RESUMO
The novel self-assembling bottlebrush polyethylene glycol-polynorbornene-thiocresol block copolymers (PEG-PNB-TC) were synthesized by the ring opening metathesis polymerization (ROMP), followed by functionalization of the polymer backbone via the thio-bromo "click" postpolymerization strategy. The PEG-PNB-TC copolymers could easily self-assemble into the nanoscale core-shell polymeric micelles. The hydrophobic anticancer drugs, such as paclitaxel (PTX), could be loaded into their hydrophobic core to form a stable drug-loaded micelle with a superior drug loading capacity of up to â¼35% (w/w). The sustained drug release behavior of the PEG-PNB-TC micelles was observed under a simulated "sink condition". Compared with commercial PTX formulation (Taxol), the PTX-loaded PEG-PNB-TC micelles showed the enhanced in vitro cellular uptake and comparable cytotoxicity in the drug-sensitive cancer cells, while the copolymers were much safer than Cremophor EL, the surfactant used in Taxol. Furthermore, curcumin (CUR), a natural chemotherapy drug sensitizer, was successfully coloaded with PTX into the PEG-PNB-TC micelles. High drug loading capacity of the PEG-PNB-TC micelles allowed for easy adjustment of drug doses and the ratio of the coloaded drugs. The combination of PTX and CUR showed synergistic anticancer effect in both the drug mixture and drug coloaded micelles at high CUR/PTX ratio, while low CRU/PTX ratio only exhibited additive effects. The combinatorial effects remarkably circumvented the PTX resistance in the multidrug resistant (MDR) cancer cells. Due to the easy polymerization and functionalization, excellent self-assembly capability, high drug loading capability, and great stability, the PEG-PNB-TC copolymers might be a promising nanomaterial for delivery of the hydrophobic anticancer drugs, especially for combination drug therapy.
Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Micelas , Paclitaxel/farmacologia , Polímeros/química , Células A549 , Antineoplásicos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Curcumina/administração & dosagem , Células HeLa , Humanos , Paclitaxel/administração & dosagem , Plásticos/químicaRESUMO
Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to ICIs, highlighting the need for superior immunotherapy. Herein, we report on a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) designed to enhance the efficacy of PD-L1 inhibitor. ARAC is a nanoparticle co-delivering PLK1 inhibitor (volasertib) and PD-L1 antibody. PLK1 is a key mitotic kinase that is overexpressed in various cancers including NSCLC and drives cancer growth. Inhibition of PLK1 selectively kills cancer cells and upregulates PD-L1 expression in surviving cancer cells thereby providing opportunity for ARAC targeted delivery in a feedforward manner. ARAC reduces effective doses of volasertib and PD-L1 antibody by 5-fold in a metastatic lung tumor model (LLC-JSP) and the effect is mainly mediated by CD8+ T cells. ARAC also shows efficacy in another lung tumor model (KLN-205), which does not respond to CTLA-4 and PD-1 inhibitor combination. This study highlights a rational combination strategy to augment existing therapies by utilizing our nanoparticle platform that can load multiple cargo types at once.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1RESUMO
The success of immunotherapy with immune checkpoint inhibitors (ICIs) in a subset of individuals has been very exciting. However, in many cancers, responses to current ICIs are modest and are seen only in a small subsets of patients. Herein, a widely applicable approach that increases the benefit of ICIs is reported. Intratumoral administration of augmenting immune response and inhibiting suppressive environment of tumors-AIRISE-02 nanotherapeutic that co-delivers CpG and STAT3 siRNA-results in not only regression of the injected tumor, but also tumors at distant sites in multiple tumor model systems. In particular, three doses of AIRISE-02 in combination with systemic ICIs completely cure both treated and untreated aggressive melanoma tumors in 63% of mice, while ICIs alone do not cure any mice. A long-term memory immune effect is also reported. AIRISE-02 is effective in breast and colon tumor models as well. Lastly, AIRISE-02 is well tolerated in mice and nonhuman primates. This approach combines multiple therapeutic agents into a single nanoconstruct to create whole-body immune responses across multiple cancer types. Being a local therapeutic, AIRISE-02 circumvents regulatory challenges of systemic nanoparticle delivery, facilitating rapid translation to the clinic. AIRISE-02 is under investigational new drug (IND)-enabling studies, and clinical trials will soon follow.
