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Chemo-immunotherapy has made significant progress in cancer treatment. However, the cancer cell self-defense mechanisms, including cell cycle checkpoint and programmed cell death-ligand 1 (PD-L1) upregulation, have greatly hindered the therapeutic efficacy. Herein, norcantharidin (NCTD)-platinum (Pt) codelivery nanoparticles (NC-NP) with tumor-sensitive release profiles are designed to overcome the self-defense mechanisms via synergistic chemo-immunotherapy. NC-NP remains stable under normal physiological conditions but quickly releases 1,2-diaminocyclohexane-platinum(II) (DACHPt, a parent drug of oxaliplatin) and NCTD in response to the tumor acidity. NCTD inhibits protein phosphatase 2A (PP2A) activity to relieve cell cycle arrest and downregulates the tumor PD-L1 expression to disrupt the programmed cell death-1 (PD-1)/PD-L1 interaction, synergistically enhancing Pt-based chemotherapy and immunogenic cell death-induced immunotherapy. As a result, NC-NP exhibits potent synergistic cytotoxicity and promotes T cell recruitment to generate robust antitumor immune responses. The dual synergism exhibits potent antitumor activity against orthotopic 4T1 tumors, providing a promising chemo-immunotherapy paradigm for cancer treatment. [ABSTRACT FROM AUTHOR]

The use of phytochemicals for purpose of cancer therapy has been accelerated due to resistance of tumor cells to conventional chemotherapy drugs and therefore, monotherapy does not cause significant improvement in the prognosis and survival of patients. Therefore, administration of natural products alone or in combination with chemotherapy drugs due to various mechanisms of action has been suggested. However, cancer therapy using phytochemicals requires more attention because of poor bioavailability of compounds and lack of specific accumulation at tumor site. Hence, nanocarriers for specific delivery of phytochemicals in tumor therapy has been suggested. The pharmacokinetic profile of natural products and their therapeutic indices can be improved. The nanocarriers can improve potential of natural products in crossing over BBB and also, promote internalization in cancer cells through endocytosis. Moreover, (nano)platforms can deliver both natural and synthetic anti-cancer drugs in combination cancer therapy. The surface functionalization of nanostructures with ligands improves ability in internalization in tumor cells and improving cytotoxicity of natural compounds. Interestingly, stimuli-responsive nanostructures that respond to endogenous and exogenous stimuli have been employed for delivery of natural compounds in cancer therapy. The decrease in pH in tumor microenvironment causes degradation of bonds in nanostructures to release cargo and when changes in GSH levels occur, it also mediates drug release from nanocarriers. Moreover, enzymes in the tumor microenvironment such as MMP-2 can mediate drug release from nanocarriers and more progresses in targeted drug delivery obtained by application of nanoparticles that are responsive to exogenous stimulus including light.

Dendritic cells (DCs), the primary antigen-presenting cells in the immune system, play a critical role in regulating tumor immune responses. However, the tumor immunosuppressive microenvironment severely impedes the process of antigen-presenting and DC maturation, thereby limiting the efficacy of cancer immunotherapy. In this work, a pH-responsive polymer nanocarrier (PAG) modified with aminoguanidine (AG) was constructed for the efficient delivery of bortezomib (BTZ) through bidentate hydrogen bonds and electrostatic adsorption formed between guanidine groups of PAG and boronic acid groups of BTZ. The obtained PAG/BTZ nanoparticles exhibited pH-responsive release of BTZ and AG in the acidic tumor microenvironment. On the one hand, BTZ induced potent immune activation by eliciting immunogenic cell death (ICD) and releasing damage-associated molecular patterns. On the other hand, the cationic AG significantly promoted antigen uptake by DCs and activated DC maturation. As a result, PAG/BTZ significantly stimulated tumoral infiltration of cytotoxic T lymphocytes (CTLs) and triggered robust antitumor immune responses. Thus, it showed potent antitumor efficacy when synergizing with an immune checkpoint-blocking antibody. A pH-responsive aminoguanidine (AG)-modified nanoparticle (PAG/BTZ) for tumoral delivery of bortezomib (BTZ) was fabricated successfully to improve the chemo-immunotherapy efficacy by eliciting immunogenic cell death (ICD), promoting dendritic cells (DCs) maturation, and synergizing with an immune checkpoint-blocking antibody (α-PDL1). [Display omitted] • The PAG/BTZ nanoparticles induced strong tumor immunogenic cell death to increase the immunogenicity. • The PAG/BTZ nanoparticles improved chemo-immunotherapy efficacy by activating DCs and promoting their maturation. • The PAG/BTZ showed potent antitumor efficacy when synergizing with an immune checkpoint-blocking antibody (αPD-L1). [ABSTRACT FROM AUTHOR]

