Polymeric Micelle System Research Articles

Targeted Polymeric Micelles System, Designed to Carry a Combined Cargo of L-Asparaginase and Doxorubicin, Shows Vast Improvement in Cytotoxic Efficacy.

L-asparaginases (ASP) and Doxorubicin (Dox) are both used in the treatment of leukemia, including in combination. We have attempted to investigate if their combination within the same targeted delivery vehicle can make such therapy more efficacious. We assembled a micellar system, where the inner hydrophobic core was loaded with Dox, while ASP would absorb at the surface due to electrostatic interactions. To make such absorption stronger, we conjugated the ASP with oligoamines, such as spermine, and the lipid components of the micelle-lipoic and oleic acids-with heparin. When loaded with Dox alone, the system yielded about a 10-fold improvement in cytotoxicity, as compared to free Dox. ASP alone showed about a 2.5-fold increase in cytotoxicity, so, assuming additivity of the effect, one could expect a 25-fold improvement when the two agents are applied in combination. But in reality, a combination of ASP + Dox loaded into the delivery system produced a synergy, with a whopping 50× improvement vs. free individual component. Pharmacokinetic studies have shown prolonged circulation of micellar formulations in the bloodstream as well as an increase in the effective concentration of Dox in micellar form and a reduction in Dox accumulation to the liver and heart (which reduces hepatotoxicity and cardiotoxicity). For the same reason, Dox's liposomal formulation has been in use in the treatment of multiple types of cancer, almost replacing the free drug. We believe that an opportunity to deliver a combination of two types of drugs to the same target cell may represent a further step towards improvement in the risk-benefit ratio in cancer treatment.

Celastrol-loaded polymeric mixed micelles shows improved antitumor efficacy in 4 T1 bearing xenograft mouse model through spatial targeting

In this study, we have proposed a novel approach that combines hyaluronic acid (HA), folic acid (FA), and celastrol (CLS) within a polymeric micelle system (CLS-HF/MLs), offering a dual-action strategy against breast cancer. Polymeric mixed micelles were prepared through the thin-film hydration method, and comprehensive quality control parameters were established, encompassing particle size, polydispersity index, zeta potential, surface morphology, encapsulation efficiency, drug content, in vitro drug release, and storage stability assessment. The average particle size of CLS-HF/MLs micelles was found to be 120 nm and their drug loading and encapsulation efficiencies were 15.9 % and 89.52 %, respectively. The in vitro release data showed that the CLS-HF/MLs targeted mixed micelles displayed a prolonged release profile compared to the free drug. Additionally, the stability of the developed polymeric mixed micelles was maintained for up to 8 weeks of storage in terms of particle size and drug content. Furthermore, both flow cytometry and confocal laser scanning microscopy studies indicated a significant enhancement in the cellular uptake efficiency and cytotoxicity of CLS-HF/MLs mixed micelles against MCF-7 cell line. In terms of pharmacokinetic analysis, the half-life and AUC values of CLS-HF/MLs mixed micelles were found to be approximately 4.71- and 7.36-folds higher than the values of free drug (CLS), respectively. The CLS-HF/MLs micelles exhibited remarkable antitumor efficacy (almost complete ablation of the 4 T1-cell bearing tumor xenografts mouse model) due to the dual receptor (CD44 and folate) targeting effects with minimal side effects. When considering the cumulative findings of our present research, it becomes evident that mixed micelles designed for chemotherapy offer a promising and potentially effective therapeutic avenue for the treatment of breast cancer

Elucidation of Spatial Cooperativity in Chemo-Immunotherapy by a Sequential Dual-pH-Responsive Drug Delivery System.

