Poly-L-aspartic acid as a carrier for doxorubicin: A comparative in vivo study of free and polymer-bound drug

Pratesi, Graziella; Savi, Giuseppina; Pezzoni, Gabriella; Bellini, O; Penco, Sergio; Tinelli, Stella; Zunino, Franco

doi:10.1038/bjc.1985.267

Cited by 39 publications

(26 citation statements)

References 8 publications

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“…(21,22) Retrospectively, DOX was covalently linked to poly-L-aspartic acid with a molecular weight of 20 000 through ester linkage and the preclinical efficacy was evaluated. (23) The conjugate was found to show a marginal therapeutic advantage over native DOX. Additionally, DOX was conjugated to PEG through amino linkage with a peptide linker.…”

Section: Discussionmentioning

confidence: 99%

Improved anti‐tumor activity of stabilized anthracycline polymeric micelle formulation, NC‐6300

Harada¹,

Bobe

Saito

et al. 2010

Cancer Science

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Anthracyclines have long been considered to be among the most active agents clinically available for the treatment of breast cancer despite their toxicity. To improve their pharmacological profiles, a new macromolecular prodrug, denoted NC-6300, was synthesized. NC-6300 comprises epirubicin covalently bound to polyethyleneglycol polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure spontaneously in aqueous media with a diameter of 60-70 nm. The block copolymers are partially substituted with hydrophobic benzyl groups to stabilize the micellar structure. The present study was designed to confirm that polymeric micelles incorporating epirubicin through an acid-labile linker improve the therapeutic index and achieve a broad range of therapeutic doses. Pharmacokinetic studies in rats showed highly enhanced plasma retention of NC-6300 compared with native epirubicin. The maximal tolerated doses in mice of NC-6300 and native epirubicin were 25 and 9 mg/kg, respectively, when administered three times with a 4-day interval between each dose. NC-6300 at 15 and 20 mg/kg with the same administration schedule regressed a Hep3B human hepatic tumor with slight and transient bodyweight loss. Remarkably, NC-6300 also inhibited growth of an MDA-MB-231 human breast tumor at the same dosage. In contrast, native epirubicin at 7 mg/kg administered three times with a 4-day interval was only able to slow tumor growth. Tissue distribution studies of NC-6300 showed efficient free epirubicin released in the tumor at 74% by area under the concentration-time curve (AUC) evaluation, supporting the effectiveness of NC-6300. In conclusion, NC-6300 improved the potency of epirubicin, demonstrating the advantage of NC-6300 attributable to the efficient drug release in the tumor. (Cancer Sci 2011; 102: 192-199) A nthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease despite their cardiotoxicity.(1) The aim of increasing their efficacy was first addressed using liposomes.(2) Efforts to design liposomes that are pH-sensitive, temperature-sensitive or antibody-targeted have all been pursued with various degrees of success.(3) However, current clinically approved liposomal formulations have still resulted in only modest increased efficacy for the treatment of cancer.(4) Its actual advantage is reduced toxicity rather than increased therapeutic effect. To increase the efficacy, polymer-based anthracyclines have also been studied extensively. (8,9) Recent strategies have been developed and successfully applied to attain desirable tumor localization through polymeric micelles composed of polyethylene glycol (PEG)-poly (amino acid) block copolymers.(10) These types of strategies involve drug release inside endosomes and lysosomes after cellular internalization, where the slightly acidic pH leads to cleavage of the acid-sensitive linkage.

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Section: Discussionmentioning

confidence: 99%

Improved anti‐tumor activity of stabilized anthracycline polymeric micelle formulation, NC‐6300

Harada¹,

Bobe

Saito

et al. 2010

Cancer Science

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“…24,25 DOX possesses positive charge and has been studied for its complexation with various anionic polymers such as poly(acrylic acid), 26,27 γ-polyglutamic acid, 28 polyaspartate, 24,29 polyglutamate, 30 block ionomers of aspartate, benzyl aspartate, [31][32][33][34] benzyl glutamate, 29 and polyethylene oxide. These polyanions form polyelectrolyte complexes with DOX.…”

Section: Introductionmentioning

confidence: 99%

Polyanionic carbohydrate doxorubicin–dextran nanocomplex as a delivery system for anticancer drugs: in vitro analysis and evaluations