Polymeric nanoparticles (NPs) play an important role in controlled cancer drug delivery. Anticancer drugs can be conjugated or encapsulated by polymeric nanocarriers, which are known as polymeric nanomedicine. Polymeric nanomedicine has shown its potential in providing sustained release of drugs with reduced cytotoxicity and modified tumor retention, but until now, few delivery systems loading drugs have been able to meet clinical demands, so more efforts are needed. This research reviews the current state of the cancer drug-loading system by exhibiting a series of published articles that highlight the novelty and functions from a variety of different architectures including micelles, liposomes, dendrimers, polymersomes, hydrogels, and metal–organic frameworks. These may contribute to the development of useful polymeric NPs to achieve different therapeutic purposes.

Stimuli-responsive polymers as drug delivery vehicles have generated remarkable interest among polymer researchers during the last decade. In the present work, we report the synthesis of a new water soluble pH- and thermo-responsive biocompatible block copolymer containing phenylalanine derivatives. The block copolymer formed micelle-like self-assembled nanoparticles above critical aggregation concentration, as confirmed from fluorescence spectroscopy, DLS, and AFM studies. The self-assembly behavior was dependent on the pH and temperature of the aqueous media. These self-assembled micellar nanoparticles were capable of encapsulating hydrophobic drugs as demonstrated by the significantly higher loading capacity value of Doxorubicin (DOX) compared to commonly reported values in the literature. The release of DOX from the nanoparticles was favored at lower pH and higher temperature, a condition prevalent in cancer cells. Biocompatibility of the block copolymer and the effectiveness of the nanoparticles in potential cancer therapy were established by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) studies using non-cancerous murine fibroblasts L929 cells and breast cancer cell line MDA MB 231 at 37 °C and 42 °C. The cytotoxicity of DOX loaded polymer nanoparticles was found to be more effective at 42 °C compared to 37 °C. Thus, these micellar nanoparticles hold promise in drug delivery application in cancer therapy. [ABSTRACT FROM AUTHOR]

Introduction: As a protein-based biomaterial for potential cancer targeting delivery, apoferritin has recently attracted interest.Areas covered: In this review, we discuss the development of this cage-like protein as an endogenous nanocarrier that can hold molecules in its cavity. We present the specific characterizations and formulations of apoferritin nanocarriers, and outline the recent progress of the protein as an appropriate tumor-delivery vehicle in different therapeutic strategies to treat solid tumors. Finally, we propose how the application for cancer drug repurposing delivery within apoferritin could expand cancer treatment in the future.Expert opinion: Being a ubiquitous iron storage protein that exists in many living organisms, apoferritin is promising as a cancer tumor-targeting nanocarrier. By exploiting its versatility, apoferritin could be used for cancer repurposed drug delivery and could reduce the high cost of new drug discovery development and shorten the formulation process. [ABSTRACT FROM AUTHOR]