Combining immune checkpoint blockade with chemotherapy through nanotechnology is promising in terms of safety and efficacy. However, the distinct subcellular distribution of each ingredient's action site makes it challenging to acquire an optimal synergism. Herein, a dual-pH responsive hybrid polymeric micelle system, HNP(αPDL16.9, Dox5.3), is constructed as a proof-of-concept for the spatial cooperativity in chemo-immunotherapy. HNP retains the inherent pH-transition of each polymer, with stepwise disassembly under discrete pH thresholds. Within weakly acidic extracellular tumor environment, αPDL1 is first released to block the checkpoint on cell membranes. The remaining intact Doxorubicin-loaded micelle NP(Dox)5.3 displays significant tropism toward tumor cells and releases Dox upon lysosomal pH for efficient tumor immunogenic cell death without immune toxicity. This sequential-released pattern boosts DC activation and primes CD8+ T cells, leading to enhanced therapeutic performance than single agent or an inverse-ordered combination in multiple murine tumor models. Using HNP, the indispensable role of conventional type 1 DC (cDC1) is identified in chemo-immunotherapy. A co-signature of cDC1 and CD8 correlates with cancer patient survival after neoadjuvant Pembrolizumab plus chemotherapy in clinic. This study highlights spatial cooperativity of chemo- and immuno-agents in immunoregulation and provides insights into the rational design of drug combination for future nanotherapeutics development.

Reductive prodrug and AIE copolymer nanoparticle for monitoring and chemotherapy

Polymeric micelle systems for drug delivery, monitor and chemotherapy have gained significant attention, and reductive polymeric micelle systems have become particularly attractive due to their controlled release behavior without additional assistance. However, there are challenges in accurately controlling drug and probe release from the nanoparticles and determining the loading content of drug and probe. To address these issues, we have developed a reduction-responsive Pt(IV) prodrug-based polymeric delivery system that can be dynamically monitored using aggregation-induced emission luminogens (AIE) based bioprobes. These polymeric micelle can self-assemble into nanoparticles and release both bio-active Pt(II) drug and bio-probe upon reduction activation. TPE molecules released in the inner endo/lysosomal microenvironment aggregate and fluoresce upon irradiation, thus allowing real-time tracking of drug biodistribution without additional contrast agents. Advantages of this system include position-specific chemical bond cleavage, control of platinum content, and monitoring of drug reduction and biodistribution.

Self-Report Amphiphilic Polymer-Based Drug Delivery System with ROS-Triggered Drug Release for Osteoarthritis Therapy.

The development of drug delivery systems with real-time cargo release monitoring capabilities is imperative for optimizing nanomedicine performance. Herein, we report an innovative self-reporting drug delivery platform based on a ROS-responsive random copolymer (P1) capable of visualizing cargo release kinetics via the activation of an integrated fluorophore. P1 was synthesized by copolymerization of pinacol boronate, PEG, and naphthalimide monomers to impart ROS-sensitivity, hydrophilicity, and fluorescence signaling, respectively. Detailed characterization verified that P1 self-assembles into 11 nm micelles with 10 μg mL-1 CMC and can encapsulate hydrophobic curcumin with 79% efficiency. Fluorescence assays demonstrated H2O2-triggered disassembly and curcumin release with concurrent polymer fluorescence turn-on. Both in vitro and in vivo studies validated the real-time visualization of drug release and ROS scavenging, as well as the therapeutic effect on osteoarthritis (OA). Overall, this nanotheranostic polymeric micelle system enables quantitative monitoring of drug release kinetics for enhanced treatment optimization across oxidative stress-related diseases.

Design, Development, and Evaluation of SA-F127:TPGS Polymeric Mixed Micelles for Improved Delivery of Glipizide Drug: In-vitro, Ex-vivo, and In-vivo Investigations.

The anti-diabetic glipizide (GLN) drug has notable pharmaceutical advantages, but poor aqueous solubility restricts its wide applications. The present work was to develop a mixed polymeric micelle system composed of SA-F127 and TPGS to improve the water solubility and effective delivery of the GLN. First, we synthesized SA-F127 and confirmed it through FTIR, NMR, and GPC techniques. The GLN-PMM were fabricated with the thin-film technique and optimized with CCD design. The developed GLN-PMM was characterized using DLS, Zeta, TEM, Rheology, FTIR, DSC, and XRD measurements. The GLN-PMM manifested a spherical morphology with 67.86 nm particle size, a -3.85 mV zeta potential, and a 0.582±0.06 PDI value. The polymeric mixed micelles showed excellent compatibility with GLN and were amorphous in nature. NMR studies confirmed the encapsulation of GLN in the core of the mixed micelle. In addition, the GLN-PMM micelles were tested in vitro for cumulative drug release, ex vivo for permeation, and in vivo for anti-diabetic investigations. The GLN-PMM release profile in the various pH environments showed over 90% after 24 h, clearly indicating sustained release. The GLN-PMM micelles gave higher 88.86±3.39% GLN permeation from the goat intestine compared with free GLN. In-vivo anti-diabetic investigation proves the powerful anti-diabetic properties of GLN-PMM in comparison to the marketed formulation. These findings demonstrated that the polymeric mixed micelles of SA-F127 and TPGS could be a promising, effective, and environment-friendly approach for oral delivery of the GLN.

