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Amphiphilic block copolymers are common materials used for the fabrication of various nanostructures with biomedical applications including nanocapsules, nanospheres, micelles and polymeric vesicles. According to the literature, polymersomes have several advantages compared to other nanostructures used as drug delivery systems comprising better stability, facile synthesis, prolonged circulation time, and passive/active targeting capability. Various types of nanoparticles are formed by varying the ratio of the hydrophobic/hydrophilic blocks. Changing hydrophobic/hydrophilic ratio of amphiphilic block copolymers has an impact on the structural characteristics of polymers such as changing molecular weight and surface functionalization of the block copolymer. Thus, polymerization strategies are an important factor that influences polymersomes quality. In this review, different polymerization strategies for the synthesis of block copolymers applied in polymersomes formation, are described. [Display omitted] • Amphiphilic block copolymers are common materials used forpolymersomes fabrication. • Polymersomes are formed by tuning the ratio of the hydrophobic/hydrophilic blocks. • Polymerization strategies are important that influences polymersomes quality. • Different polymerization for the synthesis of block copolymers are described. [ABSTRACT FROM AUTHOR]

In spite of huge developments in cancer treatment, versatile combinational formulations of different chemotherapeutic agents to enhance anticancer activity while reducing systemic toxicity still remains a challenge. In this regard, in the current study, an amphiphilic hyaluronic acid- b -polycaprolactone diblock copolymer was synthesized using "click chemistry". The synthesized copolymer was self-assembled to form polymersomal structures for co-encapsulation of hydrophilic doxorubicin (DOX) and hydrophobic camptothecin (CPT) in their interior aqueous compartment and their bilayer, respectively with 1:10 and 1:1 ratios. The prepared polymersomal combinational formulation surrounded by hyaluronic acid brush as hydrophilic segment, could provide active targeting of the system against CD44 marker expressed on the surface of cancerous cells. The hyaluronic acid shell could also provide flexible chemistry for the conjugation of therapeutic FOXM1-specific DNA aptamer (Forkhead Box M1; against transcription factor FOXM1) on the surface of polymersomes in order to further suppress cancerous cell proliferation. The obtained results demonstrated that the prepared co-formulation provided sustained, controlled release of the entrapped drugs during 200 h. In vitro cytotoxicity experiments on non-small cell lung cancer, A549 and SK-MES-1 cell lines, demonstrated that the co-formulation of DOX and CPT provided synergistic effect and significantly higher cytotoxicity in comparison with free drugs. The cytotoxicity experiment also indicated that the aptamer conjugation on the co-formulations surface could significantly increase the cytotoxicity and induce apoptosis in combination therapy on both A549 and SK-MES-1 cell lines while aptamer-conjugated blank NPs did not show any cytotoxicity which emphasizes on the sensitization capability of the FOXM1 DNA aptamer against non-small cell lung cancer. Furthermore, it was shown that the co-formulation with or without aptamer renders the formulation specific tumor accumulation in vivo 24 h post-administration, assisting the combination synergy observed in vitro to be translated to in vivo antitumor efficacy. This combinatorial delivery platform strongly offers a novel approach for the synergistic controlled transportation of several chemotherapeutics for the treatment of non-small cell lung cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

The progress in advanced materials using nanoscale components can be conducted by an innovative idea involving combining nanotechnology approaches with supramolecular chemistry. This concept which is called self-assembly, is employed for formation of nanoscale self-assembled architectures with desirable properties. Self-assembly has emerged as a potent procedure for controlling the structure and characteristics of ensembles. Among self-assembled structures, polymersomes have revealed prodigious potential in drug delivery and development of smart nanomedicine due to their morphological similarities to cellular membranes and viral capsids. Moreover, their functional, tunable and stable membrane render them more advantageous to their lipid counter parts. Polymersomes have been used as different therapeutic carriers as drugs and imaging agents, as well as nanoreactors and artificial organelles. Here we review different basis of self-assembling polymersomes and their properties, the synthesis of various amphiphilic copolymers for vesicles preparation and potential applications of smart controlled release vesicles. Unlabelled Image • Self-assembled polymer vesicles applicable against cancer are discussed • The self-assembly processes to form in vesicle shape are introduced • Synthesis of required polymers and drug loading into vesicles are briefly overviewed • Different stimulus factors used for drug release from polymer vesicles are reviewed [ABSTRACT FROM AUTHOR]

