HER2-Specific Reduction-Sensitive Immunopolymersomes with High Loading of Epirubicin for Targeted Treatment of Ovarian Tumor

Abstract

Monoclonal antibodies can effectively target to tumors in patients, as validated by antibody−drug conjugates (ADCs). The clinically used ADCs, nevertheless, are restricted to toxins only and suffer from low drug content, excessive use of antibody, and high cost. Here, we report on trastuzumab-decorated disulfide-cross-linked polymersomes (Tra-Ps) for specific delivery of epirubicin hydrochloride (EPI•HCl) to HER2-positive SKOV-3 ovarian tumor. EPI• HCl-loaded Tra-Ps (Tra-Ps-EPI) with a small size of 50−60 nm and varying Tra surface densities (0.5 to 2.4 Tra per Ps) were conveniently obtained via post-conjugation of thiolated trastuzumab onto the surface of maleimide-functionalized Ps-EPI with a drug loading content of 12.7 wt %. Interestingly, Tra-Ps with 1.3 trastuzumab on the surface exhibited a 6-fold higher binding affinity to the HER2 extracellular domain than that of native trastuzumab. In vitro studies revealed that Tra-Ps-EPI with long-term storage stability could rapidly release drugs under a reductive condition and efficiently deliver a large amount of EPI• HCl to HER2-positive SKOV-3 cells, leading to stronger cytotoxicity than the nontargeted Ps-EPI. Moreover, Tra-Ps-EPI displayed a long circulation time (ca. 8 h), deep tumor penetration, and superior tumor growth inhibition in SKOV-3 ovarian tumor-bearing nude mice, which were more effective than free EPI•HCl and nontargeted Ps-EPI. These HER2-specific reduction-sensitive immunopolymersomes with high loading of epirubicin emerge as an attractive treatment for HER2-positive tumors.

Nanobodies Enhancing Cancer Visualization, Diagnosis and Therapeutics

“…PET radioisotopes are favorable due to Nbs having a short half-life and can be effective in tumor detection/imaging [10,32]. Thus, an anti-EGFR Nb [32] and an anti-HER-2 Nb (2Rs15d) [29] were radiolabeled with 68 Ga. In nude mice bearing A431 xenografts, the 68 Ga-EGFR-Nb showed a high tumor uptake as well as high tumor-to-normal tissue ratios (Table 3) [32].…”

“…Thus, an anti-EGFR Nb [32] and an anti-HER-2 Nb (2Rs15d) [29] were radiolabeled with 68 Ga. In nude mice bearing A431 xenografts, the 68 Ga-EGFR-Nb showed a high tumor uptake as well as high tumor-to-normal tissue ratios (Table 3) [32]. In HER-2+ tumors, 68 Ga-NOTA-2Rs15d showed fast, specific uptake and high tumor-toblood ratios, leading to high-specific contrast PET/CT images with no observed toxicity (Table 3) [29].…”

“…Chemotherapeutic drugs can be conjugated to an Ab/Nb in order to increase the drugs' tumor specificity and protect healthy tissues from drug toxicity. Ding et al (2019) demonstrated the use of trastuzumab (Tra)-decorated polymersomes (Ps) for the targeted delivery of epirubicin hydrochloride (EPI•HCL) to HER-2+ SKOV-3 ovarian tumors [68]. The EPI•HCL-loaded Tra-Ps (Tra-Ps-EPI) was able to deliver substantial amounts of EPI•HCL to cells, which induced a higher level of cytotoxicity than non-targeted Ps-EPI (in vitro) [68].…”

“…Ding et al (2019) demonstrated the use of trastuzumab (Tra)-decorated polymersomes (Ps) for the targeted delivery of epirubicin hydrochloride (EPI•HCL) to HER-2+ SKOV-3 ovarian tumors [68]. The EPI•HCL-loaded Tra-Ps (Tra-Ps-EPI) was able to deliver substantial amounts of EPI•HCL to cells, which induced a higher level of cytotoxicity than non-targeted Ps-EPI (in vitro) [68]. Additionally, in SKOV-3 ovarian tumor-bearing nude mice, Tra-Ps-EPI demonstrated deep tumor penetration and a greater tumor growth inhibition than that of free EPI•HCL as well as non-targeted Ps-EPI [68].…”

The rise of bio-inspired polymer compartments responding to pathology-related signals

“…Polymersomes that are inherently sensitive to the surrounding reduction/oxidation conditions have been reported to function as drug delivery systems, but their architecture disintegrated to release the cargo. 50,[174][175][176] Nevertheless, intact polymersomes exist that are turned into reduction-sensitive systems by biomolecules. A recent example of reduction-responsive polymersomes with preserved integrity has been obtained by inserting genetically engineered OmpF in the membrane of PMOXA 6 -PDMS 44 -PMOXA 6 -based polymersomes.…”