Polymeric micelles loaded in situ gel with prednisolone acetate for ocular inflammation: development and evaluation.

Aim: Our study developed a prednisolone acetate polymeric micelles (PM) system for ocular inflammation related to allergic uveitis. Methods: For PM development, athin-film hydration procedure was used. Irritation, in vitro, ex vivo transcorneal permeation, micelle size, entrapment efficiencyand histology within the eye wereall calculated for PM. Results: The optimized in situ gel (A4) showed superior ex vivo transcorneal permeation with zero-order kinetics. Conclusion: The developed formulation could be a promising candidate for treating anterior uveitis via topical application to the anterior segment of the eye.

PH-Responsive Poly(ethylene glycol)-b-poly(2-vinylpyridine) Micelles for the Triggered Release of Therapeutics

The use of pH-responsive polymeric micelles is a promising approach to afford the targeted, pH-mediated delivery of hydrophobic drugs within the low-pH tumour milieu and intracellular organelles of cancer cells. However, even for a common pH-responsive polymeric micelle system-e.g., those utilising poly(ethylene glycol)-b-poly(2-vinylpyridine) (PEG-b-PVP) diblock copolymers-there is a lack of available data describing the compatibility of hydrophobic drugs, as well as the relationships between copolymer microstructure and drug compatibility. Furthermore, synthesis of the constituent pH-responsive copolymers generally requires complex temperature control or degassing procedures that limit their accessibility. Herein we report the facile synthesis of a series of diblock copolymers via visible-light-mediated photocontrolled reversible addition-fragmentation chain-transfer polymerisation, with a constant PEG block length (90 repeat units (RUs)) and varying PVP block lengths (46-235 RUs). All copolymers exhibited narrow dispersity values (Đ ≤ 1.23) and formed polymeric micelles with low polydispersity index (PDI) values (typically <0.20) at physiological pH (7.4), within a suitable size range for passive tumour targeting (<130 nm). The encapsulation and release of three hydrophobic drugs (cyclin-dependent kinase inhibitor (CDKI)-73, gossypol, and doxorubicin) were investigated in vitro at pH 7.4-4.5 to simulate drug release within the tumour milieu and cancer cell endosome. Marked differences in drug encapsulation and release were observed when the PVP block length was increased from 86 to 235 RUs. With a PVP block length of 235 RUs, the micelles exhibited differing encapsulation and release properties for each drug. Minimal release was observed for doxorubicin (10%, pH 4.5) and CDKI-73 exhibited moderate release (77%, pH 4.5), whereas gossypol exhibited the best combination of encapsulation efficiency (83%) and release (91% pH 4.5) overall. These data demonstrate the drug selectivity of the PVP core, where both the block molecular weight and hydrophobicity of the core (and accordingly the hydrophobicity of the drug) have a significant effect on drug encapsulation and release. These systems remain a promising means of achieving targeted, pH-responsive drug delivery-albeit for select, compatible hydrophobic drugs-which warrants their further investigation to develop and evaluate clinically relevant micelle systems.

Applications of Polymeric Micelles for Drug Delivery

Polymeric micelles have attracted more and more attention in the biomedical field due to their controlled synthesis and sustained drug release, where a diverse of different drug carriers based on the polymeric micelles have been developed in recent years. This research will analyze the application and development of polymeric micelles that derived from block copolymers in biomedicine. There are three processes in drug delivery of drug carriers prepared by polymeric micelles, including micellar drug loading, micellar drug release and targeted therapy. In the polymeric micelles system, the reason why the solubilization and stabilization of drugs are improved is that the hydrophobic interaction and forming of hydrogen bond between micelles-system and drugs. This research also gives basic mechanism for polymeric micelles for passive and active drug targeting. What makes micelles ideal hosts for hydrophobic anti-cancer drugs or other targeted drugs is the hydrophobic nature of its core. This can make the drug more stable. In addition, this research is written to cover the latest information on polymeric micelles and methods of synthesis for applications. The advantages and disadvantages of its use as a drug carrier are also included. And it highlights the conditions that polymeric micelles need to meet as specific delivery tools in various targeting situations.

