Tuning the Organ Tropism of Polymersome for Spleen-Selective Nanovaccine Delivery to Boost Cancer Immunotherapy.

The past few decades have witnessed explosive development in drug delivery systems. However, in vivo delivery suffers from non-specific distribution in non-targeted organs or tissues, which may cause undesired side effects and even genotoxicity. Here, a general strategy that enables tuning the tropism of polymersomes for liver- and spleen-selective delivery is reported. By using a library screening approach, spleen-targeted polymersome PH9-Aln-8020 and liver-targeted polymersome PA9-ZP3-5050 are identified accordingly. Meanwhile, the second near-infrared (NIR-II) fluorescence imaging allows for in vivo dynamic evaluation of their spatial and temporal accumulation in specific tissues. O ur findings indicate that both polymer composition and protein corona on the surface are essential to determine the in vivo fate of polymersomes and tendency for specific organs. Importantly, PH9-Aln-8020 is employed as a systemic nanocarrier to co-deliver the antigen and adjuvant, which remarkably boost splenic immune responses in acute myeloid leukemia, melanoma, and melanoma lung metastasis mouse models. This study may open a new frontier for polymersomes in organ-selective delivery and other biomedical applications.

Transferrin-guided intelligent nanovesicles augment the targetability and potency of clinical PLK1 inhibitor to acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a most lethal hematological malignancy, partly because of its slow development of targeted therapies compared with other cancers. PLK1 inhibitor, volasertib (Vol), is among the few molecular targeted drugs granted breakthrough therapy status for AML; however, its fast clearance and dose-limiting toxicity greatly restrain its clinical benefits. Here, we report that transferrin-guided polymersomes (TPs) markedly augment the targetability, potency and safety of Vol to AML. Vol-loaded TPs (TPVol) with 4% transferrin exhibited best cellular uptake, effective down-regulation of p-PLK1, p-PTEN and p-AKT and superior apoptotic activity to free Vol in MV-4-11 leukemic cells. Intravenous injection of TPVol gave 6-fold higher AUC than free Vol and notable accumulation in AML-residing bone marrow. The efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood, bone marrow, liver and spleen, effectively enhanced mouse survival rate, and impeded bone loss. This transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.

CD38-Directed Vincristine Nanotherapy for Acute Lymphoblastic Leukemia.

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 CD38-directed 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 IC50 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.

Daratumumab Immunopolymersome-Enabled Safe and CD38-Targeted Chemotherapy and Depletion of Multiple Myeloma.

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.

Polymeric nanomedicines targeting hematological malignancies.

Hematological malignancies (HMs) typically persisting in the blood, lymphoma, and/or bone marrow invalidate surgery and local treatments clinically used for solid tumors. The presence and drug resistance nature of cancer stem cells (CSCs) further lends HMs hard to cure. The development of new treatments like molecular targeted drugs and antibodies has improved the clinical outcomes for HMs but only to a certain extent, due to issues of low bioavailability, moderate response, occurrence of drug resistance, and/or dose-limiting toxicities. In the past years, polymeric nanomedicines targeting HMs including refractory and relapsed lymphoma, leukemia and multiple myeloma have emerged as a promising chemotherapeutic approach that is shown capable of overcoming drug resistance, delivering drugs not only to cancer cells but also CSCs, and increasing therapeutic index by lessening drug-associated adverse effects. In addition, polymeric nanomedicines have shown to potentiate next-generation anticancer modalities such as therapeutic proteins and nucleic acids in effectively treating HMs. In this review, we highlight recent advance in targeted polymeric nanoformulations that are coated with varying ligands (e.g. cancer cell membrane proteins, antibodies, transferrin, hyaluronic acid, aptamer, peptide, and folate) and loaded with different therapeutic agents (e.g. chemotherapeutics, molecular targeted drugs, therapeutic antibodies, nucleic acid drugs, and apoptotic proteins) for directing to distinct targets (e.g. CD19, CD20, CD22, CD30, CD38, CD44, CD64, CXCR, FLT3, VLA-4, and bone marrow microenvironment) in HMs. The advantages and potential challenges of different designs are discussed.

α3 integrin-binding peptide-functionalized polymersomes loaded with volasertib for dually-targeted molecular therapy for ovarian cancer.

