Multiple myeloma (MM) is a second ranking hematological malignancy. Despite the fast advancement of new treatments such as bortezormib and daratumumab, MM patients remain incurable and tend to eventually become relapsed and drug‐resistant. Development of novel therapies capable of depleting MM cells is strongly needed. Here, daratumumab immunopolymersomes carrying vincristine sulfate (Dar‐IPs‐VCR) are reported for safe and high‐efficacy CD38‐targeted chemotherapy and depletion of orthotopic MM in vivo. Dar‐IPs‐VCR made by postmodification via strain‐promoted click reaction holds tailored antibody density (2.2, 4.4 to 8.7 Dar per IPs), superb stability, small size (43–49 nm), efficacious VCR loading, and glutathione‐responsive VCR release. Dar4.4‐IPs‐VCR induces exceptional anti‐MM activity with an IC50 of 76 × 10−12 m to CD38‐positive LP‐1 MM cells, 12‐ and 20‐fold enhancement over nontargeted Ps‐VCR and free VCR controls, respectively. Intriguingly, mice bearing orthotopic LP‐1‐Luc MM following four cycles of i.v. administration of Dar4.4‐IPs‐VCR at 0.25 mg VCR equiv. kg−1 reveal complete depletion of LP‐1‐Luc cells, superior survival rate to all controls, and no body weight loss. The bone and histological analyses indicate bare bone and organ damage. Dar‐IPs‐VCR appears as a safe and targeted treatment for CD38‐overexpressed hematological malignancies.

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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.

Actively targeted nanomedicines have promised to revolutionize cancer treatment; however, their clinical translation has been limited by either low targetability, use of unsafe materials, or tedious fabrication. Here, we developed CD44 and folate receptor (FR) dually targeted nanoparticulate doxorubicin (HA/FA-NP-DOX) based on a direct conjugate of two purely natural ligands, hyaluronic acid and folic acid (FA), for safe, highly specific, and potent treatment of ovarian tumors in vivo. HA/FA-NP-DOX had a small size and high DOX loading, wherein the particle size decreased from 115, 93, to 89 nm with increasing degree of substitution of FA from 6.4, 8.5, to 11.1, while increased from 80, 93, to 103 nm with increasing DOX loading from 15.0, 23.1, to 31.4 wt %. Interestingly, HA/FA-NP-DOX exhibited excellent lyophilization redispersibility and long-term storage stability with negligible drug leakage while it released 91% of DOX in 48 h at pH 5.0. Cellular studies corroborated that HA/FA-NP-DOX possessed high selectivity to both CD44 and FR, resulting in strong killing of CD44- and FR-positive SKOV-3 ovarian cancer cells while low toxicity against CD44- and FR-negative L929 fibroblast cells. In vivo studies revealed a long elimination half-life of 5.6 h, an elevated tumor accumulation of 12.0% ID/g, and an effective inhibition of the SKOV-3 ovarian tumor for HA/FA-NP-DOX, leading to significant survival benefits over free DOX·HCl and phosphate-buffered saline controls. These dually targeted nanomedicines are simple and safe, providing a potentially translatable treatment for CD44- and FR-positive malignancies.

Targeted nanomedicines particularly armed with monoclonal antibodies are considered to be the most promising advanced chemotherapy for malignant cancers; however, their development is hindered by their instability and drug leakage problems. Herein, we constructed a robust cetuximab−polymersome−mertansine nanodrug (C-P-DM1) for highly potent and targeted therapy of epidermal growth factor receptor (EGFR)-positive solid tumors. C-P-DM1 with a tailored cetuximab surface density of 2 per P-DM1 exhibited a size of ca. 60 nm, high stability with minimum DM1 leakage, glutathione-triggered release of native DM1, and 6.0−11.3-fold stronger cytotoxicity in EGFR-positive human breast (MDA-MB-231), lung (A549), and liver (SMMC-7721) cancer cells (IC 50 = 27.1−135.5 nM) than P-DM1 control. Notably, intravenous injection of C-P-DM1 effectively repressed subcutaneous MDA-MB-231 breast cancer and orthotopic A549-Luc lung carcinoma in mice without inducing toxic effects. Strikingly, intratumoral injection of C-P-DM1 completely cured 60% of mice bearing breast tumor without recurrence. This robust cetuximab−polymersome−mertansine nanodrug provides a promising new strategy for targeted treatment of EGFR-positive solid malignancies.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although intensive chemotherapy greatly improved the survival rate, it is often accompanied by severe and lifelong side effects as a result of weak ALL selectivity. The intensive and poorly selective chemotherapy is also detrimental to patients' immune system. There is an urgent need to develop more selective and less toxic chemotherapy for ALL. Here, we report daratumumab-polymersome-vincristine (DP-VCR) as a CD38directed nanotherapy for ALL. DP-VCR showed selective uptake in CD38-positive 697 and Nalm-6-Luc ALL cells and potent anti-ALL activity with an IC 50 as low as 0.06 nM VCR, which was 13.7-fold more potent than free VCR. In contrast, no toxicity to human peripheral blood mononuclear cells was detected for DP-VCR even at 108.3 nM VCR. The apoptotic assays confirmed a high selectivity of DP-VCR to CD38-positive ALL cells. DP-VCR exhibited superior treatment of both 697 and Nalm-6-Luc orthotopic ALL models to all controls, as revealed by significant survival benefit and marked reduction of leukemia burden in bone marrow, blood, spleen, and liver. Importantly, DP-VCR induced few side effects. DP-VCR emerges as a safe and potent nanotherapy for CD38-positive ALL.

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