Orthogonal Covalent Entrapment of Cargo into Biodegradable Polymeric Micelles via Native Chemical Ligation.

Polymeric micelles (PMs) are promising platforms for enhanced tissue targeting of entrapped therapeutic agents. Strategies to circumvent premature release of entrapped drugs include cross-linking of the micellar core as well as covalent attachment of the drug cargo. The chemistry employed to obtain cross-linked micelles needs to be mild to also allow entrapment of fragile molecules, such as certain peptides, proteins, oligonucleotides, and fluorescent dyes. Native chemical ligation (NCL) is a mild bio-orthogonal reaction between a N-terminal cysteine residue and a thioester that proceeds under physiological conditions. Here, we designed a trifunctional cross-linker containing two cysteine residues for the micelle core-cross-linking reaction and an azide residue for ring-strained alkyne conjugation of fluorescent dyes. We applied this approach to thermosensitive methoxypolyethylene glycol-b-N-(2-hydroxypropyl)methacrylamide-lactate (mPEG-b-HPMAmLacn) based block copolymers of a core-cross-linked polymeric micelle (CCPM) system by attaching thioester residues (using ethyl thioglycolate-succinic anhydride, ETSA) for NCL cross-linking with the trifunctional cross-linker under physiological conditions. By use of mild copper-free click chemistry, we coupled fluorescent dyes, Sulfo.Cy5 and BODIPY, to the core via the azide residue present on the cross-linker by triazole ring formation. In addition, we employed a recently developed cycloheptyne strain promoted click reagent (TMTHSI, CliCr) in comparison to the frequently employed cyclooctyne derivative (DBCO), both achieving successful dye entrapment. The size of the resulting CCPMs could be tuned between 50 and 100 nm by varying the molecular weight of the thermosensitive block and ETSA content. In vitro cell experiments showed successful internalization of the dye entrapped CCPMs, which did not affect cell viability up to a polymer concentration of 2 mg/mL in PC3 cells. These fluorescent dye entrapped CCPMs can be applied in diagnostic imaging and the chemistry developed in this study serves as a steppingstone toward covalently entrapped fragile drug compounds with tunable release in CCPMs.

Chain-shattering polymeric sulfur dioxide prodrug micelles for redox-triggered gas therapy of osteosarcoma.

Sulfur dioxide (SO2) based gas therapy has received great attention recently. Nevertheless, it is still a challenge to fabricate a SO2 delivery system to achieve effective delivery and on-demand stimuli triggered release at tumor sites. Herein, a chain-shattering polymeric SO2 prodrug micelle system was fabricated for effective SO2 based gas therapy. First, an amphiphilic polymer (mPEG-P(HDI-DN)) was prepared by polycondensation of poly(ethylene glycol) methyl ether, hexamethylene diisocyanate and monomer containing SO2. mPEG-P(HDI-DN) can self-assemble into spherical micelles with a diameter of around 50-90 nm. Triggered release of SO2 from micelles can be achieved in the presence of GSH with the degradation of mPEG-P(HDI-DN) into small molecules. The in vitro experiment proved that mPEG-P(HDI-DN) micelles can enter into osteosarcoma cells and inhibit the growth of osteosarcoma cells by increasing the ROS level in cells. The in vivo experiments demonstrate that mPEG-P(HDI-DN) micelles can inhibit the growth of osteosarcoma effectively without obvious tissue toxicity. These results indicate that this chain-shattering polymeric SO2 prodrug micelle system is a promising candidate for effective SO2 based gas therapy.

An Integrated Tumor Microenvironment Responsive Polymeric Micelle for Smart Drug Delivery and Effective Drug Release.