The stimulator of interferon genes (STING) pathway plays an important role in the immune surveillance of cancer and, accordingly, agonists of STING signaling have recently emerged as promising therapeutics for remodeling of the immunosuppressive tumor microenvironment (TME) and enhancing response rates to immune checkpoint inhibitors. 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) is the endogenous ligand for STING, but is rapidly metabolized and poorly membrane permeable, restricting its use to intratumoral administration. Nanoencapsulation has been shown to allow for systemic administration of cGAMP and other cyclic dinucleotides (CDN), but little is known about how nanocarriers affect important pharmacological properties that impact the efficacy and safety of CDNs. Using STING-activating nanoparticles (STING-NPs) – a polymersome platform designed to enhance cGAMP delivery – we investigate the pharmacokinetic (PK)-pharmacodynamic (PD) relationships that underlie the ability of intravenously (i.v.) administered STING-NPs to induce STING activation and inhibit tumor growth. First, we demonstrate that nanoencapsulation improves the half-life of encapsulated cGAMP by 40-fold, allowing for sufficient accumulation of cGAMP in tumors and activation of the STING pathway in the TME as assessed by western blot analysis and gene expression profiling. Nanoparticle delivery also changes the biodistribution profile, resulting in increased cGAMP accumulation and STING activation in the liver and spleen, which we identify as dose limiting organs. As a consequence of STING activation in tumors, i.v. administered STING-NPs reprogram the TME towards a more immunogenic antitumor milieu, characterized by an influx of >20-fold more CD4+ and CD8+ T-cells. Consequently, STING-NPs increased response rates to αPD-L1 antibodies, resulting in significant improvements in median survival time in a B16-F10 melanoma model. Additionally, we confirmed STING-NP monotherapy in an additional melanoma (YUMM1.7) and breast adenocarcinoma (E0771) models leading to >50% and 80% reduction in tumor burden, respectively, and significant increases in median survival time. Collectively, this work provides an examination of the PK-PD relationship governing STING activation upon systemic delivery using STING-NPs, providing insight for future optimization for nanoparticle-based STING agonists and other immunomodulating nanomedicines. Unlabelled Image • STING-NPs are polymersomes designed to increase cytosolic delivery of cyclic dinucleotide STING agonists. • Nanoparticle encapsulation of 2′,3′-cGAMP in STING-NPs extends drug half-life and exposure. • Hepatic and splenic toxicities are dose limiting. • Intravenous administration of STING-NPs remodels the tumor immune microenvironment. • Systemic STING-NPs improve survival in models of melanoma and breast cancer. [ABSTRACT FROM AUTHOR]

The chemotherapy toward glioblastoma (GBM) is severely challenged by blood-brain barrier and dose-limiting toxicity. Herein, we adopt brain delivery of Plk1 inhibitor volasertib (Vol), which is highly specific and presents low off-target toxicity, as a new means to treat GBM, for which angiopep-2-docked chimaeric polypeptide polymersome (ANG-CPP) was designed and prepared from poly(ethylene glycol)- b -poly(L-tyrosine)- b -poly(L-aspartic acid) for loading Vol to its watery interior via electrostatic interactions. ANG-CPP loaded with 13.9 wt% Vol (ANG-CPP-Vol) exhibited a small size of about 76 nm, superb colloidal stability (against dilution, serum and long-term storage), and enzyme-triggered drug release behavior (about 73% of Vol released within 8 h with proteinase K). In sharp contrast to free Vol, ANG-CPP-Vol induced complete G2/M cell cycle arrest in U-87 MG GBM cells giving 7.8-times better anti-tumor activity, prolonged circulation time and largely increased GBM enrichment. ANG-CPP-Vol effectively suppressed the growth of orthotopic U-87 MG GBM and significantly boosted mice survival rate. Importantly, ANG-CPP-Vol showed further reduced toxicity over free Vol. This great safety and remarkable efficacy of ANG-CPP-Vol renders it a high potential for treating GBM. Unlabelled Image • Brain delivery of volasertib (Vol) is enabled by chimaeric polypeptide polymersome. • Vol-loaded angiopep-2-docked polymersome (ANG-CPP-Vol) is small, stable and smart. • ANG-CPP-Vol induces complete G2/M cell cycle arrest in U-87 MG GBM cells. • ANG-CPP-Vol potently suppresses orthotopic GBM and boosts mice survival rate. • ANG-CPP-Vol offers a novel and highly appealing molecular therapy for GBM. [ABSTRACT FROM AUTHOR]

