Co-administration of a charge-conversional dendrimer enhances antitumor efficacy of conventional chemotherapy.

Despite extensive investigations, the clinical translation of nanocarrier-based drug delivery systems (NDDS) for cancer therapy is hindered by inefficient delivery and poor tumor penetration. Conventional chemotherapy by administration of free small molecule anticancer drugs remains the standard of care for many cancers. Herein, other than for carrying and releasing drugs, small nanoparticles were used as a potentiator of conventional chemotherapy by co-administration with free chemotherapeutic agents. This strategy avoided the problems associated with drug loading and controlled release encountered in NDDS, and was also much simpler than NDDS. Negatively charged poly(amido amine)-2,3-dimethylmaleic monoamide (PAMAM-DMA) dendrimers were prepared, which possessed low toxicity and can be converted to positively charged PAMAM dendrimers responsive to tumor acidic pH. The in situ formed PAMAM in tumor tissue promoted cellular uptake of co-administered doxorubicin by increasing the cell membrane permeability, and subsequently enhanced the cytotoxicity of doxorubicin. The small size of the dendrimers was favorable for deep penetration in tumor. Co-injection of PAMAM-DMA with doxorubicin into nude mice bearing human tumors almost completely inhibited tumor growth, with a mean tumor weight reducing by 55.9% after the treatment compared with the treatment with doxorubicin alone.

Polymeric micelles with α-glutamyl-terminated PEG shells show low non-specific protein adsorption and a prolonged in vivo circulation time.

Although PEG remains the gold standard for stealth functionalization in drug delivery field up to date, complete inhibition of protein corona formation on PEG-coated nanoparticles remains a challenge. To improve the stealth property of PEG, herein an α-glutamyl group was conjugated to the end of PEG and polymeric micelles with α-glutamyl-terminated PEG shells were prepared. After incubation with bovine serum albumin or in fetal calf serum, the size of the micelles changed slightly, while the size of the micelles of similar diblock copolymer but without α-glutamyl group increased markedly. These results indicated that the micelles with α-glutamyl-terminated PEG shells showed low non-specific protein adsorption. In vivo blood clearance kinetics assay showed that the micelles with α-glutamyl-terminated PEG shells exhibited a longer in vivo blood circulation time compared with similar micelles but without α-glutamyl groups. The better stealth property of the micelles with α-glutamyl-terminated PEG shells was presumably attributed to the zwitterionic property of the α-glutamyl groups.