The treatment of Glioblastoma Xenografts by surfactant conjugated dendritic nanoconjugates

Polysorbate 80 (P80) anchored poly(propyleneimine) (PPI) dendritic nanoconjugate was developed and evaluated for targeting anti-cancer drug, docetaxel (DTX) to the brain tumor. In vitro cytotoxicity studies of free DTX, DTX-PPI and DTX-P80-PPI dendrimers were carried out using U87MG human glioblastoma cell line. The in?vivo anti-cancer activity in brain tumor bearing rats revealed that DTX loaded P80 conjugated dendrimers reduced the tumor volume extremely significantly (p?相似文献   

Glycoconjugated peptide dendrimers-based nanoparticulate system for the delivery of chloroquine phosphate

Dendrimers consisting of different molecules of metabolic pathways such as amino acids can greatly reduce the toxicity associated with amine-terminated dendrimers e.g. polyamidoamine (PAMAM) and polypropylene imine (PPI) dendrimers. In the present study, poly-L-lysine dendrimers having polyethyleneglycol (PEG-1000) as core, were synthesized upto fourth generation. Dendrimers were synthesized by alternating protection and deprotection steps of L-lysine by di-BOC (di-tertiary butyl pyrocarbonate) till the formation of 4.0 G peptide dendrimer took place. D-galactose was selected as model sugar for peripheral conjugation (coating) of these peptide dendrimer. The complete formation of uncoated and galactose-coated poly-L-lysine dendrimers was characterized by transmission electron microscopy (TEM), IR, NMR and MALDI TOF mass spectroscopic studies. Chloroquine phosphate (CP)-loaded uncoated and coated dendrimers were evaluated for in vitro drug release rate, hemolytic toxicity and stability studies. Ex vivo cellular uptake studies of uncoated and coated drug dendrimer formulations in macrophages revealed almost 5 times reduced phagocytosis due to galactose coating (p<0.0001). In vitro-in vivo release behavior indicated possibilities of galactose-coated drug dendrimers formulation in controlled drug delivery of CP. Galactose coated formulations drastically reduced hemolytic toxicity compared to uncoated poly-L-lysine formulation as well as plain drug. Hematological data suggests that galactose-coated formulations are less immunogenic compared to uncoated formulations. Finally, it can be concluded that galactose-coated polylysine dendrimers can be utilized for controlled delivery of CP more safely compared to its uncoated formulation both in vitro and in vivo.     

Generation dependent cancer targeting potential of poly(propyleneimine) dendrimer

Dendrimer-mediated delivery of bioactive is a successful and widely explored concept. This paper desribes comparative data pertaining to generation dependent cancer targeting propensity of Poly(propyleneimine) (PPI) dendrimers. This debut report reportsthe drug targeting and antciancer potential of different dendrimer generations. PPI dendrimers of different generations (3.0G, 4.0G and 5.0G) were synthesized and loaded with Melphalan. Results from loading, hemolysis, hematologic, cytotoxicty and flow cytometry assay depicted that as the generation of dendrimer increased from fourth to fifth, the only parameter i.e. toxicty is increased exponentionally. However, others parameters, i.e. loading, sustained release behavior, and targeting efficacy increased negligibly. Kaplan–Meier survival curves clearly depicted comparable therapeutic potential of PPI4M with PPI5M. In vivo investigations in Balb/c mice again favored 4.0G PPI dendrimer to be preferable nanocarrier for anticancer drug delivery owing to analogous anticancer potential. The outcomes of the investigation evidently projects 4.0G PPI dendrimer over 3.0G and 5.0G dendrimer in respect of its drug delivery benefit as well as superior biocompatibility. Thus, much against the common belief, 4.0G PPI dendrimers may be considered to be optimum in respect of drug delivery precluding the use of much more toxic 5.0G PPI dendrimer, which offers no benefit over 4.0G.     

