Glioma targeting peptide modified apoferritin nanocage

Therapeutic outcome for the treatment of glioma was often limited due to the non-targeted nature of drugs and the physiological barriers, including the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). An ideal glioma-targeted delivery system must be sufficiently potent to cross the BBB and BBTB and then target glioma cells with adequate optimized physiochemical properties and biocompatibility. However, it is an enormous challenge to the researchers to engineer the above-mentioned features into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. In this study, we demonstrate a strategy for glioma targeting by encapsulating vincristine sulfate (VCR) into a naturally available apoferritin nanocage-based drug delivery system with the modification of GKRK peptide ligand (GKRK-APO). Apoferritin (APO), an endogenous nanosize spherical protein, can specifically bind to brain endothelial cells and glioma cells via interacting with the transferrin receptor 1 (TfR1). GKRK is a peptide ligand of heparan sulfate proteoglycan (HSPG) over-expressed on angiogenesis and glioma, presenting excellent glioma-homing property. By combining the dual-targeting delivery effect of GKRK peptide and parent APO, GKRK-APO displayed higher glioma localization than that of parent APO. After loading with VCR, GKRK-APO showed the most favorable antiglioma effect in vitro and in vivo. These results demonstrated that GKRK-APO is an important potential drug delivery system for glioma-targeted therapy.     

Glucose transporter and folic acid receptor-mediated Pluronic P105 polymeric micelles loaded with doxorubicin for brain tumor treating

Abstract

In this study, glucose transporter and folic acid (FA) receptor-mediated Pluronic P105 polymeric micelles loaded with DOX (GF-DOX) were prepared for enhancing the blood–brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. The pH-triggered DOX release of GF-DOX indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The transport of GF-DOX across the in vitro BBB model showed that GF-DOX exhibited higher BBB transportation ability with the transporting ratio of 21.47% in 4?h. The carrier was internalized into C6 glioma cells upon crossing the BBB model for the combined effect of the brain targeting by transportation of glucose transporter and active tumor cell targeting by FA receptor-mediated endocytosis. Moreover, minimized weight changes and high suppression ratio of tumor growth were observed after intravenous injection of GF-DOX. In conclusion, the glucose transporter and FA dual-targeting micelles would provide a safe and effective strategy for new modalities to treat brain tumor.     

Co-delivery of doxorubicin and siRNA for glioma therapy by a brain targeting system: angiopep-2-modified poly(lactic-co-glycolic acid) nanoparticles

It is very challenging to treat brain cancer because of the blood–brain barrier (BBB) restricting therapeutic drug or gene to access the brain. In this research project, angiopep-2 (ANG) was used as a brain-targeted peptide for preparing multifunctional ANG-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which encapsulated both doxorubicin (DOX) and epidermal growth factor receptor (EGFR) siRNA, designated as ANG/PLGA/DOX/siRNA. This system could efficiently deliver DOX and siRNA into U87MG cells leading to significant cell inhibition, apoptosis and EGFR silencing in vitro. It demonstrated that this drug system was capable of penetrating the BBB in vivo, resulting in more drugs accumulation in the brain. The animal study using the brain orthotopic U87MG glioma xenograft model indicated that the ANG-targeted co-delivery of DOX and EGFR siRNA resulted in not only the prolongation of the life span of the glioma-bearing mice but also an obvious cell apoptosis in glioma tissue.     

Salmonella-mediated blood‒brain barrier penetration,tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy

Chemotherapy is an important adjuvant treatment of glioma, while the efficacy is far from satisfactory, due not only to the biological barriers of blood?brain barrier (BBB) and blood?tumor barrier (BTB) but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as up-regulation of P-glycoprotein (P-gp). To address these limitations, we report a bacteria-based drug delivery strategy for BBB/BTB transportation, glioma targeting, and chemo-sensitization. Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment, including macrophages repolarization and neutrophils infiltration. Specifically, tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin (DOX)-loaded bacterial outer membrane vesicles (OMVs/DOX). By virtue of the surface pathogen-associated molecular patterns derived from native bacteria, OMVs/DOX could be selectively recognized by neutrophils, thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting effect. Moreover, the P-gp expression on tumor cells was silenced by bacteria type III secretion effector to sensitize the efficacy of DOX, resulting in complete tumor eradication with 100% survival of all treated mice. In addition, the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk, and cardiotoxicity of DOX was also avoided, achieving excellent compatibility. This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.     

