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Nanoscale ; 11(18): 9163-9175, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31038150


Diabetes is a chronic metabolic disorder disease characterized by high blood glucose levels and has become one of the most serious threats to human health. In recent decades, a number of insulin delivery systems, including bulk gels, nanogels, and polymeric micelles, have been developed for the treatment of diabetes. Herein, a kind of glucose and H2O2 dual-responsive polymeric nanogel was designed for enhanced glucose-responsive insulin delivery. The polymeric nanogels composed of poly(ethylene glycol) and poly(cyclic phenylboronic ester) (glucose and H2O2 dual-sensitive groups) were synthesized by a one-pot thiol-ene click chemistry approach. The nanogels displayed glucose-responsive release of insulin and the release rate could be promoted by the incorporation of glucose oxidase (GOx), which generated H2O2 at high glucose levels and H2O2 further oxidizes and hydrolyzes the phenylboronic ester group. The nanogels have characteristics of long blood circulation time, a fast response to glucose, and excellent biocompatibility. Moreover, subcutaneous delivery of insulin to diabetic mice with the insulin/GOx-loaded nanogels presented an effective hypoglycemic effect compared to that of injection of insulin or insulin-loaded nanogels. This kind of nanogel would be a promising candidate for the delivery of insulin in the future.

Glucose Oxidase/química , Glucose/metabolismo , Peróxido de Hidrogênio/metabolismo , Hipoglicemiantes/metabolismo , Insulina/metabolismo , Polietilenoglicóis/química , Polietilenoimina/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Química Click , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Portadores de Fármacos/química , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Glucose/química , Glucose Oxidase/metabolismo , Teste de Tolerância a Glucose , Peróxido de Hidrogênio/química , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Insulina/química , Insulina/uso terapêutico , Camundongos , Células NIH 3T3 , Polietilenoglicóis/toxicidade , Polietilenoimina/toxicidade
Colloids Surf B Biointerfaces ; 180: 376-383, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082775


Large amounts of insulin-loaded glucose-responsive micelles based on poly(amino acid)s have been developed for diabetes treatment over last decades, but most of them could not effectively protect insulin from enzymatic degradation in vivo because the micellar core was biodegradable and lacked protective structure for insulin, which would lower the efficacy of insulin to a large extent. In this study, we fabricated a new type of insulin-loaded glucose-responsive complex micelles (CMs), which were self-assembled by a phenylboronic acid (PBA)-modified block copolymer PEG-b-P(Asp-co-AspPBA) and a glucosamine (GA)/nitrilotriacetic acid (NTA)-functionalized block copolymer PNIPAM-b-P(Asp-co-AspGA-co-AspNTA), for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo. The CMs possessed mixed shell of PEG/PNIPAM and cross-linked core of PBA/GA complex, which could be disintegrated under the condition of high glucose concentration (5 g/L) while maintaining stable at low glucose concentration (1 g/L). The NTA groups of CMs greatly improved the loading content of insulin by specifically bind insulin via the chelated zinc ions. More importantly, PNIPAM chains in the mixed shell would collapse under 37 °C and form hydrophobic domains around the micellar core, which could significantly protect the micellar core as well as the encapsulated insulin from attacking by external proteases. In a murine model of type 1 diabetes, the CMs with insulin chelated by NTA showed a long hypoglycemic effect, which is superior to insulin-loaded simple micelles without PNIPAM and insulin in PBS buffer (pH 7.4). Therefore, this kind of CMs could be a potential candidate for insulin delivery in diabetes therapy.

Biomater Sci ; 7(7): 2986-2995, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31106796


Because of their abnormal vasculature and the dense tumor extra-cellular matrix, solid tumors prevent the deep and uniform penetration of nanocarriers. Numerous studies have shown that nanocarriers with a positively charged surface exhibit enhanced tumor penetration. Therefore, a hypoxia responsive nanocarrier [responsive micelles (RMs)] was developed, which can gradually increase the positive surface charge by responding to hypoxia gradients, and eventually achieve deep penetration in tumors. The nanocarrier was composed of a poly(caprolactone) core and a mixed shell of poly(ethylene glycol) (PEG) and 4-nitrobenzyl chloroformate (NBCF)-modified polylysine (PLL). During the blood circulation, the NBCF-modified PLL was shielded by the PEG, which gave it the ability to inhibit its rapid removal by the immune system. After reaching the tumor, the hypoxia microenvironment triggered partial NBCF degradation that recovered the amine groups of PLL, leading to a remarkable change in the surface to a positively charged one that enabled the penetration of the nanocarrier into the tumor. As the nanocarrier penetrated into the interior of the tumor, the decrease in oxygen concentration led to the further degradation of the NBCF-modified PLL, resulting in the increase of the positive surface charge which further facilitated the deep penetration. The subsequent in vitro and in vivo experiments certified that RM/doxorubicin had a better penetration ability and improved inhibition efficacy on tumor tissues, which demonstrated its potential application in cancer therapy.