Assuntos
Imunoterapia , Nanopartículas , RNA Interferente Pequeno , Animais , Camundongos , VacinaçãoRESUMO
Combination therapy is considered to be a promising strategy for improving the therapeutic efficiency of cancer treatment. In this study, an on-demand pH-sensitive nanocluster (NC) system was prepared by the encapsulation of gold nanorods (AuNR) and doxorubicin (DOX) by a pH-sensitive polymer, poly(aspartic acid-graft-imidazole)-PEG, to enhance the therapeutic effect of chemotherapy and photothermal therapy. At pH 6.5, the NC systems formed aggregated structures and released higher drug amounts while sustaining a stable nano-assembly, structured with less systemic toxicity at pH 7.4. The NC could also increase antitumor efficacy as a result of improved accumulation and release of DOX from the NC system at pHex and pHen with locally applied near-infrared light. Therefore, an NC system would be a potent strategy for on-demand combination treatment to target tumors with less systemic toxicity and an improved therapeutic effect.
RESUMO
Background: A very common and simple method (known as the blending method) to formulate drug delivery systems with required properties is to physically mix amphiphilic block copolymers with different hydrophobicity. In addition to its simplicity, this blending strategy could help avoid the time and effort involved in the synthesis of block copolymers with the desired structure required for specific drug formulations. Purpose: We used the blending strategy to design a system that could overcome the problem of high hydrophobicity and be a good candidate for drug product development using PEG-PLA-PEG triblock copolymers. Methods: Two types of PEG-PLA-PEG triblock copolymers with similar (long) PLA molecular weights (MWs) and different PEG MWs were synthesized. The micellar formulations were prepared by blending the two block copolymers in various ratios. The size and stability of the blending systems were subsequently investigated to optimize the formulations for further studies. The loading properties of doxorubicin or paclitaxel into the optimized blending system were compared to that in mono systems (systems composed of only a single type of triblock copolymer). In vitro and in vivo anti-cancer effects of the preparations were evaluated to assess the use of the blending system as an optimal nanomedicine platform for insoluble anticancer agents. Results: The blending system (B20 system) with an optimized ratio of the triblock copolymers overcame the drawbacks of mono systems. Drug uptake from the drug-loaded B20 system and its anticancer effects against KB cells were superior compared to those of free drugs (doxorubicin hydrochloride and free paclitaxel). In particular, doxorubicin-loaded B20 resulted in extensive doxorubicin accumulation in tumor tissues and significantly higher in vivo anti-cancer effects compared to free doxorubicin. Conclusion: The blending system reported here could be a potential nanoplatform for drug delivery due to its simplicity and efficiency for pharmaceutical application.
Assuntos
Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Animais , Antineoplásicos/farmacologia , Coloides/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Células KB , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Paclitaxel/farmacologia , Poliésteres/química , Polietilenoglicóis/química , Solubilidade , Distribuição Tecidual/efeitos dos fármacosRESUMO
Correction for 'Synergistic photodynamic therapeutic effect of indole-3-acetic acid using a pH sensitive nano-carrier based on poly(aspartic acid-graft-imidazole)-poly(ethylene glycol)' by Taehoon Sim et al., J. Mater. Chem. B, 2017, 5, 8498-8505.