Cisplatin (CDDP) is a potent first-line antitumor drug but suffers severe side effects and poor pharmacokinetics. Its complexation with polycarboxylic acids, such as polyglutamic acids, is generally used to fabricate nanoformulations for CDDP delivery; however, the multiple strong complexations makes intracellular drug release slow. Herein, we report a novel polyphenol-metal coordination method to fabricate CDDP-incorporated core-shell nanoparticles, which are stable in blood circulation but dissociate in the tumor. Methoxyl-PEG terminated with one or two gallic acids (PEG-GA or PEG-GA2) complexed CDDP and produced well-defined nanoparticles (PEG-GAx/Pt) with CDDP loading contents as high as 17.7% to 29.8%. The PEG-GAx/Pt nanoparticles were very stable in the physiological conditions and had slow blood clearance and efficient tumor accumulation, but dissociated quickly and released CDDP in response to the tumor acidity or elevated levels of reactive oxygen species (ROS). PEG-GAx/Pt nanoparticles exhibited improved antitumor efficiency against 4 T1 breast cancer and A549 lung carcinoma with much-reduced toxicity compared to free CDDP. The work demonstrates a new strategy of cisplatin-polyphenol coordination for developing platinum drugs' nanomedicines. Unlabelled Image [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are a heterogeneous population of lipid bilayer membrane-enclosed vesicles and act like 'messages in a bottle' in cell-cell communication by transporting their cargoes to recipient cells. Small EVs (sEVs, < 200 nm) are highly researched recently and have been harnessed as novel delivery systems for the treatment of various diseases, including neurodegenerative disorders, cardiovascular diseases, and most importantly cancer primarily because of their non-immunogenicity, tissue penetration and cell-tropism. This review will first provide a comprehensive overview of sEVs regarding the current understanding on their properties, biogenesis, new classification by the ISEV, composition, as well as their roles in cancer development (thereby called "oncosomes"). The primary focus will be given to the current state of sEVs as natural nanocarriers for cancer drug delivery, the technologies and challenges involved in sEV isolation and characterization, therapeutic cargo loading, and surface modification to enhance tumor-targeting. We will also provide examples of sEV products under clinical trials. Furthermore, the current challenges as well as the advance in "sEV mimetics" to address some of the sEVs limitations is briefly discussed. We seek to advance our understanding of sEVs to unlock their full potential as superior drug delivery vehicles in cancer therapy. [ABSTRACT FROM AUTHOR]

Therapeutic responses to chimeric antigen receptor (CAR) T cell therapy in patients with limited treatment options have been appealing in several clinical trials. However, the efficacy of CAR‐T therapy has been challenged by several obstacles when treating patients with solid tumors, such as severe toxicities, restricted access to tumor sites, suboptimal therapeutic persistence, and manufacturing issues. Nanotechnology has the advantages of protecting CAR‐T cells from being suppressed by tumor microenvironment (TME) and favorably adapting immune‐modulating drugs' pharmacokinetics by modifying their spatiotemporal release profiles. Loaded with nanoparticles and packed onto CAR‐T cells, immune‐modulating drugs can be delivered to the tumor site and lymph node more efficiently, stimulating the expansion and activity of CAR‐T cells. To protect normal tissues from the nonspecific toxicity of the activated CAR‐T cells, formulations are optimized toward tumor targeting delivery of nanotechnology. This review summarizes the nanotechnology strategies to improve the safety and efficacy of CAR‐T therapy. In addition, the unsolved problems existing in the clinical application of CAR‐T therapy are focused on, where study and exploration by the way of nanotechnology is needed. [ABSTRACT FROM AUTHOR]

The field of nanomedicine shows promising implications in the concurrent delivery of therapeutic and diagnostic (theranostics) compounds in a single platform. Nanotheranostics is incredibly promising since it offers simultaneous non-invasive disease detection and treatment together with the exciting ability to track drug release and distribution in real-time, thereby forecasting and evaluating the efficacy of the therapy. The cancer theranostic approach improves the cancer prognosis safely and effectively. Common classes of nanoscale biomaterials, including magnetic nanoparticles, quantum dots, upconversion nanoparticles, mesoporous silica nanoparticles, carbon- based nanoparticles, and organic dye-based nanoparticles, have demonstrated enormous potential for theranostic activity. The need for improved disease detection and enhanced chemotherapeutic treatments, together with realistic considerations for clinically translatable nanomaterials will be key driving factors for theranostic agent research shortly. The developments of precision theranostic nanomaterials are employed in imaging systems like, MRI, PET, and SPECT with multifunctional ability. In this review, different nanoparticles/nanomaterials that are used/developed for theranostic activity are discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

• Investigation of Nano-Ghosts manufacturing-process robustness. • Examination of post-production shelf-life through stability and storage studies. • Demonstration of NGs labelling methods and loading of different therapeutics. Currently, nano-carriers for anti-cancer drug delivery are complex systems, which struggle with immunogenicity and enhanced permeability effect (EPR)-related problems that halt the clinical translation of many therapeutics. Consequently, a rapidly growing field of research has been focusing on biomimetic nano-vesicles (BNVs) as an effective delivery alternative. Nevertheless, the translation of many BNVs is limited due to scalability problems, inconsistent production process, and insufficient loading efficiency. Here we discuss the process of our previously published BNVs, termed Nano-Ghosts (NGs), which are produced from the membrane of mesenchymal stem cells. We demonstrate the flexibility of the process, while alternating physical methodologies (sonication or extrusion) to produce the NGs while preserving their desired characteristics. We also show that our NGs can be labeled using multiple methods (fluorescence, radiolabeling, and genetic engineering) for tracking and diagnostic purposes. Lastly, we demonstrate that the loading efficiency can be improved by using electroporation to accommodate a range of therapeutics (small molecules, peptides and DNA) that can be delivered by the NGs. Our results emphasize the robustness of the NGs technology, its versatility and a vast range of applications, differentiating it from other BNVs and leading the way towards clinical translation. [ABSTRACT FROM AUTHOR]

