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1.
Sci China Chem ; 65(6): 1010-1075, 2022.
Article in English | MEDLINE | ID: mdl-35505924

ABSTRACT

Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.

2.
Nat Commun ; 12(1): 1359, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33649336

ABSTRACT

Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.


Subject(s)
Antibodies, Monoclonal/metabolism , Immunomodulation , Immunotherapy , Nanoparticles/chemistry , Neoplasms/immunology , Neoplasms/therapy , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cytotoxicity, Immunologic , Female , Immobilized Proteins/metabolism , Immunity , Killer Cells, Natural/immunology , Male , Mice, Inbred C57BL , Nanoparticles/ultrastructure , T-Lymphocytes/immunology
3.
Adv Healthc Mater ; 3(11): 1792-803, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24947820

ABSTRACT

Patients with Her2-overexpressing (Her2(+)) breast cancers generally have a poorer prognosis due to the high aggressiveness and chemoresistance of the disease. Small interfering RNA (siRNA) targeting the gene encoding polo-like kinase 1 (Plk1; siPlk1) has emerged as an efficient therapeutic agent for Her2(+) breast cancers. Poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA)-based nanoparticles for siRNA delivery were previously developed and optimized. In this study, for targeted delivery of siPlk1 to Her2(+) breast cancer, anti-Her2 single-chain variable fragment antibody (ScFv(Her2))-decorated PEG-PLA-based nanoparticles with si Plk1 encapsulation (ScFv(Her2)-NP(si) Plk1) are developed. With the rationally designed conjugation site, ScFv(Her2)-NP(siRNA) can specifically bind to the Her2 antigen overexpressed on the surface of Her2(+) breast cancer cells. Therefore, ScFv(Her2)-NP(si) Plk1 exhibits improved cellular uptake, promoted Plk1 silencing efficiency, and induced enhanced tumor cell apoptosis in Her2(+) breast cancer cells, when compared with nontargeted NP(si) Plk1. More importantly, ScFv(Her2)-NP(siRNA) markedly enhances the accumulation of siRNA in Her2(+) breast tumor tissue, and remarkably improves the efficacy of tumor suppression. Dose-dependent anti-tumor efficacy further demonstrates that ScFvHer2 -decorated PEG-PLA-based nanoparticles with siPlk1 encapsulation can significantly enhance the inhibition of Her2(+) breast tumor growth and reduce the dose of injected siRNA. These results suggest that ScFvHer2 -decorated PEG-PLA-based nanoparticles show great potential for targeted RNA interference therapy of Her2(+) breast tumor.


Subject(s)
Breast Neoplasms/therapy , Nanoparticles/administration & dosage , Polyethylene Glycols/administration & dosage , RNA, Small Interfering/administration & dosage , Single-Chain Antibodies/administration & dosage , Apoptosis/drug effects , Breast Neoplasms/metabolism , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Female , Genetic Therapy/methods , Humans , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Receptor, ErbB-2/metabolism , Polo-Like Kinase 1
4.
Adv Drug Deliv Rev ; 78: 63-76, 2014 Nov 30.
Article in English | MEDLINE | ID: mdl-24548540

ABSTRACT

Despite the wide use of antibiotics, bacterial infection is still one of the leading causes of hospitalization and mortality. The clinical failure of antibiotic therapy is linked with low bioavailability, poor penetration to bacterial infection sites, and the side effects of antibiotics, as well as the antibiotic resistance properties of bacteria. Antibiotics encapsulated in nanoparticles or microparticles made up of a biodegradable polymer have shown great potential in replacing the administration of antibiotics in their "free" form. Polymeric particles provide protection to antibiotics against environmental deactivation and alter antibiotic pharmacokinetics and biodistribution. Polymeric particles can overcome tissue and cellular barriers and deliver antibiotics into very dense tissues and inaccessible target cells. Polymeric particles can be modified to target or respond to particular tissues, cells, and even bacteria, and thereby facilitate the selective concentration or release of the antibiotic at infection sites, respectively. Thus, the delivery of antibiotics with polymeric particles augments the level of the bioactive drug at the site of infection while reducing the dosage and the dosing frequency. The end results are improved therapeutic effects as well as decreased "pill burden" and drug side effects in patients. The main objective of this review is to analyze recent advances and current perspectives in the use of polymeric antibiotic delivery systems in the treatment of bacterial infection.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Drug Delivery Systems , Polymers/chemistry , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Drug Resistance, Bacterial , Humans , Microspheres , Nanoparticles , Tissue Distribution
5.
Mol Ther ; 22(5): 964-73, 2014 May.
Article in English | MEDLINE | ID: mdl-24496383