Ovarian cancer (OC) is a high-mortality malignancy in women with a five-year survival rate of 30-40%. There is an urgent need to develop high-efficacy and low toxic treatments for OC. Herein, we report an appealing strategy that combines α3 integrin targeted polymersomes (A3-Ps) and targeted molecular drug, polo-like kinase 1 (PLK1) inhibitor volasertib (Vol) for dually targeted molecular therapy of OC in vivo. A3-Ps had good Vol loading of 7.7-8.0 wt.% and small size of 25-32 nm, depending on the density of α3 integrin binding peptide A3. Interestingly, cellular uptake studies using FITC-labeled Vol revealed that A3-Ps with 20% peptide gave 2.3 and 3.3-fold better internalization in SKOV-3 OC cells compared with non-targeted Ps and free Vol, respectively. Accordingly, Vol loaded in A3-Ps showed the best inhibitory activity to SKOV-3 cells with an IC50 of 49 nM, which was 3.5 times lower than free Vol. Importantly, the in vivo experiments demonstrated that A3-Ps-Vol proficiently repressed the growth of SKOV-3 tumors in mice while continuous tumor growth was observed for Ps-Vol and free Vol-treated mice. A3-Ps-Vol besides boosting anti-OC activity also reduced the systemic toxicity of Vol. This dually targeted molecular drug nanoformulation has appeared to be an especially potent and low toxic treatment modality for human ovarian cancers. STATEMENT OF SIGNIFICANCE: Volasertib provides a potential molecular therapy for PLK1-positive advanced OC patients. The initial clinical outcomes, nevertheless, showed a suboptimal efficacy, possibly resulting from its fast clearance, deficient tumor deposition and dose-limiting toxicities. Here, we show for the first time that dually targeted molecular therapy of OC using α3 integrin-binding peptide-modified polymersomes as a vehicle gives markedly improved potency, better toleration, and depleted adverse effects in SKOV-3 tumor models, greatly outperforming free volasertib. This dually targeted strategy has emerged as an appealing treatment for malignant PLK1-positive ovarian tumors.

A6 peptide-tagged, ultra-small and reduction-sensitive polymersomal vincristine sulfate as a smart and specific treatment for CD44+ acute myeloid leukemia.

Acute myeloid leukemia (AML) is a severe blood malignancy associated with a high relapse rate. The current clinical chemotherapy is typically perplexed with serious side effects. Here, A6 peptide-tagged, small and reduction-sensitive polymersomal vincristine sulfate (A6-cPS-VCR) is reported as a novel, smart and specific treatment for CD44 positive AML. A6-cPS-VCR stably loaded with 3.3 wt% VCR displays a size of ≈ 31 nm and pronounced selectivity toward CD44-overexpressed MV4-11 leukemia cells. Intriguingly, A6-cPS-VCR effectively represses the outgrowth of orthotopic MV4-11 AML in vivo, as revealed by significant reduction of leukemia burdens in the circulation, bone marrow, liver and spleen, and significantly extends the median survival time of MV4-11 AML-bearing mice. In addition to active targetability and therapeutic benefits, A6-cPS-VCR has the advantage of easy fabrication, rendering it potentially interesting for clinical translation.

Actively targeted nanomedicines for precision cancer therapy: Concept, construction, challenges and clinical translation.

The development of targeted nanomedicines for cancer therapy has been an utmost focus of research across different fields including materials science, nanotechnology, biotechnology, pharmaceutics, and clinical medicine. Vehicle-mediated, enhanced and tumor-selective delivery is deemed as a powerful tool to boost the efficacy and meanwhile minimize the off-target effect of potent chemo drugs, and to potentiate biopharmaceuticals such as nucleic acids (DNA, siRNA, miRNA, mRNA, CRISPR/Cas9, etc.), proteins and peptides that poorly penetrate the cell membrane on their own while having explicit effects intracellularly. The targeted nanomedicines may further provide imminent treatments for intractable brain tumors by transporting drugs across the blood-brain barriers, multi-drug resistant (MDR) tumors by evading the MDR pathways, metastatic tumors by inhibiting migratory tumor cells, and relapsed tumors by eliminating the cancer stem cells. The preclinical and clinical investigations demonstrate the clear benefits of targeted nanomedicines in treating advanced solid and hematological malignancies. In this review, we highlight the design and construction of conceptually interesting and clinically viable actively targeted cancer nanomedicines containing small molecular drugs, nucleic acid drugs, or protein/peptide drugs, discuss their pros and cons, and give perspectives on the future developments and clinical translation. We are convinced that with collaborative research and development across the disciplines, actively targeted cancer nanomedicines will make a breakthrough and become an indispensable platform for precision cancer therapy.