Hypoxia-responsive polymeric nanoparticles for tumor-targeted drug delivery

Hypoxia is a condition found in various intractable diseases. Here, we report self-assembled nanoparticles which can selectively release the hydrophobic agents under hypoxic conditions. For the preparation of hypoxia-responsive nanoparticles (HR-NPs), a hydrophobically modified 2-nitroimidazole derivative was conjugated to the backbone of the carboxymethyl dextran (CM-Dex). Doxorubicin (DOX), a model drug, was effectively encapsulated into the HR-NPs. The HR-NPs released DOX in a sustained manner under the normoxic condition (physiological condition), whereas the drug release rate remarkably increased under the hypoxic condition. From in vitro cytotoxicity tests, it was found the DOX-loaded HR-NPs showed higher toxicity to hypoxic cells than to normoxic cells. Microscopic observation showed that the HR-NPs could effectively deliver DOX into SCC7 cells under hypoxic conditions. In vivo biodistribution study demonstrated that HR-NPs were selectively accumulated at the hypoxic tumor tissues. As consequence, drug-loaded HR-NPs exhibited high anti-tumor activity in vivo. Overall, the HR-NPs might have a potential as nanocarriers for drug delivery to treat hypoxia-associated diseases.     

PEGylated PAMAM dendrimer–doxorubicin conjugate-hybridized gold nanorod for combined photothermal-chemotherapy

We prepared pH-sensitive drug–dendrimer conjugate-hybridized gold nanorod as a promising platform for combined cancer photothermal-chemotherapy under in vitro and in vivo conditions. Poly(ethylene glycol)-attached PAMAM G4 dendrimers (PEG–PAMAM) were first covalently linked on the surface of mercaptohexadecanoic acid-functionalized gold nanorod (MHA-AuNR), with subsequent conjugation of anti-cancer drug doxorubicin (DOX) to dendrimer layer using an acid-labile-hydrazone linkage to afford PEG–DOX–PAMAM–AuNR particles. The particles with a high PEG–PAMAM dendrimer coverage density (0.28 per nm² AuNR) showed uniform sizes and excellent colloidal stability. In vitro drug release studies demonstrated that DOX released from PEG–DOX–PAMAM–AuNR was negligible under normal physiological pH, but it was enhanced significantly at a weak acidic pH value. The efficient intracellular acid-triggered DOX release inside of lysosomes was confirmed using confocal laser scanning microscopy analysis. Furthermore, the combined photothermal-chemo treatment of cancer cells using PEG–DOX–PAMAM–AuNR for synergistic hyperthermia ablation and chemotherapy was demonstrated both in vitro and in vivo to exhibit higher therapeutic efficacy than either single treatment alone, underscoring the great potential of PEG–DOX–PAMAM–AuNR particles for cancer therapy.     

Reducing cytotoxicity while improving anti-cancer drug loading capacity of polypropylenimine dendrimers by surface acetylation

Polypropylenimine (PPI) dendrimers have been widely used as effective delivery vehicles for drugs and nucleic acids during the past decade. However, biomedical applications of PPI dendrimers were limited because of their serious cytotoxicity and low drug loading capacity. In the present study, acetylated PPI dendrimers with different degrees of acetylation ranging from 14.2% to 94.3% were synthesized and used to encapsulate drugs, including methotrexate sodium, sodium deoxycholate and doxorubicin. Acetylated PPI dendrimers with a degree of acetylation >80% showed a significantly decreased cytotoxicity (>90% cell viability) on MCF-7 and A549 cells. The drug loading capacity of acetylated PPI dendrimers increased proportionally with the degree of acetylation on the dendrimer surface. In addition, 94.3% acetylated PPI dendrimers exhibited a pH-responsive release profile of anticancer drugs loaded within the nanoparticles. The cytotoxicities of methotrexate sodium and doxorubicin on MCF-7 and A549 cells were significantly reduced when they were complexed with acetylated PPI dendrimers with high degrees of acetylation (>80%), owing to sustained drug release from the dendrimers. The results suggest that surface acetylation can reduce the cytotoxicity and improve the anticancer drug loading capacity of cationic dendrimers, and that acetylated PPI dendrimers are promising vehicles for anticancer drugs in clinical trials.     