ABSTRACT

The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cyclin-Dependent Kinase 4/genetics , Genetic Therapy , Proto-Oncogene Proteins/genetics , RNA, Small Interfering/genetics , ras Proteins/genetics , Animals , Carcinoma, Non-Small-Cell Lung/therapy , Cell Line, Tumor , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Gene Expression Regulation, Neoplastic , Gene Transfer Techniques , Humans , Mice , Nanoparticles/therapeutic use , Proto-Oncogene Proteins p21(ras) , RNA, Small Interfering/therapeutic use , Xenograft Model Antitumor Assays
6.
ACS Nano ; 7(12): 10636-45, 2013 Dec 23.
Article in English | MEDLINE | ID: mdl-24200225

ABSTRACT

Differential anticancer drug delivery that selectively releases a drug within a tumor represents an ideal cancer therapy strategy. Herein, we report differential drug delivery to the tumor through the fabrication of a special bacteria-accumulated tumor environment that responds to bacteria-sensitive triple-layered nanogel (TLN). We demonstrate that the attenuated bacteria SBY1 selectively accumulated in tumors and were rapidly cleared from normal tissues after intravenous administration, leading to a unique bacteria-accumulated tumor environment. Subsequent administrated doxorubicin-loaded TLN (TLND) was thus selectively degraded in the bacteria-accumulated tumor environment after its accumulation in tumors, triggering differential doxorubicin release and selectively killing tumor cells. This concept can be extended and improved by using other factors secreted by bacteria or materials to fabricate a unique tumor environment for differential drug delivery, showing potential applications in drug delivery.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Carriers , Drug Delivery Systems , Neoplasms, Experimental/drug therapy , Neoplasms/drug therapy , Alkaline Phosphatase/chemistry , Animals , Bacteria/metabolism , Burkholderia cepacia/metabolism , Cell Line , Cell Line, Tumor , Doxorubicin , Female , Green Fluorescent Proteins/chemistry , Humans , Infusions, Intravenous , Lipase/chemistry , Liver/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Nanomedicine , Neoplasm Transplantation , Tissue Distribution
7.
Biomaterials ; 34(26): 6284-98, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23714243

ABSTRACT

The interaction of nanocarriers with cells including their transcellular behavior is vital not only for a drug delivery system, but also for the safety of nanomaterials. In an attempt to clarify how the structures of polymers impact the transport mechanisms of their nanocarriers in epithelial cells, three amphiphilic polymers (PEEP-PCL, PEG-PCL and PEG-DSPE) with different hydrophilic or hydrophobic blocks were synthesized or chosen to form different micelle systems here. The endocytosis, exocytosis, intracellular colocalization, paracellular permeability and transcytosis of these micelle systems were compared using Förster resonance energy transfer analysis, real-time confocal images, colocalization assay, transepithelial electrical resistance study, and so on. All micelle systems were found intact during the studies with cells. The endocytosis and exocytosis studies with undifferentiated MDCK cells and the transcytosis study with differentiated MDCK monolayers all indicated the fact that PEG-DSPE micelles achieved the most and fastest transport, followed by PEG-PCL and PEEP-PCL in order. These might be because DSPE has higher hydrophobicity than PCL while PEG has lower hydrophilicity than PEEP. Different in hydrophilic or hydrophobic structures, all kinds of micelles demonstrated similar pathways during endocytosis and exocytosis, both caveolae- and clathrin-mediated but with difference in degree. The colocalization studies revealed different behaviors in intracellular trafficking among the three polymer micelles, suggesting the decisive role of hydrophilic shells on this process. Finally, all micelle systems did not impact the paracellular permeability of test cell monolayer. In conclusion, the hydrophilic and hydrophobic structures of test micelles could influence their transport ability, intracellular trafficking and the transport level under each pathway in MDCK cells.