Yousefpour

Atyabi

Farahani³

et al. 2011

IJN

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This study deals with the preparation and investigation of a nanoscale delivery system for the anticancer drug doxorubicin (DOX) using its complexation with polyanionic carbohydrate dextran sulfate (DS). Dynamic light scattering, SEM, and zeta potential determination were used to characterize nanocomplexes. DOX-DS complexation was studied in the presence of ethanol as a hydrogen-bond disrupting agent, NaCl as an electrostatic shielding agent, and chitosan as a positively charged polymer. Thermodynamics of DOX-DS interaction was studied using isothermal titration calorimetry (ITC). A dialysis method was applied to investigate the release profile of DOX from DOX-DS nanocomplexes. Spherical and smooth-surfaced DOX-DS nanocomplexes (250–500 nm) with negative zeta potential were formed at a DS/DOX (w/w) ratio of 0.4–0.6, with over 90% drug encapsulation efficiency. DOX when complexed with DS showed lower fluorescence emission and 480 nm absorbance plus a 15 nm bathometric shift in its visible absorbance spectrum. Electrostatic hydrogen bonding and π-π stacking interactions are the main contributing interactions in DOX-DS complexation. Thermal analysis of DOX-DS complexation by ITC revealed that each DOX molecule binds with 3 DS glycosyl monomers. Drug release profile of nanocomplexes showed a fast DOX release followed by a slow sustained release, leading to release of 32% of entrapped DOX within 15 days. DOX-DS nanocomplexes may serve as a drug delivery system with efficient drug encapsulation and also may be taken into consideration in designing DOX controlled-release systems.

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“…Poly(aspartic acid) is used as a substitute for nonbiodegradable polyacrylates, for which many technical applications are described (35), such as water treatment (water softeners) and others (4,32). Biomedical applications of poly(aspartic acid) have also been described (19,30,43). In addition, it can be also considered a source of arginine and aspartic acid, and therefore there is strong interest in producing CGP.…”

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confidence: 99%

Protamylasse, a Residual Compound of Industrial Starch Production, Provides a Suitable Medium for Large-Scale Cyanophycin Production

Elbahloul

Frey

Sanders

et al. 2005

Appl Environ Microbiol

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Protamylasse is a residual compound occurring during the industrial production of starch from potatoes. It contains a variety of nutrients and all necessary minerals and could be used as a carbon, nitrogen, and energy source for the growth of bacteria and also for cyanophycin (CGP) biosynthesis. Media containing protamylasse as the sole compound diluted only in water were therefore examined for their suitability in CGP production. Among various bacterial strains investigated in this study, a recombinant strain of Escherichia coli DH1 harboring plasmid pMa/c5-914::cphA 6803 , which carries the cyanophycin synthetase structural gene (cphA) from Synechocystis sp. strain PCC6803, was found to be most suitable. Various cultivation conditions for high CGP contents were first optimized in shake flask cultures. The optimized conditions were then successfully applied to 30-and 500-liter fermentation scales in stirred tank reactors. A maximum CGP content of 28% (wt/wt) CGP per cell dry matter was obtained in 6% (vol/vol) protamylasse medium at an initial pH of 7.0 within a cultivation period of only 24 h. The CGP contents obtained with this recombinant strain employing protamylasse medium were higher than those obtained with the same strain cultivated in mineral salts medium or in expensive commercial complex media such as Luria-Bertani or Terrific broth. It was shown that most amino acids present in the protamylasse medium were almost completely utilized by the cells during cultivation. Exceptions were alanine, tryptophan, tyrosine, and most interestingly, arginine. Furthermore, CGP was easily isolated from protamylasse-grown cells by applying the acid extraction method. The CGP exhibited a molecular mass of about 26 to 30 kDa and was composed of 50% (mol/mol) aspartate, 46% (mol/mol) arginine, and 4% (mol/mol) lysine. The use of cheap residual protamylasse could contribute in establishing an economically and also ecologically feasible process for the biotechnological production of CGP.

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Poly-L-aspartic acid as a carrier for doxorubicin: A comparative in vivo study of free and polymer-bound drug

Cited by 39 publications

References 8 publications

Improved anti‐tumor activity of stabilized anthracycline polymeric micelle formulation, NC‐6300

Improved anti‐tumor activity of stabilized anthracycline polymeric micelle formulation, NC‐6300

Polyanionic carbohydrate doxorubicin–dextran nanocomplex as a delivery system for anticancer drugs: in vitro analysis and evaluations

Protamylasse, a Residual Compound of Industrial Starch Production, Provides a Suitable Medium for Large-Scale Cyanophycin Production

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Poly-L-aspartic acid as a carrier for doxorubicin: A comparative in vivo study of free and polymer-bound drug

Cited by 39 publications

References 8 publications

Improved anti‐tumor activity of stabilized anthracycline polymeric micelle formulation, NC‐6300

Improved anti‐tumor activity of stabilized anthracycline polymeric micelle formulation, NC‐6300

Polyanionic carbohydrate doxorubicin&ndash;dextran nanocomplex as a delivery system for anticancer drugs: in vitro analysis and evaluations

Protamylasse, a Residual Compound of Industrial Starch Production, Provides a Suitable Medium for Large-Scale Cyanophycin Production

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Polyanionic carbohydrate doxorubicin–dextran nanocomplex as a delivery system for anticancer drugs: in vitro analysis and evaluations