The use of a new functional glucose conjugate material,TPGS1000-Glu,in treatment of brain glioma by incorporating into epirubicin liposomes

Most of anticancer agents can not be used for treatment of brain glioma due to the existence of the blood brain barrier (BBB). The over-expression of glucose transporters (GLUTs) on the BBB and brain glioma cells enables the possibility that the GLUTs ligand modified drug carrier transports across the BBB, and targets to the brain glioma cells. The objectives of the present study were to synthesize a new glucose conjugate material, TPGS₁₀₀₀-Glu, develop a kind of TPGS₁₀₀₀-Glu modified epirubicin liposomes, and evaluate their efficacy. The studies were performed on the BBB co-culture model and brain glioma cells in vitro. TPGS1000-Glu was synthesized by conjugating TPGS_1000-COOH with 4-aminophenyl-β-D-glucopyranoside (Glu), and confirmed by MALDI-TOF-MSspectrum. TPGS₁₀₀₀-Glu modified epirubicin liposomes were prepared with a high drug encapsulation efficiency (>97%), a nanosize (approximately 90 nm), and a minimal drug leakage in fetal bovine serum (FBS)-containing buffer system. The BBB co-culture model was established, and after applying TPGS₁₀₀₀-Glu modified epirubicin liposomes to the model, transport of liposomal drug across the BBB was evidenced. Besides, TPGS₁₀₀₀-Glu modified epirubicin liposomes showed the strongest cellular drug uptake and anti-glioma efficacy after transport across the BBB in vitro. The synthesized TPGS1000-Glu material could offer a new targeting ligand for the BBB, while the developed TPGS₁₀₀₀-Glu modified epirubicin liposomes might provide a potential anticancer formulation for treatment of brain glioma.     

Dual-targeting prodrug nanotheranostics for NIR-Ⅱ fluorescence imaging-guided photo-immunotherapy of glioblastoma

Glioblastoma (GBM) therapy is severely impaired by the blood–brain barrier (BBB) and invasive tumor growth in the central nervous system. To improve GBM therapy, we herein presented a dual-targeting nanotheranostic for second near-infrared (NIR-II) fluorescence imaging-guided photo-immunotherapy. Firstly, a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor (D-A-D) backbone was synthesized. Then, the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1 (JPC) and T7 ligand-modified PEG_5k-DSPE. T7 can cross the BBB for tumor-targeted delivery of JPC and MRP. JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells. MRP could generate NIR-II fluorescence to navigate 808 nm laser, induce a photothermal effect to trigger in-situ antigen release at the tumor site, and ultimately elicit antitumor immunogenicity. Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo. The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.     

Synergistic dual-modified liposome improves targeting and therapeutic efficacy of bone metastasis from breast cancer

Breast cancer frequently metastasizes to bone, where it leads to poor clinical prognosis. Due to the peculiarity of the bone microstructure, the uptake of drugs often happens at non-targeted sites, which produces a similar cytotoxicity in both cancerous and healthy cells. In this study, a rational strategy was implemented to take advantage of a combination of both an octapeptide with eight repeating sequences of aspartate (Asp₈) and folate to create a more selective and efficient drug delivery system to target cancer cells in bone tissue. Asp₈ and folate were conjugated to the distal ends of DSPE-PEG₂₀₀₀-maleimide and DSPE-PEG₂₀₀₀-amine to create DSPE-PEG₂₀₀₀-Asp₈ and DSPE-PEG₂₀₀₀-Folate, respectively, which were incorporated onto the surface of a doxorubicin (DOX)-loaded liposomes (A/F-LS). Asp₈, similar to the hydroxyapatite-binding domains of osteopontin and osteocalcin, has been used as bone-targeting moieties for exclusive delivery of drugs to bone. The folate moiety binds selectively to folate receptor-positive tumors. The dual-targeting effects were evaluated by both in vitro and in vivo experiments. By taking advantages of dual-targeting drug delivery, the dual-modified liposomal drug system could relieve pain and improve survival. Inspired by its enhanced therapeutic efficacy and low toxicity, DOX-loaded A/F-LS could serve as an effective drug system for targeted therapy of bone metastases.     