Tumor microenvironment (TME) responsive polymeric micelles are promising carriers for drug delivery. In order to meet the needs of various applications, multifarious TME-responsive switches are used to construct smart polymeric micelles, which causes the complexity and corpulence of the polymeric micelle system and increases the difficulty of preparation. In this study, we designed and synthesized an ingenious TME-responsive switch through grafting disulfide bond-modified piperidinepropionic acid (CPA) on copolymer poly(ethylene glycol)-b-poly(aspartate)(PEG-b-PAsp) and built a novel pH/reduction-responsive PEG-b-PAsp-g-CPA polymeric micelle delivery system. The CPA-pendants can reverse the surface charge of the polymeric micelle from negative to positive at pH 6.5 because of the protonation of piperidine groups, thereby enhancing the internalization of cell. Subsequently, more piperidine groups are protonated at pH 5.0 which will increase the hydrophilicity of polymeric micelles and cause the hydrophobic core to swell, thus making the disulfide bonds packed in the core to be more easily broken by GSH. With the synergistic effect of the pH-triggered protonation of piperidine groups and reduction triggered break of disulfide bonds, the polymeric micelles will disintegrate and achieve efficient intracellular drug release. The TME-responsive polymeric micelles exhibited good biological safety, enhanced internalization, and rapid intracellular doxorubicin (DOX) release in vitro. Moreover, the PEG-b-PAsp-g-CPA/DOX polymeric micelles showed excellent antitumor efficacy and low systemic toxicity in lung tumor-bearing BALB/C mice. These results indicated that the novel integrated TME-responsive switch CPA helps the PEG-b-PAsp-g-CPA polymeric micelles to obtain excellent TME-responsiveness and antitumor drug delivery capabilities, while it also makes the preparation of TME-responsive polymeric micelles simpler and more convenient. This work provides a new idea for the architecture of TME-responsive polymeric micelles.

Alendronate-functionalized hypoxia-responsive polymeric micelles for targeted therapy of bone metastatic prostate cancer

Bone metastasis is one of the leading causes of cancer-related death and remains incurable in spite of great efforts. Bone-targeted nanoparticle-based drug carriers can overcome the difficulties in delivering therapeutic agents to metastatic bone and endowing them with a stimuli-responsive feature for controllable drug release can further maximize their therapeutic outcome. In light of hypoxic microenvironment of bone metastasis, we herein reported a bone-targeted and hypoxia-responsive polymeric micelle system for effective treatment of bone metastatic prostate cancer. The micelles were self-assembled from a polyethylene glycol and poly-l-lysine based copolymer using alendronate as a bone-targeted moiety and azobenzene as a hypoxia-responsive linker, showing a high affinity to metastatic bone and a high sensitivity in responding to hypoxia in vitro. In vivo studies further showed that after a selective accumulation in metastatic bone, the micelles could respond to hypoxic bone metastasis for rapid drug release to an effective therapeutic dosage. As a result, the micelles could suppress tumor growth in bone and inhibit bone destruction by inhibiting osteoclast activity and promoting osteoblast activity, achieving an enhanced therapeutic outcome with relieved bone pain and prolonged survival time. Bone-targeted and hypoxia-responsive nanocarriers therefore represent a promising advancement for treating bone metastasis. To our best knowledge, it might be the first example of the application of hypoxia-responsive nanocarriers in treating bone metastasis.

Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis.

Treatment against visceral leishmaniasis (VL) is mainly hampered by drug toxicity, long treatment regimens and/or high costs. Thus, the identification of novel and low-cost antileishmanial agents is urgent. Acarbose (ACA) is a specific inhibitor of glucosidase-like proteins, which has been used for treating diabetes. In the present study, we show that this molecule also presents in vitro and in vivo specific antileishmanial activity against Leishmania infantum. Results showed an in vitro direct action against L. infantum promastigotes and amastigotes, and low toxicity to mammalian cells. In addition, in vivo experiments performed using free ACA or incorporated in a Pluronic® F127-based polymeric micelle system called ACA/Mic proved effective for the treatment of L. infantum-infected BALB/c mice. Treated animals presented significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes when compared to the controls, as well as the development of antileishmanial Th1-type humoral and cellular responses based on high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and IgG2a isotype antibodies. In addition, ACA or ACA-treated animals suffered from low organ toxicity. Treatment with ACA/Mic outperformed treatments using either Miltefosine or free ACA based on parasitological and immunological evaluations performed one and 15 days post-therapy. In conclusion, data suggest that the ACA/Mic is a potential therapeutic agent against L. infantum and merits further consideration for VL treatment.