Abstract Porous and biodegradable hyaluronic acid (HA) nanogel and their copolymeric forms with sucrose (Suc), HA:Sucrose (HA:Suc) nanogels, were synthesized by employing glycerol diglycidyl ether (GDE) as crosslinker with a single step reaction in surfactant-free medium. The size of the nanogels was determined as 150 ± 50 nm in dried state from SEM images and found to increase to about 540 ± 47 nm in DI water measured with DLS measurements. The surface areas of HA and HA:Suc nanogels were measured as 18.07 ± 2.4 and 32.30 ± 6.1 m2/g with porosities of 3.58 ± 1.8, and 9.44 ± 3.1 nm via BET analysis, respectively. The zeta potentials for HA and HA:Suc nanogels were measured as −33 ± 1.4 and − 30 ± 1.2 mV, respectively. The thermal degradation of both types of nanogels revealed similar trends, while hydrolytic degradation of the nanogels was about 22.7 ± 0.2 wt% in 15 days. Both HA and HA:Suc nanogels were stable in blood up to 250 μg/mL concentration with approximately 0.5 ± 0.1% hemolysis ratio and 76 ± 12% blood clotting indices, respectively. Finally, these nanogels were used as a sustained slow-release or long-term delivery system over 2 days for a hydrophobic cancer drug, 3‑((E)‑3‑(4‑hydroxyphenyl)acryloyl)‑ 2H ‑chromen‑2‑on (A#) established by our group. The nanogels successfully delivered the model drug A at 10.43 ± 2.12 mg/g for 2 days. Highlights • Facile synthesis of HA and HA:Suc nanogels in a surfactant free environment with high yield • HA based nanogels with few hundred nm sizes, irregular shaped, mesoporous structure • HA:Suc nanogels as biodegradable, blood compatible and cancer drug delivery device [ABSTRACT FROM AUTHOR]

The use of phytochemicals for purpose of cancer therapy has been accelerated due to resistance of tumor cells to conventional chemotherapy drugs and therefore, monotherapy does not cause significant improvement in the prognosis and survival of patients. Therefore, administration of natural products alone or in combination with chemotherapy drugs due to various mechanisms of action has been suggested. However, cancer therapy using phytochemicals requires more attention because of poor bioavailability of compounds and lack of specific accumulation at tumor site. Hence, nanocarriers for specific delivery of phytochemicals in tumor therapy has been suggested. The pharmacokinetic profile of natural products and their therapeutic indices can be improved. The nanocarriers can improve potential of natural products in crossing over BBB and also, promote internalization in cancer cells through endocytosis. Moreover, (nano)platforms can deliver both natural and synthetic anti-cancer drugs in combination cancer therapy. The surface functionalization of nanostructures with ligands improves ability in internalization in tumor cells and improving cytotoxicity of natural compounds. Interestingly, stimuli-responsive nanostructures that respond to endogenous and exogenous stimuli have been employed for delivery of natural compounds in cancer therapy. The decrease in pH in tumor microenvironment causes degradation of bonds in nanostructures to release cargo and when changes in GSH levels occur, it also mediates drug release from nanocarriers. Moreover, enzymes in the tumor microenvironment such as MMP-2 can mediate drug release from nanocarriers and more progresses in targeted drug delivery obtained by application of nanoparticles that are responsive to exogenous stimulus including light. [Display omitted] [ABSTRACT FROM AUTHOR]

