein we systematically study the in vivo dynamic biostability, biodistribution, and toxicity of supramolecular nanofibers formed by Nap-GFFYGRGD (l-amino acid-based, l-fibers) and Nap-G^DF^DF^DYGRGD (d-amino acid–based, d-fibers), respectively. The d-fibers have better in vitro and in vivo biostabilities than l-fibers. It is found that d-fibers keep a good integrity in plasma during 24 h, while half of l-fibers are digested upon incubation in plasma for 6 h. The biodistributions of l- and d-fibers are also studied using the iodine-125 radiolabeling technique. The results reveal that l-fibers mainly accumulate in stomach, whereas d-fibers preferentially distribute in liver. Successive administrations of both l- and d-fibers with the dose of 30 mg/kg/dose cause no significant inflammation, liver and kidney function damages, immune reaction, and dysfunction of hematopoietic system. This study will provide fundamental guidelines for utilization of self-assembling peptide-based supramolecular nanomaterials in biomedical applications, such as drug delivery, bioimaging, and regenerative medicine