Abstract
In this work, we developed a novel active targeting and pH-responsive system for delivering the drug doxorubicin (DOX) to tumor sites using folic acid (FA)-modified multiwalled carbon nanotubes (MWCNTs). Acid-treated MWCNTs with carboxyl groups were first covalently conjugated with polyethyleneimine (PEI). Subsequent sequential modification with FA (via a polyethylene glycol spacer), fluorescein isothiocyanate (FI), and acetic anhydride/triethylamine resulted in multifunctional FA-bound MWCNT (MWCNT-PEI.Ac-FI-PEG-FA) nanomaterials that possessed exceptional colloidal stability and good biocompatibility in a given concentration range. The FA-bound MWCNTs were characterized using various techniques and exhibited a high drug loading and an encapsulation efficiency as high as 70.4%. DOX/MWCNT-PEI.Ac-FI-PEG-FA nanocomplexes (DOX/MWCNT NCs) exhibited pH-responsive release in acidic environments. Importantly, the DOX/MWCNT NCs targeted tumor cells overexpressing FA receptors (FARs) and effectively inhibited their growth. In vivo anticancer experiments demonstrated that DOX/MWCNT NCs not only enhanced the suppression of tumor growth but also decreased the side effects of free DOX. The developed FA-modified MWCNTs with an unconventionally high DOX loading boosted in vivo anti-tumor efficacy, and the lower systemic toxicity may be utilized for tumor therapy upon clinical translation.
Highlights
Doxorubicin (DOX), a typical anthracycline-class chemotherapeutic agent, is widely used in clinics for the chemotherapy of various cancers, including hematological malignancies, lymphoma, and many other types of solid tumors
For the samples that had received further modification, an additional 21.6% weight loss was observed when multiwalled carbon nanotubes (MWCNTs)-PEI-polyethylene glycol (PEG)-folic acid (FA) was heated to the same temperature due to the covalent conjugation of COOH-PEG-FA to terminal PEI amines
The zeta potential of MWCNT-PEI decreased to þ20.7 mV as some of the terminal amines were consumed by subsequent modification with COOH-PEG-FA and fluorescein isothiocyanate (FI)
Summary
Doxorubicin (DOX), a typical anthracycline-class chemotherapeutic agent, is widely used in clinics for the chemotherapy of various cancers, including hematological malignancies, lymphoma, and many other types of solid tumors. We hypothesize that dendrimer- or PEI-modified MWCNTs may adsorb DOX through p–p stacking interactions, thereby providing DOX-loaded MWCNT nanocomplexes (NCs) as chemotherapeutic agents for cancer. Most of these contrast or therapeutic agents suffer from poor delivery without targeting ligands, leading to the accumulation of only small amounts of injected drugs in target tissues (Zerda et al, 2012). The multifunctional MWCNTs designed in this study were expected to be coupled with PEI for further modification with targeting ligands, creating a novel system to load and release DOX for precise treatment of cancer. We designed a novel drug delivery system based on FA-modified DOX-loaded MWCNT NCs for the chemotherapy of tumors. After the nanomaterials were loaded with DOX, their potential for in vivo targeted chemotherapy of tumors was evaluated in detail
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