Chemo-immunotherapy has made significant progress in cancer treatment. However, the cancer cell self-defense mechanisms, including cell cycle checkpoint and programmed cell death-ligand 1 (PD-L1) upregulation, have greatly hindered the therapeutic efficacy. Herein, norcantharidin (NCTD)-platinum (Pt) codelivery nanoparticles (NC-NP) with tumor-sensitive release profiles are designed to overcome the self-defense mechanisms via synergistic chemo-immunotherapy. NC-NP remains stable under normal physiological conditions but quickly releases 1,2-diaminocyclohexane-platinum(II) (DACHPt, a parent drug of oxaliplatin) and NCTD in response to the tumor acidity. NCTD inhibits protein phosphatase 2A (PP2A) activity to relieve cell cycle arrest and downregulates the tumor PD-L1 expression to disrupt the programmed cell death-1 (PD-1)/PD-L1 interaction, synergistically enhancing Pt-based chemotherapy and immunogenic cell death-induced immunotherapy. As a result, NC-NP exhibits potent synergistic cytotoxicity and promotes T cell recruitment to generate robust antitumor immune responses. The dual synergism exhibits potent antitumor activity against orthotopic 4T1 tumors, providing a promising chemo-immunotherapy paradigm for cancer treatment., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Malignant melanoma is the most lethal form of skin cancer in humans which is difficult to treat by conventional surgery and chemotherapeutics. Despite unquestionable progresses in recent years demonstrated by anticancer drug carriers to target tumor local microenvironment, it is growing at a rate of one million new cases being reported annually because overcoming the skin physiological barriers and the side effects associated with chemotherapy still remain threatening challenges. Herein, we designed and developed a novel polysaccharide-based prodrug composed of carboxymethylcellulose (CMC) polymer with anticancer drug doxorubicin (DOX) forming electrostatic nanocomplexes in aqueous solution. The results evidenced the effect of degree of substitution (DS = 0.77 and 1.22) of CMC on the physicochemical properties of the CMC-DOX complexes associated with the formation of supramolecular colloidal nanostructures. They were stabilized by electrostatic interactions between anionic carboxylate groups from CMC and cationic amino groups of DOX while the polysaccharide polymer chain encapsulated the hydrophobic drug in the aqueous medium. Moreover, these polymer-drug nanoparticulate systems were crosslinked with citric acid for producing advanced tuned drug delivery hydrogels. The results demonstrated the effect of DS of CMC and the addition of DOX on the physicochemical properties of the hydrogel network structures produced including the swelling behavior and gel fraction. Moreover, the distinct DS of CMC tailored the DOX release kinetics in vitro showing activity for killing melanoma cancer cells while less cytotoxicity towards normal cells. To this end, an innovative platform was developed based on colloidal polysaccharide-drug nanocomplexes producing anticancer hydrogels offering promising perspectives for skin cancer applications using transdermal drug delivery chemotherapy. [ABSTRACT FROM AUTHOR]

A pH-responsive polymer derived from polyethyleneimine with zwitterionic function was used as a shell around super paramagnetic iron oxide nanoparticles (SPIONs), to introduce an efficient drug carrier for cancer drug delivery and imaging. Core-shell magnetic Fe3O4@FA-PEI-SUC (SUC: Succinate conjugated) nanoparticles were attained and characterized. Right chemical attachments, 61.34% modification of primary amino groups of poly(ethyleneimine) (PEI) in PEI-SUC, spherical shape, core-shell structure, crystal structure of SPIONs, 18.23% polymer coating of NPs, 8% decrease in magnetization following polymer coating around SPIONs, doxorubicin loading efficiency 85.19%, two times more released amount in acidic pH, and proper toxicity results were obtained by different analysis methods. [ABSTRACT FROM AUTHOR]

Abstract: The recent emergence of biomimetic nanotechnology has facilitated the development of next‐generation nanodelivery systems capable of enhanced biointerfacing. In particular, the direct use of natural cell membranes can enable multivalent targeting functionalities. Herein, this study reports on the remote loading of small molecule therapeutics into cholesterol‐enriched platelet membrane‐derived vesicles for disease‐targeted delivery. Using this approach, high loading yields for two model drugs, doxorubicin and vancomycin, are achieved. Leveraging the surface markers found on platelet membranes, the resultant nanoformulations demonstrate natural affinity toward both breast cancer cells and methicillin‐resistant Staphylococcus aureus. In vivo, this translates to improved disease targeting, increasing the potency of the encapsulated drug payloads compared with free drugs and the corresponding nontargeted nanoformulations. Overall, this work demonstrates that the remote loading of drugs into functional platelet membrane‐derived vesicles is a facile means of fabricating targeted nanoformulations, an approach that can be easily generalized to other cell types in the future. [ABSTRACT FROM AUTHOR]