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. A6 peptide functionalized polymersomal vincristine sulfate with good safety and exceptional targeting ability to orthotopic MV4-11 leukemia causes significant reduction of leukemia burdens and striking survival benefits compared to free vincristine sulfate and non-targeted counterparts, providing a high-efficiency treatment for acute myeloid leukemia. Unlabelled Image • A6 peptide-tagged smart polymersomal vincristine (A6-cPS-VCR) is developed. • A6-cPS-VCR outperforms cPS-VCR and free VCR in inhibiting CD44+ leukemia cells. • A6-cPS-VCR effectively targets leukemia cells in circulation and bone marrow. • A6-cPS-VCR significantly improves the survival of MV4-11-Luc-GFP AML-bearing mice. [ABSTRACT FROM AUTHOR]

Therapeutic nanoreactors are currently emerging as promising nanoplatforms to in situ transform inert prodrugs into active drugs. Nevertheless, it is still challenging to engineer a nanoreactor with balanced key features of tunable selective membrane permeability and structural stability for prodrug delivery and activation in diseased tissues. Herein, we present a facile strategy to engineer a polymersome nanoreactor with tumor-specific tunable membrane permeability to load both hydrophobic phenylboronic ester-caged anticancer prodrugs (e.g. , camptothecin or paclitaxel prodrug) and hydrophilic glucose oxidase (GOD) in the membranes and cavities, respectively. The nanoreactors maintain inactive during blood circulation and in normal tissues. Upon accumulation in tumors, the mild acidic microenvironment triggers selective membrane permeability to allow small molecules (glucose and O 2) to diffuse across the membrane and react under the catalysis of GOD. The massively generated H 2 O 2 triggers in situ transformation of innocuous prodrugs into toxic parental drugs through cleavage of the self-immolative degradable caging groups. The developed system showed significantly enhanced antitumor efficacy by H 2 O 2 production and prodrug activation via combined oxidation-chemotherapy. The well-devised polymersome nanoreactors with tumor-pH-tunable membrane permeability to coload H 2 O 2 -responsive prodrug and GOD represent a novel strategy to realize prodrug delivery and activation for enhanced therapeutic efficacy with low side toxicity. Unlabelled Image • Enzymes and prodrugs were integrated into one polymersome nanoreactor. • Tumor pH-tunable membrane permeability activated the polymersome nanoreactor. • H 2 O 2 production under the catalysis of the enzymes induced prodrug activation. • Oxidation-chemotherapy by H 2 O 2 and drugs achieved synergistic therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Abstract In the current study, thermoresponsive poly(N-isopropylacrylamide)-doxorubicin (PNIPAM-DOX) hydrogel was synthesized and loaded into pH-responsive poly ethylene glycol)-2,4,6- trimethoxy benzylidene pentaerythritol carbonate (PEG-PTMBPEC) polymersomes in order to fabricate a smart thermo-pH stimuli responsive drug delivery system. Thermo-pH responsive polymersomal formulation of DOX revealed average size of 170 ± 11.2 nm. The prepared system was loaded with PNIPAM-DOX conjugate with encapsulation efficiency of 30.80%. The in vivo release evaluation demonstrated that the DOX release from polymersomal formulation was pH-dependent, i.e. significantly faster drug release at pH 5.5and 6.5 compared to physiological pH. On the other hand, the drug release rate was significantly decreased at 37 °C due to the gelation of PNIPAM-DOX conjugate in the interior compartment of the pH-responsive polymersomes. The in vivo