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Clinically relevant anticancer polymer Paclitaxel therapeutics.

Yang D, Yu L, Van S - Cancers (Basel) (2010)

Bottom Line: However, none have as yet been approved by the U.S. Food and Drug Administration.PGG-PTX has its own unique property of forming nano-particles.This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Engineering and Technology Institute, Institutes for Advanced Interdisciplinary Research, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China. yu_lei@gg.nitto.co.jp.

ABSTRACT
The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(L-g-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.

No MeSH data available.


Related in: MedlinePlus

Structure of PG-PTX (a), paclitaxel (b), and PGG-PTX (c).
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f3-cancers-03-00017: Structure of PG-PTX (a), paclitaxel (b), and PGG-PTX (c).

Mentions: The concepts of coupling an anti-cancer drug to a polymer were essentially developed in the early 1980s [8,11]. It took about 20 years for the first polymer-paclitaxel conjugate (PNU166945) to enter a Phase I clinical trial [12]. Polymer-paclitaxel conjugates have been designed to improve the plasma pharmacokinetics by avoiding kidney filtration and to passively target hypervasculature, defective vascular architecture, and an impaired lymphatic drainage of tumor tissues, that is known as “enhanced permeability and retention” effects [13]. Recent clinical advances in polymer-paclitaxel conjugates are credited to co-polymer hydroxypropylmethacrylamide-paclitaxel conjugate (HPMA-PTX) [12] and poly(l-glutamic acid)-paclitaxel conjugate (PG-PTX) [14]. A schematic representation of the chemical structure of HPMA-PTX and PG-PTX is shown in Figure 2 and Figure 3a, respectively. HPMA-PTX is a water-soluble co-polymer in which paclitaxel is covalently bound through an ester bond at its 2′-OH position with an enzymatic degradable linker of Gly-Phe-Leu-Gly peptide. The polymer:paclitaxel ratio was approximately 19:1 (5%) by weight to weight. To improve paclitaxel drug loading, Li et al. [15] changed the polymer backbone to poly(l-glutamic acid). The amount of paclitaxel loading of PG-PTX improved to 20% by weight to weight, but the resulting conjugate contained mixed paclitaxel substitutions at both the C-2′ and C-7 ester positions [15]. With optimization of coupling chemistry of paclitaxel, paclitaxel loading increased to 37% by weight by weight [16]. In a similar platform, poly(lL-γ-glutamylglutamine)-paclitaxel nanoconjugate (PGG-PTX, as shown in Figure 3 (c)), was reported that with an additional glutamic acid as a linker between poly(l-glutamic acid) and paclitaxel, the paclitaxel drug loading was 35% weight by weight, and dissolution of PGG-PTX was faster than that of PG-PTX [17]. Futhermore, the glutamic acid linker provided enough flexibility of the PGG-PTX for self-assembly into nanoparticles whose size remains in the range of 12–15 nm (volume) over the concentration range of 25 to 2,000 μg/mL in saline [17]. Conjugation of paclitaxel can be achieved quantitatively, but it requires highly dried conditions to facilitate the completion of ester coupling in the presence of a 4-dimethylaminopyridine catalyst.


Clinically relevant anticancer polymer Paclitaxel therapeutics.

Yang D, Yu L, Van S - Cancers (Basel) (2010)

Structure of PG-PTX (a), paclitaxel (b), and PGG-PTX (c).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756347&req=5

f3-cancers-03-00017: Structure of PG-PTX (a), paclitaxel (b), and PGG-PTX (c).
Mentions: The concepts of coupling an anti-cancer drug to a polymer were essentially developed in the early 1980s [8,11]. It took about 20 years for the first polymer-paclitaxel conjugate (PNU166945) to enter a Phase I clinical trial [12]. Polymer-paclitaxel conjugates have been designed to improve the plasma pharmacokinetics by avoiding kidney filtration and to passively target hypervasculature, defective vascular architecture, and an impaired lymphatic drainage of tumor tissues, that is known as “enhanced permeability and retention” effects [13]. Recent clinical advances in polymer-paclitaxel conjugates are credited to co-polymer hydroxypropylmethacrylamide-paclitaxel conjugate (HPMA-PTX) [12] and poly(l-glutamic acid)-paclitaxel conjugate (PG-PTX) [14]. A schematic representation of the chemical structure of HPMA-PTX and PG-PTX is shown in Figure 2 and Figure 3a, respectively. HPMA-PTX is a water-soluble co-polymer in which paclitaxel is covalently bound through an ester bond at its 2′-OH position with an enzymatic degradable linker of Gly-Phe-Leu-Gly peptide. The polymer:paclitaxel ratio was approximately 19:1 (5%) by weight to weight. To improve paclitaxel drug loading, Li et al. [15] changed the polymer backbone to poly(l-glutamic acid). The amount of paclitaxel loading of PG-PTX improved to 20% by weight to weight, but the resulting conjugate contained mixed paclitaxel substitutions at both the C-2′ and C-7 ester positions [15]. With optimization of coupling chemistry of paclitaxel, paclitaxel loading increased to 37% by weight by weight [16]. In a similar platform, poly(lL-γ-glutamylglutamine)-paclitaxel nanoconjugate (PGG-PTX, as shown in Figure 3 (c)), was reported that with an additional glutamic acid as a linker between poly(l-glutamic acid) and paclitaxel, the paclitaxel drug loading was 35% weight by weight, and dissolution of PGG-PTX was faster than that of PG-PTX [17]. Futhermore, the glutamic acid linker provided enough flexibility of the PGG-PTX for self-assembly into nanoparticles whose size remains in the range of 12–15 nm (volume) over the concentration range of 25 to 2,000 μg/mL in saline [17]. Conjugation of paclitaxel can be achieved quantitatively, but it requires highly dried conditions to facilitate the completion of ester coupling in the presence of a 4-dimethylaminopyridine catalyst.

Bottom Line: However, none have as yet been approved by the U.S. Food and Drug Administration.PGG-PTX has its own unique property of forming nano-particles.This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Engineering and Technology Institute, Institutes for Advanced Interdisciplinary Research, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China. yu_lei@gg.nitto.co.jp.

ABSTRACT
The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(L-g-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic.

No MeSH data available.


Related in: MedlinePlus