Paclitaxel (PTX) is one of the most effective anticancer drugs for the treatment of various solid tumors, but its clinical use is limited by its poor solubility, low bioavailability, and severe systemic toxicity. Encapsulation of PTX in polymeric nanoparticles is used to overcome these problems but these micelles still need improvements in stability, pharmacokinetics, therapeutic efficacy, and safety profiles. In this study, we demonstrate a facile fabrication of a stable PTX-binding micelle made from poly (ethylene glycol)-block-dendritic polylysine, whose primary amines were reacted with phenethyl isothiocyanate (PEITC), a hydrophobic anticancer agent under clinical study. The amphiphilic conjugate (PEG-Gx-PEITC; Gx, the generation of the polylysine dendron) formed well-defined micelles whose core was composed of phenyl groups and thiourea groups binding PTX via π-π stacking and hydrogen bonding. Compared with the PTX-loaded poly(ethylene glycol)-block-poly(D,L-lactide) (PEGPDLLA/ PTX) micelles in clinical use, PTX-loaded PEG-Gx-PEITC third-generation (PEG-G3-PEITC/PTX) micelles showed slowed blood clearance, enhanced tumor accumulation, and thus much improved in vivo therapeutic efficacy in both subcutaneous and orthotopic human breast cancer xenografts. Therefore, PEG-G3-PEITC is a promising drug delivery system for PTX in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Oxazaphosphorines including cyclophosphamide, trofosfamide and ifosfamide (IFO) belong to the alkylating agent class and are indicated in the treatment of numerous cancers. However, IFO is subject to limiting side-effects in high-dose protocols. To circumvent IFO drawbacks in clinical practices, preactivated IFO analogs were designed to by-pass the toxic metabolic pathway. Among these IFO analogs, some of them showed the ability to self-assemble due to the use of a poly-isoprenyloxy chain as preactivating moiety. We present here, the in vitro activity of the nanoassembly formulations of preactivated IFO derivatives with a C-4 geranyloxy, farnesyloxy and squalenoxy substituent on a large panel of tumor cell lines. The chemical and colloidal stabilities of the geranyloxy-IFO (G-IFO), farnesyloxy-IFO (F-IFO) and squalenoxy-IFO (SQ-IFO) NAs were further evaluated in comparison to their free formulation. Finally, pharmacokinetic parameters and maximal tolerated dose of the most potent preactivated IFO analog (G-IFO) were determined and compared to IFO, paving the way to in vivo studies. [ABSTRACT FROM AUTHOR]

Tumor vessels are leaky and immature, which causes poor oxygen and nutrient supply to tumor vessels and results in cancer cell metastasis to distant organs. This instability of tumor blood vessels also makes it difficult for anticancer drugs to penetrate and reach tumors. Numerous tumor vessel normalization approaches have been investigated for improving drug delivery into tumors. In this study, we investigated whether phosphoinositide 3-kinase (PI3K) inhibitors are able to improve vascular structure and function over the prolonged period necessary to achieve effective vessel normalization. The PI3K inhibitors, HS-173 and BEZ235 potently suppressed tumor growth and hypoxia, and increased tumor apoptosis in animal models. PI3K inhibitors also induced a regular, flat monolayer of endothelial cells (ECs) in vessels, improving stability of vessel structure, and normalized tumor vessels by increasing vascular maturity, pericyte coverage, basement membrane thickness, and tight-junctions. These effects resulted in a decrease in tumor vessel tortuosity and vessel thinning, and improved vessel function and blood flow. The tumor vessel stabilization effect of the PI3K inhibitor HS-173 also decreased the number of metastatic lung nodules in vivo metastasis model. Furthermore, HS-173 improved the delivery of doxorubicin into the tumor region, enhancing its anticancer effects. Mechanistic studies suggested that PI3K inhibitor HS-173-induced vessel normalization reflected changes in endothelial Notch signaling. Taken together, our findings indicate that vessel normalization by PI3K inhibitors restrained tumor growth and metastasis while improving chemotherapy by enhancing drug delivery into the tumor, suggesting that HS-173 may have a therapeutic value as an enhancer or an anticancer drug. [ABSTRACT FROM AUTHOR]

[Display omitted] Over the past three decades, the enhanced permeability and retention (EPR) effect has been considered the basis of tumor-targeted drug delivery. Various cancer nanomedicines, including macromolecular drugs, have been designed to utilize this mechanism for preferential extravasation and accumulation in solid tumors. However, such nanomedicines have not yet achieved convincing therapeutic benefits in clinics. Increasing evidence suggests that the EPR effect is over-represented in human tumors, especially in metastatic tumors. This review covers the evolution of the concept, the heterogeneity and limitation of the EPR effect in clinical realities, and prospects for alternative strategies independent of the EPR effect. [ABSTRACT FROM AUTHOR]

