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1.
Biomaterials ; 101: 296-309, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27315213

RESUMO

The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50% wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive "T11" mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Portadores de Fármacos/química , Oxazóis/química , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico
2.
J Control Release ; 208: 67-75, 2015 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-25725361

RESUMO

The clinically and commercially successful taxanes, paclitaxel and docetaxel suffer from two major drawbacks, namely their very low aqueous solubility and the risk of developing resistance. Here, we present a method that overcomes both drawbacks in a very simple manner. We formulated 3rd generation taxoids, able to avoid common drug resistance mechanisms with doubly amphiphilic poly(2-oxazoline)s (POx), a safe and highly efficient polymer for the formulation of extremely hydrophobic drugs. We found excellent solubilization of different 3rd generation taxoids irrespective of the drug's chemical structures with essentially quantitative drug loading and final drug to polymer ratios around unity. The small, highly loaded micelles with a hydrodynamic diameter of less than 100nm are excellently suited for parenteral administration. Moreover, a selected formulation with the taxoid SB-T-1214 is about one to two orders of magnitude more active in vitro than paclitaxel in the multidrug resistant breast cancer cell line LCC6-MDR. In contrast, in wild-type LCC6, no difference was observed. Using a q4d×4 dosing regimen, we also found that POx/SB-T-1214 significantly inhibits the growth of LCC6-MDR orthotropic tumors, outperforming commercial paclitaxel drug Taxol and Cremophor EL formulated SB-T-1214.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Oxazóis/química , Taxoides/química , Taxoides/farmacologia , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Preparações de Ação Retardada , Feminino , Humanos , Camundongos , Camundongos Nus , Micelas , Tamanho da Partícula , Ensaios Antitumorais Modelo de Xenoenxerto
3.
ACS Nano ; 8(3): 2686-96, 2014 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-24548260

RESUMO

Defined aggregates of polymers such as polymeric micelles are of great importance in the development of pharmaceutical formulations. The amount of drug that can be formulated by a drug delivery system is an important issue, and most drug delivery systems suffer from their relatively low drug-loading capacity. However, as the loading capacities increase, i.e., promoted by good drug-polymer interactions, the drug may affect the morphology and stability of the micellar system. We investigated this effect in a prominent system with very high capacity for hydrophobic drugs and found extraordinary stability as well as a profound morphology change upon incorporation of paclitaxel into micelles of amphiphilic ABA poly(2-oxazoline) triblock copolymers. The hydrophilic blocks A comprised poly(2-methyl-2-oxazoline), while the middle blocks B were either just barely hydrophobic poly(2-n-butyl-2-oxazoline) or highly hydrophobic poly(2-n-nonyl-2-oxazoline). The aggregation behavior of both polymers and their formulations with varying paclitaxel contents were investigated by means of dynamic light scattering, atomic force microscopy, (cryogenic) transmission electron microscopy, and small-angle neutron scattering. While without drug, wormlike micelles were present, after incorporation of small amounts of drugs only spherical morphologies remained. Furthermore, the much more hydrophobic poly(2-n-nonyl-2-oxazoline)-containing triblock copolymer exhibited only half the capacity for paclitaxel than the poly(2-n-butyl-2-oxazoline)-containing copolymer along with a lower stability. In the latter, contents of paclitaxel of 8 wt % or higher resulted in a raspberry-like micellar core.


Assuntos
Portadores de Fármacos/química , Oxazóis/química , Paclitaxel/química , Química Farmacêutica , Interações Hidrofóbicas e Hidrofílicas , Micelas , Modelos Moleculares , Conformação Molecular , Solubilidade
4.
Macromol Rapid Commun ; 33(19): 1613-31, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22865555

RESUMO

Poly(2-oxazoline)s (POx) are currently discussed as an upcoming polymer platform for biomaterials design and especially for polymer therapeutics. POx meet specific requirements needed for the development of next-generation polymer therapeutics such as biocompatibility, high modulation of solubility, variation of size, architecture as well as chemical functionality. Although in the early 1990s first and promising POx-based systems were presented, the field lay dormant for almost two decades. Only very recently, POx-based polymer therapeutics came back into the focus of very intensive research. In this review, we give an overview on the chemistry and physicochemical properties of POx and summarize the research of POx-protein conjugates, POx-drug conjugates, POx-based polyplexes and POx micelles for drug delivery.