Functionalized polymeric hybrid micelles as an efficient nanotheranostic agent for thrombus imaging and thrombolysis

Pathological thrombosis within a vessel hampers blood flow and is the mainspring of numerous fatal cardiovascular complications. In order to specifically image and dissolve a thrombus, we rationally designed a functionalized polymeric hybrid micelle (PHM) system self-assembled from amphiphilic polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethylene glycol (PCL-PEG). Based on a biological component of thrombi, activated coagulation factor XIII (FXIIIa), which is responsible for fibrin crosslinking, we further developed FXIIIa-targeted near infrared imaging and thrombolytic nanoparticles, termed IR780/FPHM/LK NPs, through chemical conjugation of peptides to the system. In a ferric chloride (FeCl3)-induced mouse carotid thrombosis model, IR780/FPHM/LK NPs specifically targeted the thrombus and significantly enhanced the photoacoustic signal for an accurate diagnosis. When loaded with the fibrinolytic drug lumbrokinase (LK), FPHM remarkably dissociated the thrombus accompanied by an increase in the d-dimer level, a fibrin degradation product, and alleviation of fatal nonspecific hemorrhagic risk. Given its thrombus-specific imaging along with potent therapeutic activities, IR780/FPHM/LK NPs hold promise for developing nanotheranostic agents in preclinical thrombotic vascular disease models.

Iridium(III) Complex-Derived Polymeric Micelles with Low Dark Toxicity and Strong NIR Excitation for Phototherapy and Chemotherapy.

Iridium(III) complexes are potent candidates for photodynamic therapy. However, their clinical usage is impeded by their poor water solubility, high dark toxicity, and negligible absorption in near-infrared region (NIR region). Here, it is proposed to solve these challenges by developing an iridium(III) complexe-based polymeric micelle system. This system is self-assembled using an iridium(III) complex-containing amphiphilic block polymer. The upconversion nanoparticles are included in the polymeric micelles to permit NIR excitation. Compared with the nonformulated iridium(III) complexes, under NIR stimulation, this polymeric micelle system exhibits higher 1 O2 generation efficiency, negligible dark toxicity, excellent tumor-targeting ability, and synergistic phototherapy-chemotherapy effect both in vitro and in vivo.

Fabrication of Mixed Polymeric Micelles Based on Stimuli-Responsive Amphiphilic Copolymers for Drug Delivery and Controlled Release

In this report, mixed polymeric micelles (MPMs) system self-assembled from two kinds of cholesterol-grafted amphiphilic block copolymers cholesterol modified poly ([Formula: see text]-amino esters)-grafted disulfide poly (ethylene glycol) methyl ether (PAE(-ss-mPEG)-[Formula: see text]-Chol) and poly([Formula: see text]-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-[Formula: see text]-mPEG-Chol) were prepared for drug delivery and controlled release with pH and redox-responsibilities. The self-assembly of two block copolymers was evaluated by measurement of critical micelle concentration (CMC) values using fluorescence spectroscopy. The hydrodynamic diameter, polydispersity index (PDI) and zeta-potential of MPMs in aqueous were recorded by dynamic light scattering (DLS) at different conditions. Doxorubicin (DOX) was efficiently encapsulated in the micellar core by the hydrophobic interaction. The drug loading content (LC) and encapsulation efficacy (EE) of MPMs with different formulations were evaluated. The DOX was released due to the swelling and disassembly of MPMs induced by low pH and high glutathione (GSH) concentrations. The in vitro results demonstrated that drug release rate and cumulative release were obviously dependent on pH values and reducing agents. The results showed that the MPMs could be the potential anticancer drug delivery carriers with pH/redox-triggered drug release profile.

A clioquinol-containing Pluronic® F127 polymeric micelle system is effective in the treatment of visceral leishmaniasis in a murine model.