T7 peptide-functionalized nanoparticles utilizing RNA interference for glioma dual targeting

Among all the malignant brain tumors, glioma is the deadliest and most common form with poor prognosis. Gene therapy is regarded as a promising way to halt the progress of the disease or even cure the tumor and RNA interference (RNAi) stands out. However, the existence of the blood–brain barrier (BBB) and blood tumor barrier (BTB) limits the delivery of these therapeutic genes. In this work, the delivery system targeting to the transferrin (Tf) receptor highly expressed on both BBB and glioma was successfully synthesized and would not compete with endogenous Tf. U87 cells stably express luciferase were employed here to simulate tumor and the RNAi experiments in vitro and in vivo validated that the gene silencing activity was 2.17-fold higher with the targeting ligand modification. The dual-targeting gene delivery system exhibits a series of advantages, such as high efficiency, low toxicity, stability and high transaction efficiency, which may provide new opportunities in RNAi therapeutics and nanomedicine of brain tumors.     

A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified,DOX-loaded PAMAM dendrimer

Glioma is the most common primary malignant brain tumour and the effect of chemotherapy is hampered by low permeability across the blood–brain-barrier (BBB). Borneol is a time-honoured ‘Guide’ drug in traditional Chinese medicine and has been proved to be capable of promoting free drugs into the brain efficiently, but there are still risks that free drugs, especially anti-glioma drugs, may be disassembled and metabolised before penetrating the BBB and caused the whole brain distribution. The purpose of this paper was to investigate whether borneol intervention could facilitate the BBB penetration and assist glioma treatment by combining with doxorubicin (DOX) loaded PAMAM dendrimers drug delivery system modified with Angiopep-2 (a ligand of the low-density lipoprotein receptor-related protein, which overexpress both in the BBB and gliomas). The results demonstrated that Angiopep-2 modification could actually enhance the affinity between the dendrimers and the targeting cells and finally increase the cell uptake and boost the anti-tumour ability. Borneol physical combination could further enhance the anti-tumour efficiency of this targeting drug delivery system (TDDS) after penetrating BBB. Compared with free DOX solution, this TDDS illustrated obviously sustained and pH-dependent drug release. This suggested that this synergetic strategy provided a promising way for glioma therapy.     

MUC1 aptamer-targeted DNA micelles for dual tumor therapy using doxorubicin and KLA peptide

Targeted delivery of DNA nanoparticles is a promising approach in cancer therapy. Using aptamers, target specific delivery of DNA nanoparticles can be achieved. Further, aptamers can indirectly improve drug encapsulation efficiency of DNA nanoparticles for drugs intercalated within nucleic acid base pairs. Using DNA blocks, a micellar hybrid nanoparticle was prepared for the targeted co-delivery of doxorubicin and a pro-apoptotic peptide, KLA to tumor cells. Results demonstrated that anti-MUC1 aptamer could specifically deliver the synthesized DNA micelle into MCF-7 cells by improving its cellular uptake. Additionally, co-delivery of doxorubicin and KLA could significantly enhance the therapeutic efficacy of the construct resulting in reduction of required dose of doxorubicin that is a pivotal point in reducing chemotherapeutics side effects. Moreover, DOX–KLA–anti-MUC1–micelle remarkably inhibited tumor growth of tumor-bearing mice when compared with free drug. DOX–KLA–anti-MUC1–micelle also reduced toxic effect of free doxorubicin as determined by percent of body weight loss and survival rate in vivo.     