Subject(s)
Lactones/metabolism , Madin Darby Canine Kidney Cells/cytology , Micelles , Phosphatidylethanolamines/metabolism , Polyesters/metabolism , Polyethylene Glycols/metabolism , Animals , Dogs , Endocytosis , Exocytosis , Hydrophobic and Hydrophilic Interactions , Lactones/analysis , Madin Darby Canine Kidney Cells/metabolism , Permeability , Phosphatidylethanolamines/analysis , Polyesters/analysis , Polyethylene Glycols/analysis , Surface-Active Agents/analysis , Surface-Active Agents/metabolism
8.
J Control Release ; 166(2): 106-14, 2013 Mar 10.
Article in English | MEDLINE | ID: mdl-23266452

ABSTRACT

Due to its efficient and specific gene silencing ability, RNA interference has shown great potential in the treatment of liver diseases. However, achieving in vivo delivery of siRNA to critical liver cells remains the biggest obstacle for this technique to be a real clinic therapeutic modality. Here, we describe a promising liver targeting siRNA delivery system based on N-acetylgalactosamine functionalized mixed micellar nanoparticles (Gal-MNP), which can efficiently deliver siRNA to hepatocytes and silence the target gene expression after systemic administration. The Gal-MNP were assembled in aqueous solution from mixed N-acetylgalactosamine functionalized poly(ethylene glycol)-b-poly(ε-caprolactone) and cationic poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) (PCL-b-PPEEA); the properties of nanoparticles, including particle size, zeta potential and the density of poly(ethylene glycol) could be easily regulated. The hepatocyte-targeting effect of Gal-MNP was demonstrated by significant enriching of fluorescent siRNA in primary hepatocytes in vitro and in vivo. Successful down-regulation of liver-specific apolipoprotein B (apoB) expression was achieved in mouse liver, at both the transcriptional and protein level, following intravenous injection of Gal-MNP/siapoB to BALB/c mice. Systemic delivery of Gal-MNP/siRNA did not induce the innate immune response or positive hepatotoxicity. The results of this study suggested therapeutic potential for the Gal-MNP/siRNA system in liver disease.


Subject(s)
Acetylgalactosamine/chemistry , Drug Delivery Systems/methods , Liver/drug effects , Nanoparticles , RNA, Small Interfering/administration & dosage , 3T3 Cells , Animals , Apolipoproteins B/genetics , Cell Survival/drug effects , Drug Carriers , Electrochemistry , Endocytosis/drug effects , Ethylene Glycols , Gene Silencing , Hepatocytes/drug effects , Male , Mice , Mice, Inbred BALB C , Micelles , Particle Size , Polyesters
9.
Biomater Sci ; 1(11): 1143-1150, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-32481937

ABSTRACT

Effective systemic therapy is often necessary to treat hepatocellular carcinoma (HCC). We synthesized a Gal-PPE nanogel consisting of a cross-linked polyphosphate core and galactosylated poly(ethylene glycol) arms for enhanced doxorubicin delivery to diethylnitrosamine-induced HCC in rats. The Gal-PPE nanogel exhibited high affinity to HepG2 cells in vitro, mediated by the asialoglycoprotein receptor. In vivo studies revealed that the Gal-PPE nanogel was taken up more efficiently by hepatocytes, in contrast to m-PPE nanogel. Consequently, doxorubicin delivery with Gal-PPE significantly inhibited the progress of HCC, reducing neoplastic liver nodules and prolonging the survival time of HCC rats more significantly. These results demonstrate the potential of Gal-PPE as a nanocarrier for improved HCC chemotherapy.

10.
Adv Mater ; 24(46): 6175-80, 2012 Dec 04.
Article in English | MEDLINE | ID: mdl-22961974

ABSTRACT

Bacteria-Responsive Multifunctional Nanogel: We developed a bacteria-responsive multifunctional nanogel for targeted antibiotic delivery, in which bacterial enzymes are utilized to trigger antibiotic release by degrading the polyphosphoester core. The mannosylated nanogel preferentially delivers drugs to macrophages and leads to drug accumulation at bacterial infection sites through macrophage transport. This nanogel provides macrophage targeting and lesion site-activatable drug release properties, which enhances bacterial growth inhibition.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Drug Carriers/chemistry , Polyethylene Glycols/chemistry , Polyethyleneimine/chemistry , Animals , Anti-Bacterial Agents/chemistry , Bacteria/enzymology , Cell Line , Embryo, Nonmammalian/metabolism , Macrophages/metabolism , Methicillin-Resistant Staphylococcus aureus/drug effects , Mice , Microscopy, Confocal , Nanogels , Phagocytosis/drug effects , Phospholipases/metabolism , Vancomycin/chemistry , Vancomycin/pharmacology , Zebrafish/growth & development
11.
Mol Pharm ; 9(10): 2863-74, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22924580