Ultra-small BaGdF5-based upconversion nanoparticles as drug carriers and multimodal imaging probes

A new type of drug-delivery system (DDS) was constructed, in which the anti-cancer drug doxorubicin (DOX) was conjugated to the ultra-small sized (sub-10 nm) BaGdF₅:Yb³⁺/Tm³⁺ based upconversion nanoparticles (UCNPs). This multifunctional DDS simultaneously possesses drug delivery and optical/magnetic/X-ray computed tomography imaging capabilities. The DOX can be selectively released by cleavage of hydrazone bonds in acidic environment, which shows a pH-triggered drug release behavior. The MTT assay shows these DOX-conjugated UCNPs exhibit obvious cytotoxic effect on HeLa cells. Moreover, to improve the upconversion luminescence intensity, core–shell structured UCNPs were constructed. The in vitro upconversion luminescence images of these UCNPs uptaken by HeLa cells show bright emission with high contrast. In addition, these UCNPs were further explored for T₁-weighted magnetic resonance (MR) and X-ray computed tomography (CT) imaging in vitro. Long-term in vivo toxicity studies indicated that mice intravenously injected with 10 mg/kg of UCNPs survived for 40 days without any apparent adverse effects to their health. The results indicate that this multifunctional drug-delivery system with optimized size, excellent optical/MR/CT trimodal imaging capabilities, and pH-triggered drug release property is expected to be a promising platform for simultaneous cancer therapy and bioimaging.     

Hydrophobic cavity formed by oligopeptide for doxorubicin delivery based on dendritic poly(L-lysine)

To deliver anti-cancer drugs to tumors, a hydrophobic cavity was prepared in the dendritic molecule, dendritic poly(L-lysine) of sixth generation (KG6), which was used as a drug carrier. The dendritic molecule was modified with polyethylene glycol (PEG)-linked hydrophobic penta-phenylalanine or penta-alanine. The hydrophobic cavity was formed between the KG6 and PEG chains. The penta-phenylalanine peptide was better in encapsulating doxorubicin (DOX) in the cavity compared with penta-alanine. The loaded DOX was slowly released from the cavity, and it depended on pH. After intravenous injection, the DOX-loaded dendrimers accumulated in the tumor by the enhanced permeability and retention effect, and showed significant suppression of tumor growth without loss of body weight. These results indicate that hydrophobic oligopeptides can be used for forming a hydrophobic cavity in a dendritic molecule for delivery of anti-cancer drugs to tumor sites.     

A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas

A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG(1000) and PEG(2000) chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced.     

Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration

Retinal neuroinflammation, mediated by activated microglia, plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in age-related macular degeneration and retinitis pigmentosa. Targeted drug therapy for attenuation of neuroinflammation in the retina was explored using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices. We show that, upon intravitreal administration, PAMAM dendrimers selectively localize within activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy controls. This pathology-dependent biodistribution was exploited for drug delivery, by covalently conjugating fluocinolone acetonide to the dendrimer. The conjugate released the drug in a sustained manner over 90 days. In vivo efficacy was assessed using the Royal College of Surgeons (RCS) rat retinal degeneration model over a four-week period when peak retinal degeneration occurs. One intravitreal injection of 1 μg of FA conjugated to 7 μg of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month. These studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuroinflammation.     

Bioreducible heparin-based nanogel drug delivery system

Bioreducible heparin (HEP)-based nanogels were prepared by derivatizing HEP with vinyl group followed by copolymerizing with cystamine bisacrylamide in aqueous medium in the absence of surfactant. The hydrodynamic diameter of the HEP nanogels could be tuned in the range from 80 to 200 nm. Doxorubicin (DOX) was loaded into the HEP nanogels, and high drug loading content (30%) and efficiency (90%) were achieved. In vitro drug release test revealed that this drug delivery system exhibited strongly redox-sensitive drug release behavior that would greatly favor the in vivo drug delivery performance of the nanogels. After injected into tumor-bearing mice through tail vein, the DOX-loaded HEP nanogels showed remarkable accumulation in tumors as demonstrated by in vivo near infared fluorescence imaging and ex vivo DOX concentration measurements. The doxorubicin accumulation at tumor site goes beyond 9% injected dose per gram of tumor through such delivery system, making that DOX-loaded HEP nanogels have significantly superior in vivo antitumor activity.     