T7肽修饰共载多柔比星与miRNA脂质体的制备及其对结肠癌细胞的增殖抑制作用

目的 制备T7肽修饰共载多柔比星(DOX)与MIFsiRNA脂质体(T7-LPs-DOX/RNA),研究其对人源结肠癌细胞(RKO)的靶向抑制作用.方法 薄膜分散法制备脂质体,透射电镜观察其形态.流式细胞仪检测RKO细胞对不同脂质体的摄取效率和摄取机制.细胞克隆形成实验检测不同脂质体对RKO细胞存活率的影响.构建RKO细胞肿瘤球模型,观察T7-LPs-DOX/RNA对实体肿瘤球的穿透能力.结果 RKO细胞对T7-LPs的摄取效率显著强于普通脂质体,T7-LPs-DOX/RNA对RKO细胞增殖抑制作用强于其他脂质体(P＜0.05).经过T7肽修饰后,脂质体对肿瘤球的穿透能力显著增强.结论 T7-LPs-DOX/RNA是一种有效的结肠癌靶向给药系统.     

Combinatorial therapeutic strategies for enhanced delivery of therapeutics to brain cancer cells through nanocarriers: current trends and future perspectives

Brain cancer is the most aggressive one among various cancers. It has a drastic impact on people''s lives because of the failure in treatment efficacy of the currently employed strategies. Various strategies used to relieve pain in brain cancer patients and to prolong survival time include radiotherapy, chemotherapy, and surgery. Nevertheless, several inevitable limitations are accompanied by such treatments due to unsatisfactory curative effects. Generally, the treatment of cancers is very challenging due to many reasons including drugs’ intrinsic factors and physiological barriers. Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are the two additional hurdles in the way of therapeutic agents to brain tumors delivery. Combinatorial and targeted therapies specifically in cancer show a very promising role where nanocarriers’ based formulations are designed primarily to achieve tumor-specific drug release. A dual-targeting strategy is a versatile way of chemotherapeutics delivery to brain tumors that gets the aid of combined ligands and mediators that cross the BBB and reaches the target site efficiently. In contrast to single targeting where one receptor or mediator is targeted, the dual-targeting strategy is expected to produce a multiple-fold increase in therapeutic efficacy for cancer therapy, especially in brain tumors. In a nutshell, a dual-targeting strategy for brain tumors enhances the delivery efficiency of chemotherapeutic agents via penetration across the blood-brain barrier and enhances the targeting of tumor cells. This review article highlights the ongoing status of the brain tumor therapy enhanced by nanoparticle based delivery with the aid of dual-targeting strategies. The future perspectives in this regard have also been highlighted.     

Vincristine and temozolomide combined chemotherapy for the treatment of glioma: a comparison of solid lipid nanoparticles and nanostructured lipid carriers for dual drugs delivery

Context: Glioma is a common malignant brain tumor originating in the central nervous system. Efficient delivery of therapeutic agents to the cells and tissues is a difficult challenge. Co-delivery of anticancer drugs into the cancer cells or tissues by multifunctional nanocarriers may provide a new paradigm in cancer treatment.

Objective: In this study, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) were constructed for co-delivery of vincristine (VCR) and temozolomide (TMZ) to develop the synergetic therapeutic action of the two drugs. The antitumor effects of these two systems were compared to provide a better choice for gliomatosis cerebri treatment.

Methods: VCR- and TMZ-loaded SLNs (VT-SLNs) and NLCs (VT-NLCs) were formulated. Their particle size, zeta potential, drug encapsulation efficiency (EE) and drug loading capacity were evaluated. The single TMZ-loaded SLNs and NLCs were also prepared as contrast. Anti-tumor efficacies of the two kinds of carriers were evaluated on U87 malignant glioma cells and mice bearing malignant glioma model.

Results: Significantly better glioma inhibition was observed on NLCs formulations than SLNs, and dual drugs displayed the highest antitumor efficacy in vivo and in vitro than all the other formulations used.

Conclusion: VT-NLCs can deliver VCR and TMZ into U87MG cells more efficiently, and inhibition efficacy is higher than VT-SLNs. This dual drugs-loaded NLCs could be an outstanding drug delivery system to achieve excellent therapeutic efficiency for the treatment of malignant gliomatosis cerebri.     