ABSTRACT

The particular characteristics of the tumor microenvironment have the potential to strongly promote tumor growth, metastasis and angiogenesis and induce drug resistance. Therefore, the development of effective, systemic therapeutic approaches specifically based on the tumor microenvironment is highly desirable. Hypoxia-inducible factor-1α (HIF-1α) is an attractive therapeutic target because it is a key transcription factor in tumor development and only accumulates in hypoxic tumors. We report here that a cationic mixed micellar nanoparticle (MNP) consisting of amphiphilic block copolymers poly(ε-caprolactone)-block-poly(2-aminoethylethylene phosphate) (PCL(29)-b-PPEEA(21)) and poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL(40)-b-PEG(45)) was a suitable carrier for HIF-1α siRNA to treat hypoxic tumors, which showed an average diameter of 58.0 ± 3.4 nm. The complex MNP(siRNA), formed by the interaction of MNP and siRNA, was transfected into PC3 prostate cancer cells efficiently, while the inhibition of HIF-1α expression by MNP loaded with HIF-1α siRNA (MNP(siHIF)) blocked PC3 cell proliferation, suppressed cell migration and disturbed angiogenesis under in vitro hypoxic mimicking conditions. It was further demonstrated that systemic delivery of MNP(siHIF) effectively inhibited tumor growth in a PC3 prostate cancer xenograft murine model without activating innate immune responses. Moreover, delivery of MNP(siHIF) sensitized PC3 tumor cells to doxorubicin chemotherapy in vitro and in vivo by downregulating MDR1 gene expression which was induced by hypoxia. The underlying concept of use of MNP(siHIF) to block HIF-1α holds promise as an example of a clinical approach using specific siRNA therapy for cancer treatment aimed at the hypoxic tumor microenvironment.


Subject(s)
Cell Hypoxia/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Nanoparticles/administration & dosage , Prostatic Neoplasms/genetics , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/chemistry , Animals , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Doxorubicin/pharmacology , Gene Silencing , Humans , Male , Mice , Mice, Nude , Micelles , Nanoparticles/chemistry , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Particle Size , Polymers/administration & dosage , Polymers/chemistry , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , RNA, Small Interfering/chemistry , Transfection/methods , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics
12.
ACS Nano ; 6(6): 4955-65, 2012 Jun 26.
Article in English | MEDLINE | ID: mdl-22646867

ABSTRACT

The clinical success of therapeutics of small interfering RNA (siRNA) is still hindered by its delivery systems. Cationic polymer or lipid-based vehicles as the major delivery systems of siRNA cannot sufficiently satisfy siRNA therapeutic applications. It is hypothesized that cationic lipid-polymer hybrid nanoparticles may take advantage of both polymeric and lipid-based nanoparticles for siRNA delivery, while diminishing the shortcomings of both. In this study, cationic lipid-polymer hybrid nanoparticles were prepared by a single-step nanoprecipitation of a cationic lipid (N,N-bis(2-hydroxyethyl)-N-methyl-N-(2-cholesteryloxycarbonyl aminoethyl) ammonium bromide, BHEM-Chol) and amphiphilic polymers for systemic delivery of siRNA. The formed hybrid nanoparticles comprised a hydrophobic polylactide core, a hydrophilic poly(ethylene glycol) shell, and a cationic lipid monolayer at the interface of the core and the shell. Such hybrid nanoparticles exhibited excellent stability in serum and showed significantly improved biocompatibility compared to that of pure BHEM-Chol particles. The hybrid nanoparticles were capable of delivering siRNA into BT474 cells and facilitated the escape of loaded siRNA from the endosome into the cytoplasm. The hybrid nanoparticles carrying polo-like kinase 1 (Plk1)-specific siRNA (siPlk1) remarkably and specifically downregulated expression of the oncogene Plk1 and induced cancer cell apoptosis both in vitro and in vivo and significantly suppressed tumor growth following systemic administration. We demonstrate that this system is stable, nontoxic, highly efficient, and easy to scale up, bringing the clinical application of siRNA therapy one important step closer to reality.


