期刊
ACS APPLIED MATERIALS & INTERFACES
卷 13, 期 5, 页码 6053-6068出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.0c21422
关键词
nanomedicine; chemotherapy; dual-prodrug; redox-responsive; pH-responsive; synergistic effect
资金
- Ningbo Municipal 3315 Project
- National Natural Science Foundation of China [21878041, 31870957]
- Fundamental Research Funds for the Central Universities [DUT17RC(3)059, DUT20YG126]
- Dalian Science& Technology Innovation Fund [2020JJ26SN050, 2020JJ26GX025]
- Talent Project of Revitalizing Liaoning [XLYC1807184]
The study developed dual prodrug nanomedicine that can sequentially respond to intracellular chemical potentials, overcoming predefined biological barriers and facilitating intracellular trafficking. The nanomedicine showed significant cytotoxic potencies due to its ability to be activated and liberated in the cytoplasm, leading to potent tumor suppression efficacy in treating solid breast adenocarcinoma.
Nanomedicine developed to date by means of directly encapsulating cytotoxins suffers from crucial drawbacks, including premature release and detoxification prior to arrival at pharmaceutics targets. To these respects, redox-responsive polymeric prodrugs of platinum (Pt) and camptothecin (CPT), selectively and concomitantly activated in the cytoplasm, were elaborated in manufacture of dual prodrug nanomedicine. Herein, multiple CPTs were conjugated to poly(lysine) (PLys) segments of block copolymeric poly(ethylene glycol) (PEG)-PLys through the redox responsive disulfide linkage [PEG-PLys(ss-CPT)] followed by reversible conversion of amino groups from PLys into carboxyl groups based on their reaction with cis-aconitic anhydride [PEG-PLys(ss-CPT&CAA)]. On the other hand, Pt(IV) in conjugation with dendritic polyamindoamine [(G3-PAMAM-Pt(IV)] was synthesized for electrostatic complexation with PEG-PLys(ss-CPT&CAA) into dual prodrug nanomedicine. Subsequent investigations proved that the elaborated nanomedicine could sequentially respond to intracellular chemical potentials to overcome a string of predefined biological barriers and facilitate intracellular trafficking. Notably, PEG-PLys(ss-CPT&CAA) capable of responding to the acidic endosomal microenvironment for transformation into endosome-disruptive PEGPLys(ss-CPT), as well as release of G3-PAMAM-Pt(IV) from nanomedicine, prompted transclocation of therapeutic payloads from endosomes into cytosols. Moreover, concurrent activation and liberation of cytotoxic CPT and Pt(II) owing to their facile responsiveness to the cytoplasmic reducing microenvironment have demonstrated overwhelming cytotoxic potencies. Eventually, systemic administration of the dual prodrug construct exerted potent tumor suppression efficacy in treatment of intractable solid breast adenocarcinoma, as well as an appreciable safety profile. The present study illustrated the first example of nanomedicine with a dual prodrug motif, precisely and concomitantly activated by the same subcellular stimuli before approaching pharmaceutic action targets, thus shedding important implication in development of advanced nanomedicine to seek maximized pharmaceutic outcomes.
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