A clioquinol (ICHQ)-containing Pluronic® F127 polymeric micelle system (ICHQ/Mic) was recently shown to be effective against Leishmania amazonensis infection in a murine model. In the present study, ICHQ/Mic was tested against L. infantum infection. BALB/c mice (n = 12 per group) were infected with L. infantum stationary promastigotes through subcutaneous injection and, 45 days after challenge, received saline or were treated via the subcutaneous route with empty micelles, ICHQ or ICHQ/Mic. In addition, animals were treated with miltefosine by the oral route, as a drug control. Half of the animals were euthanized 1 and 15 days after treatment, aiming to evaluate two endpoints after therapy, when parasitological and immunological parameters were investigated. Results showed that the treatment using miltefosine, ICHQ or ICHQ/Mic induced significantly higher anti-parasite IFN-γ, IL-12, GM-CSF, nitrite and IgG2a isotype antibody levels, which were associated with low IL-4 and IL-10 production. In addition, a higher frequency of IFN-γ and TNF-α-producing CD4+ and CD8+ T-cells was found in these animals. The parasite load was evaluated in distinct organs, and results showed that the treatment using miltefosine, ICHQ or ICHQ/Mic induced significant reductions in organic parasitism in the treated and infected mice. A comparison between the treatments suggested that ICHQ/Mic was the most effective in inducing a highly polarized Th1-type response, as well as reducing the parasite load in significant levels in the treated and infected animals. Data obtained 15 days after treatment suggested maintenance of the immunological and parasitological responses. In conclusion, ICHQ/Mic could be considered in future studies for the treatment of visceral leishmaniasis.

Oxidation-Responsive and Aggregation-Induced Emission Polymeric Micelles with Two-Photon Excitation for Cancer Therapy and Bioimaging.

Polymeric micelles with stimuli-triggered drug release and AIE active bioimaging have emerged as potential candidates for theranostics. Herein, a curcumin (Cur) loaded oxidation-responsive mPEG-b-PLG (Se)-TP polymeric micelle system with great aggregation-induced emission (AIE) active and two-photon imaging property has been developed for simultaneous antitumor treatment and bioimaging. Cur-loaded polymeric micelles with a core-shell structure and a homogeneous size of 136 nm show great physiological stability while rapidly disassemble under oxidation environment with accelerated drug release. The excellent biocompatibility and great AIE property and two-photon excitation endow these functional mPEG-b-PLG (Se)-TP micelles as bioprobes for the two-photon imaging of cells and deeper tissues. Furthermore, the biodistribution of nanocarriers and intracellular drug delivery can also be traced. Moreover, the Cur-loaded micelles also show great tumor inhibition ability and minimal side effects in vivo compared with free drug. These novel polymeric micelles are expected to be potential candidates for cancer theranostics.

Polymeric Micellar Formulation Enhances Antimicrobial and Anticancer Properties of Salinomycin.

Salinomycin (SAL) is a polyether compound that exhibits strong antimicrobial as well as anticancer activity. Nanomedicine has been at the forefront of drug delivery research with the aim of increasing the efficacy, specificity and reduce toxicity of drugs. There is an intersection between infection and cancer, and cancer patients are prone to bacterial infections. In this study, polymeric micelles were prepared using Pluronic® F127 (PM) to encapsulate SAL (PM_SAL) with the view of enhancing antimicrobial and anticancer activity. A Quality by Design (QbD) approach was utilized to synthesize PM_SAL, and nanoformulation activity was determined against bacterial (S. aureus, MRSA and E. coli). Effects on cancer cell line A549, i.e. cell viability, prevention of P-gp efflux, vimentin expression, effects on migratory ability of A549 cells. Anticancer activity was determined by ability to eradicate cancer stem-like cells. PM_SAL demonstrated only efficacy against MRSA, being even higher than that obtained with SAL. In A549 cells, a 15-fold increase in P-gp's expression as well as a significant decrease of the cell's migration, was observed. PM_SAL can interfere with the oncogenic protein VIM, involved in the crucial mechanisms EMT, downregulating its expression. Altogether data obtained indicates that this antibiotic and the developed polymeric micelle system is a very promising inhibitor of tumor cell growth.