Assuntos
Portadores de Fármacos/química , Oxazóis/química , Materiais Biocompatíveis/química , Micelas , Nanomedicina , Nanopartículas/química , Preparações Farmacêuticas/química , Polímeros/química , Proteínas/química
5.
Mol Pharm ; 9(8): 2302-13, 2012 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-22681126

RESUMO

Many effective drugs for cancer treatment are poorly water-soluble. In combination chemotherapy, needed excipients in additive formulations are often toxic and restrict their applications in clinical intervention. Here, we report on amphiphilic poly(2-oxazoline)s (POx) micelles as a promising high capacity delivery platform for multidrug cancer chemotherapy. A variety of binary and ternary drugs combinations of paclitaxel (PTX), docetaxel (DTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), etoposide (ETO) and bortezomib (BTZ) were solubilized in defined polymeric micelles achieving unprecedented high total loading capacities of up to 50 wt % drug per final formulation. Multidrug loaded POx micelles showed enhanced stability in comparison to single-drug loaded micelles. Drug ratio dependent synergistic cytotoxicity of micellar ETO/17-AAG was observed in MCF-7 cancer cells and of micellar BTZ/17-AAG in MCF-7, PC3, MDA-MB-231 and HepG2 cells.


Assuntos
Micelas , Oxazóis/química , Antineoplásicos/química , Benzoquinonas/química , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Etoposídeo/química , Etoposídeo/farmacologia , Células Hep G2 , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Taxoides/química , Taxoides/farmacologia
6.
J Control Release ; 153(1): 73-82, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21513750

RESUMO

The family of poly(2-oxazoline)s (POx) is being increasingly investigated in the context of biomedical applications. We tested the relative cytotoxicity of POx and were able to confirm that these polymers are typically not cytotoxic even at high concentrations. Furthermore, we report structure-uptake relationships of a series of amphiphilic POx block copolymers that have different architectures, molar mass and chain termini. The rate of endocytosis can be fine-tuned over a broad range by changing the polymer structure. The cellular uptake increases with the hydrophobic character of the polymers and is observed even at nanomolar concentrations. Considering the structural versatility of this class of polymers, the relative ease of preparation and their stability underlines the potential of POx as a promising platform candidate for the preparation of next-generation polymer therapeutics.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Oxazóis/química , Oxazóis/metabolismo , Polímeros/química , Polímeros/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular , Humanos
7.
Biomaterials ; 31(18): 4972-9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20346493

RESUMO

Solubilization of highly hydrophobic drugs with carriers that are non-toxic, non-immunogenic and well-defined remains a major obstacle in pharmaceutical sciences. Well-defined amphiphilic di- and triblock copolymers based on poly(2-oxazolines) were prepared and used for the solubilization of Paclitaxel (PTX) and other water-insoluble drugs. Probing the polymer micelles in water with the fluorescence probe pyrene, an unusual high polar microenvironment of the probe was observed. This coincides with an extraordinary large loading capacity for PTX of 45 wt.% active drug in the formulation as well as high water solubility of the resulting formulation. Physicochemical properties of the formulations, ease of preparation and stability upon lyophilization, low toxicity and immunogenicity suggest that poly(2-oxazoline)s are promising candidates for the delivery of highly challenging drugs. Furthermore, we demonstrate that PTX is fully active and provides superior tumor inhibition as compared to the commercial micellar formulation.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Micelas , Neoplasias/tratamento farmacológico , Oxazóis/química , Paclitaxel/administração & dosagem , Polímeros/química , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos C57BL , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Solubilidade
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