Doxorubicin-Bound Hydroxyethyl Starch Conjugate Nanoparticles with pH/Redox Responsive Linkage for Enhancing Antitumor Therapy

Abstract

Background: Chemotherapeutic drugs used for tumor treatments often show limited efficiency due to their short lifetime, nonspecific delivery, and slow or insufficient intracellular drug release, and also, they can cause severe system or organ toxicity. The development of chemotherapeutic nanomedicines with high efficacy and satisfactory safety still remains a challenge for current tumor chemotherapy. Methods: A novel type of conjugate was synthesized using hydroxyethyl starch (HES) as a carrier while binding doxorubicin (DOX) onto HES backbone through a pH/redox responsive linker containing both disulfide and hydrazone bonds in series. The built conjugates were self-assembled into nanoparticles (NPs) (HES-SS-hyd-DOX NPs) for achieving enhanced antitumor therapy and adequate safety. Results: HES-SS-hyd-DOX NPs had a certain ability for the tumor-orientated drug accumulation and were capable of releasing DOX itself rather than DOX derivatives. It was found that the pH/redox responsive linkage enabled the NPs to achieve fast and sufficient intracellular drug release. Based on the tumor-bearing mouse model, antitumor results demonstrated that these NPs were able to inhibit the growth of the advanced tumors with significantly enhanced efficacy when compared to free DOX, and to those conjugate NPs containing only a single responsive or unresponsive bond. Besides, HES-SS-hyd-DOX NPs also showed adequate safety to the normal organs of the treated mice. Conclusion:The pH/redox responsive linkage in HES-SS-hyd-DOX was found to play a critical role in mediating the drug accumulation and the fast and sufficient intracellular drug release. The HES-exposed surface of HES-SS-hyd-DOX NPs endowed the NPs with long circulation capability and remarkably reduced the DOX-induced side effects.

Advanced Skin Antisepsis: Application of UVA-Cleavable Hydroxyethyl Starch Nanocapsules for Improved Eradication of Hair Follicle-Associated Microorganisms

“…From the literature various starch-based NCs are known involving the possibility of a controlled drug release triggered by pH [ 48 , 49 ], GSH [ 50 ], glucose or temperature [ 51 ]. To our knowledge, the presented NCs are the first UVA-responsive o -nitrobenzyl-based HES-NCs.…”

A Supramolecular Nanovehicle Featuring a pH/Enzyme Co‐Response for Targeted Delivery of the Antitumor Compound

“…As we know, the human body features diverse characteristics of normal and diseased organs, tissues, and cells, such as normal tissue has a pH of 7.4, while the pH of the extracellular environment of tumor cells is ~6.8, and even the pH of lysosomes in tumor cells can be lowered to 5 ~4.5. [11][12][13][14][15][16] Meanwhile, multiple enzyme levels are often expressed abnormally in tumor cells and are associated with many diseases. [17] For example, Acetylcholinesterase (AChE) is aberrantly expressed in a variety of tumor cells and is involved in tumor cell genesis, proliferation, and apoptosis.…”