Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo

Maeda, Hiroshi; Seymour, Leonard W.; Miyamoto, Yukio

doi:10.1021/bc00017a001

Cited by 546 publications

(332 citation statements)

References 78 publications

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“…In this context, macromolecular anticancer drugs can be conjugated with biocompatible polymers, which function as carriers and stabilizers, resulting in decreased drug toxicity and increased therapeutic efficacy. 61 By conjugating BSAO with polyethylene glycol hydrogels, with the aim of increasing its plasmatic half-life or its targetability in administrable form, the yield of immobilization was 38%. 62 In conclusion, these results suggest promising applications of BSAO in anticancer therapy, in particular against MDR tumors.…”

Section: Discussionmentioning

confidence: 99%

Enzymatic oxidation products of spermine induce greater cytotoxic effects on human multidrug‐resistant colon carcinoma cells (LoVo) than on their wild‐type counterparts

Calcabrini¹,

Arancia²,

Marra³

et al. 2002

Intl Journal of Cancer

122

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The occurrence of resistance to cytotoxic agents in tumor cells, associated with several phenotypic alterations, is one of the major obstacles to successful anticancer chemotherapy. A new strategy to overcome MDR of human cancer cells was studied, using BSAO, which generates cytotoxic products from spermine, H 2 O 2 and aldehyde(s). The involvement of these products in causing cytotoxicity was investigated in both drug-sensitive (LoVo WT) and drug-resistant (LoVo DX) colon adenocarcinoma cells. Evaluation of clonogenic cell survival showed that LoVo DX cells are more sensitive than LoVo WT cells. Fluorometric assay and treatments performed in the presence of catalase demonstrated that the cytotoxicity was due mainly to the presence of H 2 O 2 . Cytotoxicity was eliminated in the presence of both catalase and ALDH. Transmission electron microscopic observations showed more pronounced mitochondrial modifications in drug-resistant than in drug-sensitive cells. Mitochondrial functionality studies performed by flow cytometry after JC-1 labeling revealed basal hyperpolarization of the mitochondrial membrane in LoVo DX cells. After treatment with BSAO and spermine, earlier and higher mitochondrial membrane depolarization was found in LoVo DX cells than in drug-sensitive cells. In addition, higher basal ROS production in LoVo DX cells than in drug-sensitive cells was detected by flow-cytometric analysis, suggesting increased mitochondrial activity in drug-resistant cells. Our results support the hypothesis that mitochondrial functionality affects the sensitivity of cells to the cytotoxic enzymatic oxidation products of spermine, which might be promising anticancer agents, mainly against drug-resistant tumor cells.

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Section: Discussionmentioning

confidence: 99%

Enzymatic oxidation products of spermine induce greater cytotoxic effects on human multidrug‐resistant colon carcinoma cells (LoVo) than on their wild‐type counterparts

Calcabrini¹,

Arancia²,

Marra³

et al. 2002

Intl Journal of Cancer

122

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“…16 The character of CPT microdistribution in the tumor tissue suggests that, by 24 h post administration, all tumor-localized drug is distributed relatively homogeneously. This can be explained by the lipophilic nature of the prodrug, which, being fully released from the carrier, is free to redistribute along cell membranes within the tumor via diffusion.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

et al. 2004

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A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t 1/2 = 2.2 ± 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t 1/2 = 2.1 ± 0.2 h, while the conjugate half-life was 14.2 ±1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.