anti-tumor efficiency of the prepared polymersomal formulation of DOX was evaluated implementing C26 tumor-bearing mice after either intravenous (i.v.) or intratumoral (i.t.) single dose injection. The obtained results demonstrated that the prepared system significantly inhibited tumor growth rate in mice receiving single dose via either intravenous or intratumoral injection in comparison with free DOX-treatment group. Furthermore, treatment with polymersomal formulation did not cause any systematic toxicity in terms of pathological alteration of vital organs, survival rate and body weight loss. The prepared smart hydrosomal formulation significantly increased the blood half life time of drug and modified the biodistribution and pharmacokinetic parameters of formulated DOX. In this regard, thermo-pH-dual-stimuli responsive hydrosomal formulation represent a novel approach in nanomedicine development for effective cancer therapy. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Due to the severe cardiotoxicity of doxorubicin, its usage is limited. This shortcoming could be overcome by modifying pharmacokinetics of the drugs via preparation of various nanoplatforms. Doxil, a well-known FDA-approved nanoplatform of doxorubicin as antineoplastic agent, is frequently used in clinics in order to reduce cardiotoxicity of doxorubicin. Since Doxil shows some shortcomings in clinics including hand and food syndrome and very slow release pattern thus, there is a demand for the development and preparation of new doxorubicin nanoformulation with fewer side effects. The new formulation of the doxorubicin, synthesized previously by our group was extensively examined in the current study. This new formulation is doxorubicin encapsulated in PEG-PLGA polymersomes (PolyDOX). The main aim of the study was to compare the distribution and treatment efficacy of a new doxorubicin-polymersomal formulation (PolyDOX) with regular liposomal formulation (Doxil-mimic) in murine colon adenocarcinoma model. Additionally, the pathological, hematological changes, pharmacodynamics, biodistribution, tolerated dose and survival rate in vivo were evaluated and compared. Murine colon cancer model was induced by subcutaneous inoculation of BALB/c mice with C26 cells. Afterwards, either Doxil-mimic or PolyDOX was administered intravenously. The obtained results from biodistribution study showed a remarkable difference in the distribution of drugs in murine organs. In this regard, Doxil-mimic exhibited prolonged (48 h) presence within liver tissues while PolyDOX preferentially accumulate in tumor and the presence in liver 48 h post-treatment was significantly lower than that of Doxil-mimic. Obtained results demonstrated comparable final length of life for mice receiving either Doxil-mimic or PolyDOX formulations whereas tolerated dose of mice receiving Doxil-mimic was remarkably higher than those receiving PolyDOX. Therapeutic efficacy of formulation in term of tumor growth rate after one injection of formulations (5 mg/kg, 10 mg/kg or 15 mg/kg) demonstrated better efficacy at lower dose for PolyDOX. Analysis of Kaplan Meier curve was in favor of both formulations in their treatment–dose. Pathological and hematological surveys of mice treated with both formulations did not show considerable difference except for a small atrophy in liver observed after successive administration of Doxil-mimic. It could be concluded that PolyDOX can potentially limit off-site effects of Doxil due to its biodegradability and sustained release properties while it exhibited favorable safety profile comparable to Doxil. [ABSTRACT FROM AUTHOR]