Amphiphilic peptide dendritic copolymer-doxorubicin nanoscale conjugate self-assembled to enzyme-responsive anti-cancer agent

Peptide dendrimer drug conjugate based nanoparticles are recently developed as a potential candidate for drug delivery vehicle. In this study, we prepared and characterized the enzyme-sensitive amphiphilc mPEGylated dendron-GFLG-DOX conjugate via two-step highly efficient click reaction. Dynamic light scattering (DLS) and transmission electron microscope (TEM) studies demonstrated the mPEGylated dendron-GFLG-DOX conjugate self-assembled into compact nanoparticles with negatively charged surface. The nanoparticles with 9.62 wt% (weight percent) of DOX showed enzyme-sensitive property by drug release tests. The nanoparticles were shown to effectively kill cancer cells in vitro. The fluorescent image indicated that the nanoparticles could accumulate and retain within tumor for a long time. Moreover, the nanoparticles substantially enhanced antitumor efficacy compared to the free DOX, exhibiting much higher effects on inhibiting proliferation and inducing apoptosis of the 4T1 murine breast cancer model confirmed as the evidences from tumor growth curves, tumor growth inhibition (TGI), immunohistochemical analysis and histological assessment. The nanoparticles reduced DOX-induced toxicities and presented no significant side effects to normal organs of both tumor bearing and healthy mice as measured by body weight shifts and histological analysis. Therefore, the mPEGylated dendron-GFLG-DOX conjugate based nanoparticle serves as a potential drug delivery vehicle for breast cancer therapy.     

Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles

Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)–poly(l-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N′, N-triacetic acid (NOTA, a macrocyclic chelator for ⁶⁴Cu) (abbreviated as PAMAM–PLA-b-PEG–TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105-negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, ⁶⁴Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than ⁶⁴Cu-labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics.     

Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin

pH responsive cisplatin prodrug crosslinked polysaccharide-based nanoparticles were developed from succinic acid decorated dextran (Dex-SA) for active loading and triggered intracellular release of doxorubicin (DOX). Nanoparticles with uniform size were formed spontaneously in aqueous medium via electrostatic interaction between anionic Dex-SA and cationic DOX, and subsequently transformed into crosslinked nanoparticles (CL-Nanoparticles) in situ by readily crosslinking the micelles via chelate interactions between the ionic polymeric carrier and the platinum (II) antitumor drug. This strategy eliminated the need of organic solvents and sophisticated processes in the drug loading procedure. The in vitro release studies showed that DOX was released from the CL-Nanoparticles in a controlled and pH-dependent manner. Furthermore, the pharmacokinetics and biodistribution investigations indicated that, as compared to the non-crosslinked nanoparticles (NCL-Nanoparticles) and free DOX, the CL-Nanoparticles significantly prolonged the blood circulation time of drug, decreased accumulation in the normal tissues and enriched drug into the tumors. As a consequence, the DOX-loaded CL-Nanoparticles exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with the NCL-Nanoparticles and free DOX, which were further confirmed by the histological and immunohistochemical analyses. These cisplatin prodrug crosslinked polysaccharide nanoparticles proved to be a promising nanomedicine drug delivery system for tumor-targeted delivery of DOX.     