Subject(s)
Lipids/chemistry , Nanocapsules/chemistry , Neoplasms, Experimental/genetics , Neoplasms, Experimental/therapy , Polymers/chemistry , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/chemistry , Animals , Cations , Cell Line, Tumor , Genetic Therapy/methods , Mice , Nanocapsules/administration & dosage , Treatment Outcome
13.
J Am Chem Soc ; 134(9): 4355-62, 2012 Mar 07.
Article in English | MEDLINE | ID: mdl-22304702

ABSTRACT

We report a new strategy for differential delivery of antimicrobials to bacterial infection sites with a lipase-sensitive polymeric triple-layered nanogel (TLN) as the drug carrier. The TLN was synthesized by a convenient arm-first procedure using an amphiphilic diblock copolymer, namely, monomethoxy poly(ethylene glycol)-b-poly(ε-caprolactone), to initiate the ring-opening polymerization of the difunctional monomer 3-oxapentane-1,5-diyl bis(ethylene phosphate). The hydrophobic poly(ε-caprolactone) (PCL) segments collapsed and surrounded the polyphosphoester core, forming a hydrophobic and compact molecular fence in aqueous solution which prevented antibiotic release from the polyphosphoester core prior to reaching bacterial infection sites. However, once the TLN sensed the lipase-secreting bacteria, the PCL fence of the TLN degraded to release the antibiotic. Using Staphylococcus aureus (S. aureus) as the model bacterium and vancomycin as the model antimicrobial, we demonstrated that the TLN released almost all the encapsulated vancomycin within 24 h only in the presence of S. aureus, significantly inhibiting S. aureus growth. The TLN further delivered the drug into bacteria-infected cells and efficiently released the drug to kill intracellular bacteria. This technique can be generalized to selectively deliver a variety of antibiotics for the treatment of various infections caused by lipase-secreting bacteria and thus provides a new, safe, effective, and universal approach for the treatment of extracellular and intracellular bacterial infections.


Subject(s)
Drug Carriers/chemistry , Drug Delivery Systems , Lipase/metabolism , Polyethylene Glycols/chemistry , Polyethyleneimine/chemistry , Polymers/chemistry , Anti-Bacterial Agents/pharmacology , Drug Carriers/metabolism , Lipase/chemistry , Microbial Sensitivity Tests , Nanogels , Polyethylene Glycols/metabolism , Polyethyleneimine/metabolism , Polymers/metabolism , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Structure-Activity Relationship , Vancomycin/pharmacology
14.
ACS Nano ; 5(5): 3679-92, 2011 May 24.
Article in English | MEDLINE | ID: mdl-21462992

ABSTRACT

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. Through the development of a drug delivery system that tethers doxorubicin onto the surface of gold nanoparticles with a poly(ethylene glycol) spacer via an acid-labile linkage (DOX-Hyd@AuNPs), we have demonstrated that multidrug resistance in cancer cells can be significantly overcome by a combination of highly efficient cellular entry and a responsive intracellular release of doxorubicin from the gold nanoparticles in acidic organelles. DOX-Hyd@AuNPs achieved enhanced drug accumulation and retention in multidrug resistant MCF-7/ADR cancer cells when it was compared with free doxorubicin. It released doxorubicin in response to the pH of acidic organelles following endocytosis, opposite to the noneffective drug release from doxorubicin-tethered gold nanoparticles via the carbamate linkage (DOX-Cbm@AuNPs), which was shown by the recovered fluorescence of doxorubicin from quenching due to the nanosurface energy transfer between the doxorubicinyl groups and the gold nanoparticles. DOX-Hyd@AuNPs therefore significantly enhanced the cytotoxicity of doxorubicin and induced elevated apoptosis of MCF-7/ADR cancer cells. With a combined therapeutic potential and ability to probe drug release, DOX-Hyd@AuNPs represent a model with dual roles in overcoming MDR in cancer cells and probing the intracellular release of drug from its delivery system.