Flash nanoprecipitation (FNP) has proven to be a powerful tool for the rapid and scalable assembly of solid-core nanoparticles from block copolymers. The process can be performed using a simple confined impingement jets mixer and provides an efficient and reproducible method of loading micelles with hydrophobic drugs. To date, FNP has not been applied for the fabrication of complex or vesicular nanoarchitectures capable of encapsulating hydrophilic molecules or bioactive protein therapeutics. Here, we present FNP as a single customizable method for the assembly of bicontinuous nanospheres, filomicelles and vesicular, multilamellar and tubular polymersomes from poly(ethylene glycol)- bl -poly(propylene sulfide) block copolymers. Multiple impingements of polymersomes assembled via FNP were shown to decrease vesicle diameter and polydispersity, allowing gram-scale fabrication of monodisperse polymersomes within minutes. Furthermore, we demonstrate that FNP supports the simultaneous loading of both hydrophobic and hydrophilic molecules respectively into the polymersome membrane and aqueous lumen, and encapsulated enzymes were found to be released and remain active following vesicle lysis. As an example application, theranostic polymersomes were generated via FNP that were dual loaded with the immunosuppressant rapamycin and a fluorescent dye to link targeted immune cells with the elicited immunomodulation of T cells. By expanding the capabilities of FNP, we present a rapid, scalable and reproducible method of nanofabrication for a wide range of nanoarchitectures that are typically challenging to assemble and load with therapeutics for controlled delivery and theranostic strategies. [ABSTRACT FROM AUTHOR]

pH-responsive polymers contain ionic functional groups as pendants in their structure. The total number of charged groups on polymer chains determines the overall response of the system to changes in the external pH. This article reviews various pH-responsive polymers classified as polyacids ( e.g., carboxylic acid based polymers, sulfonamides, anionic polysaccharides, and anionic polypeptides) and polybases ( e.g., polyamines, pyridine and imidazole containing polymers, cationic polysaccharides, and cationic polypeptides). We correlate the pH variations in the body at the organ level ( e.g. , gastrointestinal tract and vaginal environment), tissue level ( e.g. , cancerous and inflamed tissues), and cellular level ( e.g. , sub-cellular organelles), with the intrinsic properties of pH-responsive polymers. This knowledge could help to select more effective (‘ smart ’) polymeric systems based on the biological target. Considering the pH differences in the body, various drug delivery systems can be designed by utilizing smart biopolymeric compounds with the required pH-sensitivity. We also review the pharmaceutical application of pH-responsive polymeric carriers including hydrogels, polymer-drug conjugates, micelles, dendrimers, and polymersomes. [ABSTRACT FROM AUTHOR]

In this study, a tumor-targeted, docetaxel encapsulated dextran-poly lactide- co -glycolide (DEX-PLGA) polymersomes was fabricated for breast cancer chemotherapy. To attain active cancer targeting, docetaxel encapsulated polymersomes was conjugated with folate for folate receptor guided delivery which is overexpressed in various cancer cells including breast adenocarcinoma. Docetaxel was encapsulated in the bilayer of DEX-PLGA or folate-conjugated DEX-PLGA (FA-DEX-PLGA) polymersomes via nanoprecipitation method in order to provide the controlled drug release. The size of polymersomes obtained were 178.53 ± 2.5 nm and offered drug encapsulation efficiency and loading content of 78.85 ± 3.81% and 9.32 ± 0.27, respectively. The data demonstrate that the prepared polymersome formulations sustained docetaxel release for a period of 6 days. Cellular uptake study and MTT assay showed that the developed folate-targeted docetaxel-loaded polymersomes had higher cytotoxicity than non-targeted ones as well as free form of drug and was accumulated in 4T1 and MCF-7 cells in vitro . The in vivo tumor inhibitory effect of folate-conjugated docetaxel–loaded DEX-PLGA polymersomes (FA-DEX-PLGA-DTX-NPs) demonstrated an increased therapeutic potency of targeted formulation over both non-targeted (DEX-PLGA-DTX-NPs) and free drug. The represented data reveal that the prepared targeted drug delivery system was able to control the docetaxel release, and also enhance the antitumor potency of docetaxel. This study may open new direction for preparation of folate receptor targeted polymersomes based on DEX-PLGA copolymers for translational purposes. [ABSTRACT FROM AUTHOR]