PEGylated dendritic diaminocyclohexyl-platinum (II) conjugates as pH-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy

Environmentally responsive peptide dendrimers loaded with drugs are suitable candidates for cancer therapy. In this study, we report the preparation and characterization of mPEGylated peptide dendrimer-linked diaminocyclohexyl platinum (II) (dendrimer-DACHPt) conjugates as pH-responsive drug delivery vehicles for tumor suppression in mice. The DACHPt has a molecular structure, is and activity closely related to oxaliplatin and was linked to dendrimer via N,O-chelate coordination. The products were pH-responsive and released drug significantly faster in acidic environments (pH 5.0) than pH 7.4. Consequently, the conjugates suppressed tumor growth better than clinical oxaliplatin^® without inducing toxicity in an SKOV-3 human ovarian cancer xenograft. Through the systemic delivery of conjugates, 25-fold higher tumor platinum uptake at 36 h post-injection was seen observed due to the enhanced permeability and retention (EPR) effect thereby remarkably enhancing the therapeutic indexes of this small-molecule drug. Thus, the mPEGylated peptide dendrimer-linked DACH-platinum conjugates are novel potential drug delivery systems with implications in future ovarian cancer therapy.     

Intracellular redox-activated anticancer drug delivery by functionalized hollow mesoporous silica nanoreservoirs with tumor specificity

In this study, a type of intracellular redox-triggered hollow mesoporous silica nanoreservoirs (HMSNs) with tumor specificity was developed in order to deliver anticancer drug (i.e., doxorubicin (DOX)) to the target tumor cells with high therapeutic efficiency and reduced side effects. Firstly, adamantanamine was grafted onto the orifices of HMSNs using a redox-cleavable disulfide bond as an intermediate linker. Subsequently, a synthetic functional molecule, lactobionic acid-grafted-β-cyclodextrin (β-CD-LA), was immobilized on the surface of HMSNs through specific complexation with the adamantyl group, where β-CD served as an end-capper to keep the loaded drug within HMSNs. β-CD-LA on HMSNs could also act as a targeting agent towards tumor cells (i.e., HepG2 cells), since the lactose group in β-CD-LA is a specific ligand binding with the asialoglycoprotein receptor (ASGP-R) on HepG2 cells. In vitro studies demonstrated that DOX-loaded nanoreservoirs could be selectively endocytosed by HepG2 cells, releasing therapeutic DOX into cytoplasm and efficiently inducing the apoptosis and cell death. In vivo investigations further confirmed that DOX-loaded nanoreservoirs could permeate into the tumor sites and actively interact with tumor cells, which inhibited the tumor growth with the minimized side effect. On the whole, this drug delivery system exhibits a great potential as an efficient carrier for targeted tumor therapy in vitro and in vivo.     

Controlled release of doxorubicin from graphene oxide based charge-reversal nanocarrier

A number of anticancer drugs, such as doxorubicin (DOX), operate only after being transported into the nucleus of cancer cells. Thus it is essential for the drug carriers to effectively release the anticancer drugs into the cytoplasm of cancer cells and make them move to nucleus freely. Herein, a pH-responsive charge-reversal polyelectrolyte and integrin α_Ⅴβ₃ mono-antibody functionalized graphene oxide (GO) complex is constituted as a nanocarrier for targeted delivery and controlled release of DOX into cancer cells. The DOX loading and releasing in vitro demonstrates that this nanocarrier cannot only load DOX with high efficiency, but also effectively release it under mild acidic pH stimulation. Cellular toxicity assay, confocal laser scanning microscopy and flow cytometer analysis results together confirm that with the targeting nanocarrier, DOX can be selectively transported into the targeted cancer cells. Then they will be effectively released from the nanocarriers in cytoplasm and moved into the nucleus subsequently, stimulating by charge-reverse of the polyelectrolyte in acidic intracellular compartments. The effective delivery and release of the anticancer drugs into nucleus of the targeted cancer cells will lead to a high therapeutic efficiency. Hence, such a targeting nanocarrier prepared from GO and charge-reversal polyelectrolytes is likely to be an available candidate for targeted drug delivery in tumor therapy.     