CD44-Specific A6 Short Peptide Boosts Targetability and Anticancer Efficacy of Polymersomal Epirubicin to Orthotopic Human Multiple Myeloma.

Chemotherapy is widely used in the clinic though its benefits are controversial owing to low cancer specificity. Nanovehicles capable of selectively transporting drugs to cancer cells have been energetically pursued to remodel cancer treatment. However, no active targeting nanomedicines have succeeded in clinical translation to date, partly due to either modest targetability or complex fabrication. CD44-specific A6 short peptide (KPSSPPEE) functionalized polymersomal epirubicin (A6-PS-EPI), which boosts targetability and anticancer efficacy toward human multiple myeloma (MM) in vivo, is described. A6-PS-EPI encapsulating 11 wt% EPI is small (≈55 nm), robust, reduction-responsive, and easy to fabricate. Of note, A6 decoration markedly augments the uptake and anticancer activity of PS-EPI in CD44-overexpressing LP-1 MM cells. A6-PS-EPI displays remarkable targeting ability to orthotopic LP-1 MM, causing depleted bone damage and striking survival benefits compared to nontargeted PS-EPI. Overall, A6-PS-EPI, as a simple and intelligent nanotherapeutic, demonstrates high potential for clinical translation.

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

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.

Triplet Tellurophene-Based Acceptors for Organic Solar Cells.

Triplet materials have been employed to achieve high-performing organic solar cells (OSCs) by extending the exciton lifetime and diffusion distances, while the triplet non-fullerene acceptor materials have never been reported for bulk heterojunction OSCs. Herein, for the first time, three triplet molecular acceptors based on tellurophene with different degrees of ring fusing were designed and synthesized for OSCs. Significantly, these molecules have long exciton lifetime and diffusion lengths, leading to efficient power conversion efficiency (7.52 %), which is the highest value for tellurophene-based OSCs. The influence of the extent of ring fusing on molecular geometry and OSCs performance was investigated to show the power conversion efficiencies (PCEs) continuously increased along with increasing the extent of ring fusing.

High Performing Ternary Solar Cells through Förster Resonance Energy Transfer between Nonfullerene Acceptors.

Nonradiative Förster resonance energy transfer (FRET) is an important mechanism of organic solar cells, which can improve the exciton migration over a long distance, resulting in improvement of efficiency of solar cells. However, the current observations of FRET are very limited, and the efficiencies are less than 9%. In this study, FRET effect was first observed between two nonfullerene acceptors in ternary solar cells, which improved both the absorption range and exciton harvesting, leading to the dramatic enhancement in the short circuit current and power conversion efficiency. Moreover, this strategy is proved to be a versatile platform for conjugated polymers with different bandgaps, resulting in a remarkable efficiency of 10.4%. These results demonstrated a novel method to enhance the efficiency of organic soar cells.

Construction of coumarin-based cross-linked micelles with pH responsive hydrazone bond and tumor targeting moiety.

It is still a major challenge for targeted cancer chemotherapy to design a stable biocompatible micellar drug delivery system. To address this dilemma, novel responsive cross-linked micelles (x-micelles) based on polyurethane with photo-responsive coumarin derivatives and pH-responsive hydrazone groups were synthesized. The polymers could be self-assembled into micelles using a typical and facile way. The x-micelles were stable at physiological conditions after UV light induced cross-linking, and can be disassociated under acidic condition. The drug loading content (DLC) and the encapsulation efficiency (EE) of the obtained x-micelles (15.2% and 60.8% respectively) were higher than those of micelles (9.8% and 39.2% respectively), and the DOX release rate of x-micelles was also improved. For targeted therapy, folic acid (FA) was then conjugated to x-micelles, resulting in x-micelles-FA. Cellular viability experiments show that both x-micelles and micelles had a low cytotoxicity and good biocompatibility of up to 1000 µg mL-1, and DOX-loaded x-micelles-FA and x-micelles exhibited half-maximal inhibitory concentration (IC50) values of 1.17 and 2.40 µg mL-1, respectively, to HeLa cells, but have lower cytotoxicity to L929 cells. The pH-responsive x-micelles-FA exhibited superior extracellular stability but activated intracellular drug release. We have demonstrated that the polyurethane with UV- and pH-responsive properties as a novel platform for tumor-targeting drug delivery.