Liposome formulated with TAT-modified cholesterol for improving brain delivery and therapeutic efficacy on brain glioma in animals

The treatment of central nervous system diseases such as brain glioma is a major challenge due to the presence of the blood-brain barrier (BBB). A cell-penetrating peptide TAT (AYGRKKRRQRRR), which appears to enter cells with alacrity, was employed to enhance the delivery efficiency of normal drug formulation to the brain. Targeting liposomal formulations often apply modified phospholipids as anchors. However, cholesterol, another liposomal component more stable and cheaper, has not been fully investigated as an alternative anchor. In our study, TAT was covalently conjugated with cholesterol for preparing doxorubicin-loaded liposome for brain glioma therapy. Cellular uptake by brain capillary endothelial cells (BCECs) and C6 glioma cells was explored. The anti-proliferative activity against C6s confirmed strong inhibitory effect of the liposomes modified with doxorubicin-loaded TAT. The bio-distribution findings in brains and hearts were evident of higher efficiency of brain delivery and lower cardiotoxic risk. The results on survival of the brain glioma-bearing animals indicate that survival time of the glioma-bearing rats treated with TAT-modified liposome was much longer than in the other groups. In conclusion, the potency of the TAT-modified liposome to enter the BBB appears to be related with the TAT on the liposome's surface. The TAT-modified liposome may improve the therapeutic efficacy on brain glioma in vitro and in vivo.     

Thermo-Sensitive Liposome co-Loaded of Vincristine and Doxorubicin Based on Their Similar Physicochemical Properties had Synergism on Tumor Treatment

Purpose

To develop vincristine (VCR) and doxorubicin (DOX) co-encapsulated thermo-sensitive liposomes (VD-TSL) against drug resistance, with increased tumor inhibition rate and decreased system toxicity, improving drug targeting efficiency upon mild hyperthermia (HT) in solid tumor.

Methods

Based on similar physicochemical properties, VCR and DOX were co-loaded in TSL with pH gradient active loading method and characterized. The time-dependent drug release profiles at 37 and 42°C were assessed by HPLC. Then we analysed the phospholipids in filtrate after ultrafiltration and studied VD-TSL stability in mimic in vivo conditions and long-time storage conditions (4°C and ?20°C). Cytotoxic effect was studied on PANC and sw-620 using MTT. Intracellular drug delivery was studied by confocal microscopy on HT-1080. In vivo imaging of TSL pharmacokinetic and biodistribution was performed on MCF-7 tumor-bearing nude mice. And therapeutic efficacy on these xenograft models were followed under HT.

Results

VD-TSL had excellent particle distribution (about 90 nm), high entrapment efficiency (>95%), obvious thermo-sensitive property, and good stability. MTT proved VD-TSL had strongest cell lethality compared with other formulations. Confocal microscopy demonstrated specific accumulation of drugs in tumor cells. In vivo imaging proved the targeting efficiency of TSL under hyperthermia. Then therapeutic efficacy revealed synergism of VCR and DOX co-loaded in TSL, together with HT.

Conclusion

VD-TSL could increase drug efficacy and decrease system toxicity, by making good use of synergism of VCR and DOX, as well as high targeting efficiency of TSL.

     

Amplification of anticancer efficacy by co-delivery of doxorubicin and lonidamine with extracellular vesicles

Chemotherapy is commonly used for the treatment of lung cancer, but strong side effects and low treatment efficacy limit its clinical application. Here, extracellular vesicles (EVs) as natural drug delivery carriers were used to load conventional anticancer drug doxorubicin (DOX) and a chemosensitizer lonidamine (LND). Two types of EVs with different sizes (16k EVs and 120k EVs) were prepared using different centrifugation forces. We found that co-delivery of DOX and LND with both EVs enhanced the cytotoxicity and reduced the dose of the anticancer drug significantly in vitro. Effective delivery of anti-cancer drugs to cancer cells was achieved by direct fusion of EVs with the plasma membrane of cancer cells. On the other hand, DOX and LND inhibited cancer cell proliferation by increasing DNA damage, suppressing ATP production, and accelerating ROS generation synergistically. DOX and LND loaded EVs were also applied to the mouse lung cancer model and exhibited significant anticancer activity. In vivo study showed that smaller EVs exhibited higher anticancer efficiency. In conclusion, the co-delivery of the anticancer drug and the chemosensitizer with EVs may have potential clinical applications for cancer therapy.     