The cancer targeting potential of d-α-tocopheryl polyethylene glycol 1000 succinate tethered multi walled carbon nanotubes

Our main aim in the present investigation was to explore the in vitro and in vivo cancer targeting potential of the doxorubicin (DOX) laden d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) tethered surface engineered MWCNTs nanoformulation (DOX/TPGS-MWCNTs) and compare it with pristine MWCNTs and free doxorubicin solution. The developed MWCNTs nanoformulations were extensively characterized by Fourier-transform infrared, Raman spectroscopy, x-ray diffraction, electron microscopy, and in vitro and in vivo studies using MCF-7 cancer cell line. The entrapment efficiency was determined to be 97.2 ± 2.50% (DOX/TPGS-MWCNTs) and 92.5 ± 2.62% (DOX/MWCNTs) ascribed to π-π stacking interactions. The developed formulations depicted the sustained release pattern at the lysosomal pH (pH 5.3). The DOX/TPGS-MWCNTs showed enhanced cytotoxicity, cellular uptake and were most preferentially taken up by the cancerous cells via endocytosis mechanism. The DOX/TPGS-MWCNTs nanoconjugate depicted the significantly longer survival span (44 days, p < 0.001) than DOX/MWCNTs (23 days), free DOX (18 days) and control group (12 days). The obtained results also support the extended residence time and sustained release profile of the drug loaded surface engineered nanotubes formulations in body as compared to DOX solution. Overall we can conclude that the developed MWCNTs nanoconjugate have higher cancer targeting potential on tumor bearing Balb/c mice.     

Conjugating doxorubicin to polymannose: a new strategy for target specific delivery to lung cancer cells

Abstract

As mannose receptors are known to be over-expressed in cancer cells, we synthesized polymannose-doxorubicin (PM-DOX) conjugates with the objective of targeting the drug to cancer cells. DOX was conjugated to oxidized PM through Schiff’s linkages to obtain PM-DOX conjugates. In order to examine the superior targeting efficacy of PM-DOX conjugate, sodium alginate (SA) was conjugated to DOX by similar chemistry and compared with PM-DOX conjugate. The cytotoxicity of the conjugates was investigated in A549 cell lines using MTT Assay and the cell uptake and retention studies, were performed using flow cytometry and cell imaging. In vitro drug release studies with both PM-DOX and SA-DOX conjugates showed an initial burst release of DOX up to 37–39% at 1?h, followed by a steady release up to 58–62% at 24?h in human plasma while negligible release was observed in phosphate buffered saline. The conjugates exhibited negligible hemolytic potential to human erythrocytes compared to free DOX. The PM-DOX conjugate showed better cytotoxic potential against A549 cells at lower concentration (equivalent to 0.27?μg/mL of DOX) at 72?h compared to free DOX and SA-DOX conjugate. Further, PM-DOX conjugate showed enhanced uptake by the cells in comparison with SA-DOX conjugate thereby confirming the target specificity of PM to the cancer cells.     

Doxorubicin loaded singlet-oxygen producible polymeric micelle based on chlorine e6 conjugated pluronic F127 for overcoming drug resistance in cancer

Drug resistance remains one of the primary obstacles to the success of cancer chemotherapy. In this work, we demonstrate a singlet-oxygen producible polymeric (SOPP) micelle based on photosensitizer (PS, chlorin e6 (Ce6)) conjugated amphiphilic copolymer (pluronic F127^®, PF127) for overcoming drug resistance in cancer by applying photochemical internalization (PCI). The doxorubicin (DOX)-loaded SOPP micelles were self-assembled from Ce6-PF127 conjugates, which have a spherical shape with a uniform size of ∼30 nm. Compared with free Ce6, enhanced singlet-oxygen generation efficiency in the DOX-loaded SOPP micelles have been demonstrated in aqueous environments due to their increased water-dispersibility. Under low dose of laser power and anti-cancer drug (DOX) conditions, in vitro and in vivo studies on drug-resistant cancer cells demonstrated that singlet-oxygen-mediated cellular membrane damage (caused by lipid peroxidation) significantly increased the cellular uptake of drug (DOX), which led to overcoming the drug resistance in cancer cells without undesirable side effects. We believe this approach could represent a promising platform for drug-resistant cancer treatment.