Construction of stable polymeric vesicles based on azobenzene and beta-cyclodextrin grafted poly(glycerol methacrylate)s for potential applications in colon-specific drug delivery.

Polymeric vesicles constructed from cyclodextrin- and azobenzene-grafted poly(glycidyl methacrylate)s showed excellent stability owing to the multiple host-guest complexation. Upon culturing in Na2S2O4-contained buffer solution, cargo-loaded vesicles disassembled, for potential applications in colon-specific drug delivery.

Reverse micelles based on biocompatible ß-cyclodextrin conjugated polyethylene glycol block polylactide for protein delivery.

A series of linear and star-shaped amphiphilic polyethylene glycol block polylactide (PEG-b-PLA) and ß-cyclodextrin (CD) conjugated PEG-b-PLA (PEG-b-PLA-CD) copolymers were synthesized. Bovine serum albumin (BSA) aqueous solution was emulsified in the copolymer organic solutions to fabricate reverse micelles (RMs), and was then further transferred into ethyl oleate (EO), a pharmaceutically acceptable vehicle, by the RMs. As identified by 1H NMR, the RMs were formed with a hydrophilic core of PEG and CD, covered with a hydrophobic corona of PLA moiety, and were spherical in shape, as observed by a scan electronic microscope. Compared with the PEG-b-PLA RMs, the PEG-b-PLA-CD RMs presented higher encapsulation efficiency. The release of BSA was influenced by the copolymer composition and architecture. BSA stability in the release aqueous phase was confirmed by circular dichroism spectroscopy. The oil-based formulation fabricated from biodegradable copolymers with high drug loading showed a great potential for protein delivery.

Dual functionalized amino poly(glycerol methacrylate) with guanidine and Schiff-base linked imidazole for enhanced gene transfection and minimized cytotoxicity.

Efficient transfection activity and minimal toxicity are of crucial importance to the development of gene delivery systems for practical applications. In this work, guanidine and Schiff-base linked imidazole dual functionalized poly(glycerol methacrylate) (IGEP) was firstly synthesized. Subsequent investigations revealed that this new biomedical material is capable of sufficiently binding to plasmid DNA (pDNA) and formulating optimal sized 100 nm nanoparticles with positive ζ potentials of 10-30 mV. Biological evaluations demonstrated the strategic use of guanidine resulting in enhanced cellular uptake and nuclear localization activities by virtue of its favorable affinity to the cellular membrane, and Schiff-base linked imidazole resulting in promoted endosomal escape and DNA cargo releasing behaviors, consequently leading to better transfection efficacy compared to PEI25K in the targeted cells. Another noteworthy fact was guanidine and imidazole minimized cytotoxicity, hence, these advantageous features provided substantial information to construct a safe and efficient gene delivery carrier towards practical development.

Self-assembly and applications of poly(glycidyl methacrylate)s and their derivatives.

In this feature article, we give an overview of the preparation and application of self-assembled architectures based on an emerging area of polymers, i.e., poly(glycidyl methacrylate)s (PGMAs) and their derivatives. A series of PGMA-based aggregates and hybrids, such as micelles, reverse micelles, capsules, nanoparticles, and inorganic-organic hybrid materials, has been constructed, and diverse morphologies were formed, driven by hydrophobic interactions, hydrogen bonding, ionic complexation, host-guest interactions, etc. In particular, the assemblies have shown great potential applications as drug vectors, gene vectors, solubilizing agents, antimicrobial agent, and so forth. Herein, the general guidelines are elaborately selected from literature examples and partially from our own. Although still in its infancy, self-assembly of PGMA-based polymers is expected to become a hot topic in polymer chemistry and materials science.

Synthesis of cross-linked carboxyl poly(glycerol methacrylate) and its application for the controlled release of doxorubicin.

A series of polymers were synthesized by cross-linking carboxyl poly(glycerol methacrylate) (PGOHMA) using hexamethylene diisocyanate (HDI). The structures and molecular weight were characterized by ¹H NMR and gel permeation chromatography (GPC). Nanoparticles were then fabricated for encapsulation of doxorubicin hydrochloride (DOX). The encapsulation and release were affected by the chemical structure and degree of cross-linking of the polymers. The polymers were quite effective in the encapsulation of DOX, and exhibited pH-dependent drug release. Specifically, the stability of nanoparticles in neutral pH was significant enhanced and the release rate was enhanced at acidic pH after cross-linking, which could be potential useful as a controlled drug release carrier, especially for anti-cancer drug.