Liposomal Co-Delivery of Omacetaxine Mepesuccinate and Doxorubicin for Synergistic Potentiation of Antitumor Activity

Purpose

Anticancer chemotherapy usually involves the administration of several anticancer drugs that differ in their action mechanisms. Here, we aimed to test whether the combination of omacetaxine mepesuccinate (OMT) and doxorubicin (DOX) could show synergism, and whether the liposomal co-delivery of these two drugs could enhance their antitumor effects in cervical carcinoma model.

Method

OMT-loaded liposomes (OL) were prepared by loading the drug in the lipid bilayers. OL were then electrostatically complexed with DOX, yielding double-loaded liposomes (DOL). DOX-loaded liposomes (DL) were formulated by electrostatic interaction with negatively charged empty liposomes (EL). The combination index (CI) values were calculated to evaluate the synergism of two drugs. In vitro antitumor effects against HeLa cells were measured using CCK-8, calcein staining, and crystal violet staining. In vivo antitumor effects of various liposomes were tested using HeLa cell-bearing mice.

Results

Combination of DOX and OMT had ratio-dependent synergistic activities, with very strong synergism observed at a molar ratio of 4:1 (DOX:OMT). The sizes of EL, DL, OL, and DOL did not significantly differ, but the zeta potentials of DL and DOL were slightly higher than those of OL and EL. In vitro, DOL showed higher antitumor activity than OL, DL or EL in cervical carcinoma HeLa cells. In vivo, unlike other liposomes, DOL reduced the tumor growths by 98.6% and 97.3% relative to the untreated control on day 15 and 25 after the cessation of treatment, respectively.

Conclusions

These results suggest that liposomal co-delivery of DOX and OMT could synergistically potentiate antitumor effects.     

Dual-modified cationic liposomes loaded with paclitaxel and survivin siRNA for targeted imaging and therapy of cancer stem cells in brain glioma

Development of safe, efficient nanocomplex for targeted imaging and therapy of cancer stem cells in brain glioma has become a great challenge. Herein, a low-density lipoprotein receptor-related protein and a RNA aptamer bound CD133 were used as dual-targeting ligands to prepare dual-modified cationic liposomes (DP-CLPs) loaded with survivin siRNA and paclitaxel (DP-CLPs–PTX–siRNA) for actively targeting imaging and treating CD133⁺ glioma stem cells after passing through the blood–brain barrier. After being administrated with DP-CLPs–PTX–siRNA nanocomplex, DP-CLPs showed a persistent target ability to bind glioma cells and brain microvascular endothelial cells (BCECs) and to deliver drugs (PTX/siRNA) to CD133⁺ glioma stem cells. Prepared DP-CLPs–PTX–siRNA nanocomplex showed very low cytotoxicity to BCECs, but induced selectively apoptosis of CD133⁺ glioma stem cells, and improved CD133⁺ glioma stem cells' differentiation into non-stem-cell lineages, also markedly inhibited tumorigenesis, induced CD133⁺ glioma cell apoptosis in intracranial glioma tumor-bearing nude mice and improved survival rates. In conclusion, prepared DP-CLPs–PTX–siRNA nanocomplex selectively induced CD133⁺ glioma stem cell apoptosis in vitro and in vivo exhibits great potential for targeted imaging and therapy of brain glioma stem cells.     

Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages

Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy. However, most reported polymeric systems have sizes above 100 nm, which limits effective extravasation into tumors that are poorly vascularized and have dense stroma. This will, in turn, limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting. In this study, we combined the passive targeting via ultra-small-sized gemcitabine (GEM)-based nanoparticles (NPs) with the active targeting provided by folic acid (FA) conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages (TAMs). We developed an FA-modified prodrug carrier based on GEM (PGEM) to load doxorubicin (DOX), for co-delivery of GEM and DOX to tumors. The co-delivery system showed small particle size of ～10 nm in diameter. The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile. The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor (FR), but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR. Interestingly, in vivo, systemic delivery of FA-PGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model. Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2, which was selectively expressed on TAMs. Thus, targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.     

Advances in nano-delivery systems for doxorubicin: an updated insight

Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumours, transplantable leukemias and lymphomas. Conventional DOX-induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet^®) and pegylated liposomal (Doxil^®) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of DOX in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimising its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumour resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on DOX nanoformulations, in this article we for the first time have given an updated insight on DOX nano delivery systems.