RESUMO
BACKGROUND: Blending micellar systems of different types of polymers has been proposed as an efficient approach for tailor-made drug formulations. The lamellar structure of hydrophobic polymers may provide a high drug loading capacity, and hydrophilic polymers may provide good colloidal stability. METHODS: In this study, the anticancer model drug docetaxel was loaded onto a nanosized blending micellar system with two pluronics (L121/F127). To achieve increased antitumor activity, the cyclic arginine-glycine-aspartic acid tripeptide (cRGD) as an active tumor targeting ligand was conjugated to the blending system. RESULTS: The docetaxel-loaded Pluronic blending system exhibited a higher drug loading capacity than that of F127 and showed high colloidal stability with a spherical structure. cRGD conjugates demonstrated enhanced drug cellular uptake and anticancer activity against αvß3 integrin-overexpressing U87MG cancer cells. In vivo animal imaging also revealed that the prepared cRGD-conjugated nanoparticles effectively accumulated at the targeted tumor site through an active and passive targeting strategy. CONCLUSION: Accordingly, the prepared nanosized system shows potential as a tailor-made, active targeting, nanomedicinal platform for anticancer therapy. We believe that this novel nanoplatform will provide insights for advancement of tumor therapy.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Peptídeos Cíclicos/química , Poloxâmero/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Nanopartículas/químicaRESUMO
Oncothermia, a special form of hyperthermia for oncological purposes, has been widely shown to be an effective mode of cancer therapy. However, its adoption among standard therapeutic practices has been limited by constraints in delivering sufficient thermal energy to tumor targets. To overcome these unique challenges in delivery presented by oncothermic therapeutics, we engineered a novel universal platform for hyperthermia cancer therapy utilizing versatile biocompatible materials. Herein, we show that Gold particle-in-particle (PIP), in which gold nanoparticles are physically confined within PLGA-PEG nanoparticles, significantly enhances thermal energy production by red-shifting the gold nanoparticle's absorption spectra via a mechanism in which we call nanoconfinement-induced therapeutic enhancement (NITE). NITE mediated Gold PIPs significantly suppress breast, skin, and multidrug resistant tumors and result in a multifold increase of heat shock protein expressed by cancer cells in vivo. Cotreatment of Gold PIP with doxorubicin shows a synergistic advantage. By using tumor-bearing mice, significant suppression of tumor growth by Gold PIPs shows the advantage of NITE mediated hyperthermia. Thus, we conclude that NITE mediated Gold PIP can be a strong anticancer therapy because of its sufficient amount of heat generation.
RESUMO
Docetaxel (DTX)-loaded polymeric micelles (DTBM) were formulated using the triblock copolymer, poly(ethylene glycol)-polylactide-poly(ethylene glycol) (PEG-PLA-PEG), to comprehensively study their pharmaceutical application as anticancer nanomedicine. DTBM showed a stable formulation of anticancer nanomedicine that could be reconstituted after lyophilization (DTBM-R) in the presence of PEG 2000 and D-mannitol (Man) as surfactant and protectant, respectively. DTBM-R showed a particle size less than 150 nm and greater than 90% of DTX recovery after reconstitution. The robustly formed micelles might minimize systemic toxicity due to their sustained drug release and also maximize antitumor efficacy through increased accumulation and release of DTX from the micelles. From the pharmaceutical development point of view, DTBM-R showing successful reconstitution could be considered as a potent nanomedicine for tumor treatment.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Poliésteres/química , Polietilenoglicóis/química , Polímeros/química , Taxoides/química , Animais , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Docetaxel , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Células KB , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Nanomedicina/métodos , Tamanho da Partícula , Tensoativos/química , Taxoides/administração & dosagemRESUMO
Polyelectrolyte has been proposed as an efficient approach for various types of drug formulations. However, one drawback of using the conventional polyelectrolyte for drug delivery is its dissociation in in vivo conditions by counter ions due to the lack of self-assembling aggregation force. In this study, we reported a stable nanoplatform based on triblock co-polyelectrolyte composed of a poly(ethylene glycol), poly(l-lysine), and poly(lactic acid). These co-polyelectrolytes formed stable aggregates through the hydrophobic interaction of PLA and showed consistent particle sizes under a high salt concentration. In addition, the doxorubicin (Dox) loaded triblock co-polyelectrolyte demonstrated enhanced cellular uptake and drug cytotoxicity with a positive charge from the poly(l-lysine) layer. In vivo, the triblock aggregates exhibited intensive accumulation at the targeted tumor site for 24h with good antitumor therapeutic efficacy. Therefore, the prepared stable triblock co-polyelectrolyte may have considerable potential as a nanomedicinal platform for anticancer and multi-drug combination therapy.
Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Nanopartículas/química , Polieletrólitos/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Células KB , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Cloreto de Sódio/química , Propriedades de SuperfícieRESUMO
A polyelectrolyte nanoparticle composed of PEG-PLL(-g-Ce6, DMA)-PLA was developed for nanomedicinal application in photodynamic therapy. These nanoparticles formed stable aggregates through the hydrophobic interaction of poly(lactic acid) and demonstrated pH-dependent behaviors such as surface charge conversion and enhanced cellular uptake at acidic pH, resulting in improved phototoxicity. In vivo animal imaging revealed that the prepared PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles effectively accumulated at the targeted tumor site through enhanced permeability and retention effects. Reversible surface charge for PEG-PLL (-g-Ce6, DMA)-PLA nanoparticles allows the nanoparticles to escape the immune system and concentrate on the tumor tissue. Tumor growth in the nude mice treated with the nanoparticles decreased significantly and the hydrophobic interaction in the poly(lactic acid) block could allow the incorporation of multiple drugs. Therefore, the PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles could have considerable potential as a nanomedicinal platform for photodynamic therapy.
Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Animais , Clorofilídeos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Células KB , Anidridos Maleicos/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Poliésteres/química , Polietilenoglicóis/química , Polilisina/análogos & derivados , Polilisina/química , Porfirinas/químicaRESUMO
Poly(aspartic acid-graft-imidazole)-poly(ethylene glycol) (P(Asp-g-Im)-PEG) was utilized as a pH-sensitive nanocarrier of the photosensitizer indole-3-acetic acid (IAA) for the treatment of skin cancer. IAA loaded micelles (ILMs) exhibited the formation of ca. 140 nm spherical particles at pH 7.4. The micelles disintegrated at acidic pHs, resulting in pH-dependent IAA release and cytotoxicity. Treatment of ILMs with visible light at a wavelength of 480 nm caused pH dependent synergistic cell damage in both in vitro and in vivo models using the B16F10 melanoma cell line. Interestingly, ILMs synergistically produced reactive oxygen species (ROS) at an acidic pH of 6.5 with visible light irradiation by proton coupled electron transfer (PCET). The pH sensitive ILMs could be considered a potent nanomedicine used to exert synergistic photodynamic therapeutic effects to treat cancers.
RESUMO
A polyelectrolyte ionomer complex (PIC) composed of cationic and anionic polymers was developed for nanomedical applications. Here, a poly(ethylene glycol)-poly(lactic acid)-poly(ethylene imine) triblock copolymer (PEG-PLA-PEI) and a poly(aspartic acid) (P[Asp]) homopolymer were synthesized. These polyelectrolytes formed stable aggregates through electrostatic interactions between the cationic PEI and the anionic P(Asp) blocks. In particular, the addition of a hydrophobic PLA and a hydrophilic PEG to triblock copolyelectrolytes provided colloidal aggregation stability by forming a tight hydrophobic core and steric hindrance on the surface of PIC, respectively. The PIC showed different particle sizes and zeta potentials depending on the ratio of cationic PEI and anionic P(Asp) blocks (C/A ratio). The doxorubicin (dox)-loaded PIC, prepared with a C/A ratio of 8, demonstrated pH-dependent behavior by the deprotonation/protonation of polyelectrolyte blocks. The drug release and the cytotoxicity of the dox-loaded PIC (C/A ratio: 8) increased under acidic conditions compared with physiological pH, due to the destabilization of the formation of the electrostatic core. In vivo animal imaging revealed that the prepared PIC accumulated at the targeted tumor site for 24 hours. Therefore, the prepared pH-sensitive PIC could have considerable potential as a nanomedicinal platform for anticancer therapy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Iminas/química , Nanopartículas/química , Polietilenoglicóis/química , Polietilenos/química , Polímeros/química , Animais , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Portadores de Fármacos , Feminino , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Nanopartículas/administração & dosagem , Eletricidade Estática , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We have developed nanomedicine vehicle based on a biocompatible tri-block copolymer, poly(ethylene glycol)-block-poly(lactic acid)-block-poly(ethylene glycol) (PEG-PLA-PEG) by simple approach without toxic linker to escalate therapeutic efficacy of anticancer agent by enhanced targeting to metastasized breast cancers. The synthesized ABA type copolymer had a low polydispersity index and formed small, highly stable spherical micelles. Furthermore, a functional group at the end site of the copolymer can be decorated with imaging agents and targeting moieties. The doxorubicin loaded micelles (DLM) showed higher drug-loading capacity, faster drug release, and better cell toxicity compared to those using di-block copolymers. DLM efficiently delivered to the metastatic breast cancers in brain and bone and suppressed growing of metastasis. In demonstration of treating metastasized animal model, we present a tri-block copolymer as a potential nanomedicine vehicle to efficiently deliver anticancer drug and to effectively treat metastatic breast cancer.