Abstract
Lung cancer, with its high mortality and increasing morbidity, has become one of the most lethal malignancies worldwide. Here, we developed cyclic RGD peptide-directed and disulfide-crosslinked polymersomal doxorubicin (cRGD-PS-Dox) as a targeted chemotherapy for human non-small cell lung cancer (NSCLC). Notably, cRGD-PS-Dox exhibited a high Dox loading (15.2 wt.%), small hydrodynamic diameter (96 nm), superb stability, prominent targetability to αvβ3 integrin overexpressing A549 human lung cancer cells, and rapid release of the drug into nuclei, leading to a significantly improved antitumor activity compared with the control groups, i.e., PS-Dox and Lipo-Dox (a liposome injection employed in clinical settings). The pharmacokinetic and biodistribution results for cRGD-PS-Dox revealed similar elimination half-lives but two-fold enhanced tumor accumulation compared with PS-Dox and Lipo-Dox. Intriguingly, cRGD-PS-Dox effectively suppressed the growth of A549 lung tumors in both subcutaneous and orthotopic models with minimal adverse effects at a Dox dose of 12 mg/kg, leading to significant survival benefits compared with PS-Dox and Lipo-Dox. This αvβ3 integrin-targeting multifunctional polymersomal doxorubicin is highly promising for targeted chemotherapy of human NSCLC.
Highlights
Lung cancers have high mortality and increasing morbidity and have become one of the most lethal malignancies worldwide.[1–3]Despite the severe side-effects, chemotherapy with potent drugs such as erlotinib, gemcitabine, cisplatin, irinotecan, doxorubicin hydrochloride (Dox·HCl), and pemetrexed continues to serve as the primary treatment and supportive care for lung cancer patients.[4–6]During the past decade, diverse anticancer nanomedicines have been investigated to increase anticancer efficacy while decreasing the adverse effects of chemotherapeutic drugs.[7–18] In a phase II clinical trial, Genexol-PM, a micellar paclitaxel formulation, in combination with gemcitabine, demonstrated favorable antitumor activity in non-small cell lung cancer (NSCLC) patients.[19]
Our results show that cRGD-PS-Dox effectively suppresses the growth of A549 lung tumors in both subcutaneous and orthotopic models in mice, resulting in clear survival benefits over PS-Dox and LipoDox
Dox·HCl could be laden into PS by a pHgradient method with high efficiency,[41] and a drug loading content (DLC) of 15.2 wt.% was achieved for cRGD-PS-Dox, which exhibited a hydrodynamic diameter of 96 nm (PDI = 0.13, Table 1)
Summary
Lung cancers have high mortality and increasing morbidity and have become one of the most lethal malignancies worldwide.[1–3]Despite the severe side-effects, chemotherapy with potent drugs such as erlotinib, gemcitabine, cisplatin, irinotecan, doxorubicin hydrochloride (Dox·HCl), and pemetrexed continues to serve as the primary treatment and supportive care for lung cancer patients.[4–6]During the past decade, diverse anticancer nanomedicines have been investigated to increase anticancer efficacy while decreasing the adverse effects of chemotherapeutic drugs.[7–18] In a phase II clinical trial, Genexol-PM, a micellar paclitaxel formulation, in combination with gemcitabine, demonstrated favorable antitumor activity in non-small cell lung cancer (NSCLC) patients.[19]. Despite the severe side-effects, chemotherapy with potent drugs such as erlotinib, gemcitabine, cisplatin, irinotecan, doxorubicin hydrochloride (Dox·HCl), and pemetrexed continues to serve as the primary treatment and supportive care for lung cancer patients.[4–6]. In a phase II clinical trial, Genexol-PM, a micellar paclitaxel formulation, in combination with gemcitabine, demonstrated favorable antitumor activity in non-small cell lung cancer (NSCLC) patients.[19]. To augment the tumor targetability, nano-drugs have been decorated with lung cancer cell-specific ligands, such as anisamide and peptides (e.g., cNGQGEQ and CSNIDARAC).[20–23]. These “targeted” systems show only a moderate improvement in therapeutic efficacy, partially due to low in vivo stability and/or slow release of drugs intracellularly. Disulfide-crosslinked nanomedicines have demonstrated excellent in vivo stability and fast intracellular drug release.[24–28]. Disulfide-crosslinked nanomedicines have demonstrated excellent in vivo stability and fast intracellular drug release.[24–28] We have described that disulfide-crosslinked chimeric polymersomes containing poly(ethylene glycol) on the outer surface and polyethylenimine mainly in the lumen efficiently mediated targeted delivery of methotrexate sodium (MTX·2Na) to lung tumor xenografts in nude mice.[29]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