Insulin is the first line therapy in type 1 diabetes and usually patients suffer from three or more daily insulin injections. It is obvious that patient compliance can be improved greatly if insulin could be formulated in an oral dosage form. In the current study, polymersomes based on amphiphilic copolymers of dextran (DEX)5000–poly(lactic-co-glycolic acid) (PLGA)13,000 and DEX25000–PLGA48000 were synthesized and used for the encapsulation of insulin. The polymersomes were prepared using a modified direct hydration method by blending an aqueous solution of insulin with DEX–PLGA copolymers at room temperature. The in vitro insulin release through the nanopolymersomal system was studied in HCl 0.1 N (pH 1.2) and phosphate buffered saline (pH 7.4). The results demonstrated that the average insulin encapsulation efficiency was > 90%. The in vitro release experiment demonstrated that while insulin release in the simulated gastric condition was negligible, a significant amount of insulin was released in the simulated intestinal condition. According to the results of a circular dichroism test, secondary and tertiary structures of the released insulin were identical to that of standard insulin. Permeability studies across MDCK cells showed that permeability levels after 240 min were 16.89 ± 0.39% with DEX5000–PLGA13000 and 9.34 ± 0.79% with DEX25000–PLGA48000, indicating a noticeable increase compared with free insulin. Significant hypoglycemic effects in the in vivo diabetic rat model revealed the efficacy of the DEX–PLGA-based polymersomes as oral insulin carriers. Thus, insulin-loaded, self-assembled DEX–PLGA polymersomes showed promising in vitro and in vivo efficiency and can be considered as a potential oral insulin carrier system. [ABSTRACT FROM AUTHOR]

Abstract: Doxorubicin (Dox), an anthracycline anticancer drug, was successfully incorporated into block copolymer vesicles of poly(trimethylene carbonate)-b-poly(l-glutamic acid) (PTMC-b-PGA) by a solvent-displacement (nanoprecipitation) method. pH conditions were shown to have a strong influence on loading capacity and release profiles. Substantial drug loading (47% w/w) was achieved at pH 10.5. After pH neutralization, aqueous dispersions of drug-loaded vesicles were found stable for a prolonged period of time (at least 6months) without vesicle disruption or drug precipitation. Dox-loaded vesicles exhibited in vitro pH and temperature-dependent drug release profiles: release kinetics fastened in acid conditions or by increasing temperature. These features strongly support the interest of developing PTMC-b-PGA polymersomes as carriers for the controlled delivery of Dox. [Copyright &y& Elsevier]

Abstract: Encapsulating delicate biomolecules into submicron-sized polymer particulate systems with preserved native conformation and sufficient loading efficiency is of great challenge. To address this issue, we developed a unique polymersome which differs from reported polymersome in that its bilayer membrane was formed of two different amphiphilic diblock copolymers in an “asymmetric” way. By adding two diblock copolymers, poly (ethylene glycol)-block-poly (ε-caprolactone) (PEG-PCL) and dextran-block-poly (ε-caprolactone) (DEX-PCL), into a so-called dextran-in-PEG aqueous two-phase system, DEX-PCL formed the inner leaflet around the dispersed dextran phase and PEG-PCL formed the outer leaflet with the PEG block facing the PEG continuous phase. We name this unique assembly process as “phase-guided assembly”. Polymersomes of asymmetric bilayer membrane possess a series of advantages over “symmetric” polymer bilayer vesicles previously reported. The asymmetric bilayer created a different chemical environment of the interior to which proteins were encapsulated highly efficiently (up to 90%) by thermodynamically favored partition. Probably due to the thermodynamic preference, erythropoietin (EPO) encapsulated in this system showed a well-preserved bioactivity in cell proliferation assay. The core of the polymersomes may be cross-linked to enhance their mechanical strength. Phase-guided assembly system and asymmetric bilayer polymersomes demonstrated in this study may serve the high demands for delivering nucleotide and protein medicines and other biological applications. [Copyright &y& Elsevier]

Abstract: Cyclotriphosphazenes grafted with equimolar amounts of a hydrophilic polyethylene glycol and a hydrophobic oligopeptide in cis-nongeminal way form a new class of tripodal amphiphiles allowing both intra- and intermolecular hydrophobic interactions that differ from linear block copolymer amphiphiles. It has been found in this study that the tripodal amphiphiles can be tuned for self-assembly from micelles to bilayered polymersomes by controlling the hydrophobicity of the oligopeptide grafted. For instance, the tripodal amphiphiles with an intermediate hydrophobicity (01) remain as stable micelles in aqueous solution. These biodegradable polymersomes exhibit outstanding physicochemical properties required for practical drug delivery and other biomedical applications. In particular, the cyclic phosphazene trimer platinated with a hydrophobic cis-bis(cyclohexylamine)Pt-moiety forms very stable polymersomes with excellent tumor selectivity by EPR effect and seems to be a promising candidate for preclinical studies. [Copyright &y& Elsevier]