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“…Mechanism two arises because tumors often exhibit a phenomenon known as the enhanced permeability and retention effect (EPR). 20 The properties of the EPR effect are summarized in Table 1. This phenomenon is thought to occur because solid tumors have a much leakier blood supply than healthy capillary beds; particles of up to approximately 0.5 μm can extravasate into the tumor from the blood.…”

Section: Targeting To Cd44 With Anti-cd44 Antibodies or Hyaluronanmentioning

confidence: 99%

“…This phenomenon is thought to occur because solid tumors have a much leakier blood supply than healthy capillary beds; particles of up to approximately 0.5 μm can extravasate into the tumor from the blood. 20 Tumors also lack a well-developed lymphatic system. This combination allows macromolecules or nanoparticles to passively accumulate within tumors due to leakage from the improperly formed tumor vasculature and remain within the tumor due to limited lymphatic clearance.…”

Section: Targeting To Cd44 With Anti-cd44 Antibodies or Hyaluronanmentioning

confidence: 99%

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

2008

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The complex system involved in the synthesis, degradation, and binding of the high molecular weight glycosaminoglycan hyaluronic acid (hyaluronan or HA) provides a variety of structures that can be exploited for targeted cancer therapy. In many cancers of epithelial origin there is an up-regulation of CD44, a receptor that binds HA. In other cancers, HA in the tumor matrix is over-expressed. Both CD44 on cancer cells and HA in the matrix have been targets for anti-cancer therapy. Even though CD44 is expressed in normal epithelial cells and HA is part of the matrix of normal tissues, selective targeting to cancer is possible. This is because macromolecular carriers predominantly extravasate into the tumor and not normal tissue; thus CD44-HA targeted carriers administered intravenously localize preferentially into tumors. Anti-CD44 antibodies have been used in patients to deliver radioisotopes or mertansine for treatment of CD44 expressing tumors. In early phase clinical trials, patients with breast or head and neck tumors treated with anti-CD44 conjugates experienced stabilized disease. A dose-limiting toxicity was associated with distribution of the antibody-drug conjugate to the skin, a site in the body with a high level of CD44. HA has been used as a drug carrier and a ligand on liposomes or nanoparticles to target drugs to CD44 over-expressing cells. Drugs can be attached to HA via the carboxylate on the glucuronic acid residue, the hydroxyl on the Nacetylglucosamine, or the reducing end which are located on a repeating disaccharide. Drugs delivered in HA-modified liposomes exhibited excellent anti-tumor activity both in vitro and in murine tumor models. The HA matrix is also a potential target for anti-cancer therapies. By manipulating the interaction of HA with cell surface receptors, either by degrading it with hyaluronidase or by interfering with CD44-HA interactions using soluble CD44 proteins, tumor progression was blocked. Finally, cytotoxic drugs or pro-drug converting enzymes can be attached to the HA matrix to generate a cytotoxic fence around the tumor. This review describes how the complex interplay among cancer biology, the CD44-HA interaction, drug carriers and drug targeting has been used to improve anti-cancer therapies. As these approaches evolve, they hold forth the prospect of significantly improved targeted anti-cancer treatments. KeywordsAntibody; Biodistribution; Cancer; Chemotherapy; Drug-conjugate; EPR effect; Liposome; Polymer; Prodrug; Recombinant Protein The Biology of the CD44-Hyaluronan InteractionHyaluronan (HA) (Figure 1) is a high molecular weight glycosaminoglycan, extracellular matrix component essential for proper cell growth, organ structural stability, and tissue organization. The amount of HA in a tissue depends upon on a complex interplay among HA synthesis by HA synthases, 1 HA internalization by cell surface receptors, 2 Interference with the CD44-HA interaction by either targeting drugs to CD44, 14 targeting drugs to the HA matrix 15 or interfering with HA ma...

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Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo

Abstract: time. One exception may be polyvinylpyrrolidone iodine complex (Isodine) (6), which was developed as a topical antiseptic agent and even now remains one of the best antiseptics available.

Cited by 546 publications

References 78 publications

Enzymatic oxidation products of spermine induce greater cytotoxic effects on human multidrug‐resistant colon carcinoma cells (LoVo) than on their wild‐type counterparts

Enzymatic oxidation products of spermine induce greater cytotoxic effects on human multidrug‐resistant colon carcinoma cells (LoVo) than on their wild‐type counterparts

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

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