Subject(s)
Doxorubicin/administration & dosage , Drug Resistance, Multiple , Gold/chemistry , Nanocapsules/chemistry , Neoplasms, Experimental/drug therapy , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Doxorubicin/chemistry , Humans , Nanocapsules/ultrastructure , Neoplasms, Experimental/pathology
15.
Macromol Rapid Commun ; 31(13): 1201-6, 2010 Jul 01.
Article in English | MEDLINE | ID: mdl-21590876

ABSTRACT

Reversibly cross-linked core-shell-corona micelles based on a triblock copolymer composed of poly(aliphatic ester), polyphosphoester, and poly(ethylene glycol) are reported. The triblock copolymer is synthesized through consecutive ring-opening polymerization of ε-caprolactone and 2,4-dinitrophenylthioethyl ethylene phosphate, followed by conjugation of poly(ethylene glycol). After deprotection under mild conditions, the amphiphilic polymer forms core-shell-corona micelles with free thiols in the shell. Cross-linking of the micelles within the shell reduces their critical micellization concentration and enhances their stability against severe conditions. The redox-sensitive cross-linkage allows the facilitated release of entrapped anticancer drugs in the cytoplasm in response to the intracellular reductive environment. With enhanced stability during circulation after administration, and accelerated intracellular drug release at the target site, the biocompatible and biodegradable shell-cross-linked polymeric micelle is promising as a drug vehicle for cancer chemotherapy.

16.
J Control Release ; 128(1): 32-40, 2008 May 22.
Article in English | MEDLINE | ID: mdl-18395283

ABSTRACT

Cellular specific micellar systems from functional amphiphilic block copolymers are attractive for targeted intracellular drug delivery. In this study, we developed reactive micelles based on diblock copolymer of poly(ethyl ethylene phosphate) and poly(epsilon-caprolactone). The micelles were further surface conjugated with galactosamine to target asialoglycoprotein receptor (ASGP-R) of HepG2 cells. The size of micellar nanoparticles was about 70nm in diameter, and nanoparticles were negatively charged in aqueous solution. Through recognition between galactose ligands with ASGP-R of HepG2 cells, cell surface binding and internalization of galactosamine-conjugated micelles were significantly promoted, which were demonstrated by flow cytometric analyses using rhodamine 123 fluorescent dye. Paclitaxel-loaded micelles with galactose ligands exhibited comparable activity to free paclitaxel in inhibiting HepG2 cell proliferation, in contrast to the poor inhibition activity of micelles without galactose ligands particularly at lower paclitaxel doses. In addition, population of HepG2 cells arrested in G2/M phase was in positive response to paclitaxel dose when cells were incubated with paclitaxel-loaded micelles with galactosamine conjugation, which was against the performance of micelles without galactose ligand, owing to the ligand-receptor interaction. The surface functionalized micellar system is promising for specific anticancer drug transportation and intracellular drug release.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Asialoglycoprotein Receptor/metabolism , Drug Carriers/pharmacology , Paclitaxel/pharmacology , Polyesters/pharmacology , Polyethylenes/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Carriers/chemistry , Drug Carriers/metabolism , Galactosamine/chemistry , Glucosamine/chemistry , Humans , Micelles , Paclitaxel/chemistry , Polyesters/chemistry , Polyesters/metabolism , Polyethylenes/chemistry , Polyethylenes/metabolism
17.
Biomacromolecules ; 9(1): 388-95, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18081252

ABSTRACT

A series of novel amphiphilic triblock copolymers of poly(ethyl ethylene phosphate) and poly(-caprolactone) (PEEP-PCL-PEEP) with various PEEP and PCL block lengths were synthesized and characterized. These triblock copolymers formed micelles composed of a hydrophobic core of poly(-caprolactone) (PCL) and a hydrophilic shell of poly(ethyl ethylene phosphate) (PEEP) in aqueous solution. The micelle morphology was spherical, determined by transmission electron microscopy. It was found that the size and critical micelle concentration values of the micelles depended on both hydrophobic PCL block length and PEEP hydrophilic block length. The in vitro degradation characteristics of the triblock copolymers were investigated in micellar form, showing that these copolymers were completely biodegradable under enzymatic catalysis of Pseudomonas lipase and phosphodiesterase I. These triblock copolymers were used for paclitaxel (PTX) encapsulation to demonstrate the potential in drug delivery. PTX was successfully loaded into the micelles, and the in vitro release profile was found to be correlative to the polymer composition. These biodegradable triblock copolymer micelles are potential as novel carriers for hydrophobic drug delivery.


Subject(s)
Drug Carriers , Micelles , Polymers/chemistry
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