Abstract: pH-Sensitive degradable polymersomes and micelles were prepared based on diblock copolymer of poly(ethylene glycol) (PEG) and an acid-labile polycarbonate, poly(2,4,6-trimethoxybenzylidenepentaerythritol carbonate) (PTMBPEC). Polymersomes of PEG(1.9k)–PTMBPEC(6k) revealed average sizes of 100–200nm. The acetals of polymersomes, similar to those of PEG(5k)–PTMBPEC(5.8k) micelles, though stable at pH 7.4 were prone to fast hydrolysis at mildly acidic pH of 4.0 and 5.0, with half lives of 0.5 and 3d, respectively. The acetal hydrolysis resulted in significant size increase of polymersomes, to over 1000nm in 24h at pH 4.0. Drug encapsulation studies revealed that polymersomes were able to simultaneously load paclitaxel (PTX, hydrophobic) and doxorubicin hydrochloride (DOX·HCl, hydrophilic), whereas micelles loaded PTX only. Notably, polymersomes showed lower drug loading efficiencies for PTX than micelles (30.0–37.7% versus 61.4–65.2%). The in vitro release studies demonstrated that release of PTX and DOX·HCl from polymersomes was highly pH-dependent, i.e. significantly faster drug release at mildly acidic pH of 4.0 and 5.0 compared to physiological pH. Furthermore, much higher release rates were observed for PTX release from the polymersomes compared to that from the micelles under otherwise the same conditions. These pH-sensitive nano-sized degradable polymersomes hold great promise for combination therapy for cancers. [Copyright &y& Elsevier]

Abstract: siRNA and antisense oligonucleotides, AON, have similar size and negative charge and are often packaged for in vitro delivery with cationic lipids or polymers—but exposed positive charge is problematic in vivo. Here we demonstrate loading and functional delivery of RNAi and AON with non-ionic, nano-transforming polymersomes. These degradable carriers are taken up passively by cultured cells after which the vesicles transform into micelles that allow endolysosomal escape and delivery of either siRNA into cytosol for mRNA knockdown or else AON into the nucleus for exon skipping within pre-mRNA. Polymersome-mediated knockdown appears as efficient as common cationic-lipid transfection and about half as effective as Lenti-virus after sustained selection. For AON, initial results also show that intramuscular injection into a mouse model of muscular dystrophy leads to the expected protein expression, which occurs along the entire length of muscle. The lack of cationic groups in antisense polymersomes together with initial tests of efficacy suggests broader utility of these non-viral carriers. [Copyright &y& Elsevier]

Abstract: Cytotoxicity can in principle be maximized if drugs with different activities can be delivered simultaneously to the same cell. However, combination therapy with drugs having distinct properties such as solubility generally requires use of multiple carriers or solvents, limiting the likelihood of simultaneous delivery. In this brief report, we describe the in vivo use of biodegradable polymersomes for systemic delivery of an anticancer cocktail. These polymer-based shells exploit a thick hydrophobic membrane and an aqueous lumen to efficiently carry both hydrophobic and hydrophilic drugs, respectively paclitaxel and doxorubicin. Polymersomes are long-circulating in vivo but also degrade and release their drugs on a time scale of about 1 day, by which time the tumors treated here will otherwise have almost doubled in volume. A single systemic injection of the dual drug combination shows a higher maximum tolerated dose than the free drug cocktail and shrinks tumors more effectively and more sustainably than free drug: 50% smaller tumors are seen at 5 days with polymersomes. The polymersomes cause two-fold higher cell death in tumors than free drug and show quantitatively similar increases in maximum tolerated dose and drug accumulation within the tumors—suggesting promise for multi-drug delivery. [Copyright &y& Elsevier]