ACS Appl Mater Interfaces ; 10(6): 5296-5304, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29338179


Targeted drug delivery of nanomedicines offered a promising strategy to improve the tumor accumulation and reduce the side effects of chemotherapeutics. However, undesired recognition of the targeting ligands on the surface of nanocarriers by immune systems or normal tissues decreased the circulation time and reduced the targeting efficiency. Here, we developed a ligand-switchable micellar nanocarrier that can hide the targeting ligands when circulating in the bloodstream and expose them on the surface when entering the tumor microenvironments. With the ligand-switching capability, the nanocarrier achieved a 66% longer blood circulation half-life and a 23% higher tumor accumulation than the nanocarrier with targeting ligands on the surface. This targeting strategy could serve as a universal approach to improve the targeting efficiency for nanomedicines.

Acta Biomater ; 65: 339-348, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29079515


Recently, zwitterionic materials have been developed as alternatives to PEG for prolonging the circulation time of nanoparticles without triggering immune responses. However, zwitterionic coatings also hindered the interactions between nanoparticles and tumor cells, leading to less efficient uptake of nanoparticles by cancer cells. Such effect significantly limited the applications of zwitterionic materials for the purposes of drug delivery and the development to novel therapeutic agents. To overcome these issues, surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(ß-amino ester) (PAE) heterogeneous surfaces were constructed. Owing to the synergistic effect of zwitterionic coatings and micro-phase-separated surfaces, PMPC mixed-shell micelles exhibited the improved blood circulation time compared to single-PEG-shell micelles (PEGSMs) and single-PMPC-shell micelles (PMPCSMs). Moreover, such MSMs can convert their surface to positively charged ones in response to the acidic tumor microenvironment, leading to a significant enhancement in cellular uptake of MSMs by tumor cells. This strategy demonstrated a general approach to enhance the cellular uptake of zwitterionic nanoparticles without compromising their long circulating capability, providing a practical method for improving the tumor-targeting efficiency of particulate drug delivery systems. STATEMENT OF SIGNIFICANCE: Herein we demonstrate a general strategy to integrate non-fouling zwitterionic surface on the nanoparticles without compromising their capability of tumor accumulation, by constructing a surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(ß-amino ester) (PAE) heterogeneous surfaces. At the blood pH (7.4), PAE chains collapsed to the inner of the shell due to the deprotonation, and the forming micro-phase separation structure was synergistic with zwitterionic surface to prolong the circulation time of MSMs in the blood. While at the tumor sites, PAE was protonated, and the positively charged surface of MSMs enhanced cellular uptake. This self-assembly-based strategy is compatible to other zwitterionic materials, endowing a great flexibility for the construction of responsive drug delivery systems particularly to the novel chemotherapeutic agents.

Tempo de Circulação Sanguínea , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas , Animais , Antineoplásicos/administração & dosagem , Células HEK293 , Células Hep G2 , Humanos , Íons , Metacrilatos/química , Micelas , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Polímeros/química , Ratos Sprague-Dawley , Propriedades de Superfície , Distribuição Tecidual , Microambiente Tumoral
Theranostics ; 6(9): 1277-92, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375779


Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.

Antibióticos Antineoplásicos/farmacologia , Catequina/administração & dosagem , Doxorrubicina/farmacologia , Portadores de Fármacos/administração & dosagem , Micelas , Nanoestruturas/administração & dosagem , Chá/química , Antibióticos Antineoplásicos/administração & dosagem , Cardiotoxicidade/prevenção & controle , Catequina/análogos & derivados , Catequina/isolamento & purificação , Catequina/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Resistência a Múltiplos Medicamentos , Humanos , Nanoestruturas/química