[Display omitted] • Superior results are found when conventional therapeutic approaches are combined with inorganic nanoparticle (INP) strategies. • INPs possess intrinsic anticancer and gene silencing properties, which make them advantageous in cancer therapy when used in combination with other agents. • INPs are highly customized, safe and effective RNA delivery vehicles that overcome the challenges associated with employing RNA as a therapeutic candidate owing to concerns about in vivo stability. • Signaling pathway targeting is challenging, hence a more efficient strategy is required. • Efficient delivery carriers, such as INP, are necessary to increase the selectivity of target CSCs or CSC signaling pathways. Inorganic nanoparticles for drug delivery in cancer treatment offer many potential advantages because they can maximize therapeutic effect through targeting ligands while minimizing off-target side-effects through drug adsorption and infiltration. Although inorganic nanoparticles were introduced as drug carriers, they have emerged as having the capacity for combined therapeutic capabilities, including anticancer effects through cytotoxicity, suppression of oncogenes and cancer cell signaling pathway inhibition. The most promising advanced strategies for cancer therapy are as synergistic platforms for RNA interference (siRNA, miRNA, shRNA) and as synergistic drug delivery agents for the inhibition of cancer cell signaling pathways. The present work summarizes relevant current work, the promise of which is suggested by a projected compound annual growth rate of ∼ 20% for drug delivery alone. [ABSTRACT FROM AUTHOR]

A novel pH and thermosensitive magnetic nanoparticle polymer composite [poly(NIPAAM@Fe 3 O 4 MNPs/TMSPMC/DOX)] was synthesized by radical polymerization of N -isopropylacrylamide (NIPAAM) and the methacrylate functionalized Fe 3 O 4 nanoparticles/DOX complex using AIBN and EGDMA, and used as a drug carrier for the DOX drug delivery. Formation of poly(NIPAAM@Fe 3 O 4 MNPs/TMSPMC/DOX) was confirmed by FTIR, XRD, UV–Vis, VSM, TGA–DTA and SEM. The results showed the high DOX loading controls release. Moreover, it showed the lower critical solution temperature of 40 °C which can be beneficial in cancer drug delivery, since the temperature of cancer cells is higher than normal ones, and DOX can be released selectively in cancer cells. [ABSTRACT FROM AUTHOR]

ABSTRACT Polyethylene glycol (PEG) is widely used as a carrier to improve the pharmaceutical properties of drugs with low molecular weight. However, PEG has few functional groups (usually two) for drug conjugation and the resulting low drug content (1-2%) has hampered its clinical applications. For this study, we synthesized biodegradable poly(ethylene glycol- co-anhydride). This polyester-based polymer possesses multiple carboxylic acid groups that can be used as facile drug carriers. Two anticancer drugs, camptothecin (CPT) and doxorubicin (DOX) were loaded into the carrier and their releasing properties and in vitro anticancer activities were studied. The polymer-drug conjugates exhibited esterase-promoted degradation and drug release. Their cytotoxicity against the human ovarian cancer cell line SKOV-3 was comparable to unconjugated drugs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 507-515 [ABSTRACT FROM AUTHOR]

Abstract: It is 40years since cancer growth was correlated with neovascularisation. Anti-angiogenic drugs remain at the forefront of cancer investigations but progress has been disappointing and unexpected toxicities are emerging. Gap junction channels are implicated in lesion spread following injury, with channel blockers shown to improve healing; in particular preventing vascular disruption and/or restoring vascular integrity. Here we briefly review connexin roles in vascular leak and endothelial cell death that occurs following acute wounds and during chronic disease, and how connexin channel regulation has been used to ameliorate vascular disruption. We then review chronic inflammatory disorders and trauma in the eye, concluding that vascular disruption under these conditions mimics that seen in tumours, and can be prevented with connexin hemichannel modulation. We apply this knowledge to tumour vessel biology, proposing that contrary to current opinion, these data suggest a need to protect, maintain and/or restore cancer vasculature. This may lead to reduced tumour hypoxia, promote the survival of normal cells, and enable improved therapeutic delivery or more effective radiation therapy. [Copyright &y& Elsevier]