Evaluation of antitumor activities of hyaluronate binding antitumor drugs: synthesis, characterization and antitumor activity

Akima, Kazuo; Itô, Hisashi; Iwata, Yuhei; Matsuo, Kayoko; Watari, Nobutoshi; Yanagi, Mitsuo; Hagi, Hiroo; Oshima, Kazumasa; Yagita, Akikuni; Atomi, Yutaka; Tatekawa, I.

doi:10.3109/10611869609046255

Cited by 71 publications

(60 citation statements)

References 12 publications

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“…An epirubicin conjugate showed no improvement. In a metastatic lung carcinoma model, HA-mitomycin c decreased the number of metastatic lung nodules at a much lower dose that free mitomycin c. 14 Drug-HA conjugates have also been used to deliver drugs with physical properties that limit dosing. For instance, the antimitotic chemotherapeutic agent paclitaxel has low aqueous solubility.…”

Section: B Hyaluronan Conjugates As Drug Carriersmentioning

confidence: 99%

“…Pharmacokinetic properties, such as circulation time and biodistribution, are influenced by incorporating the targeting and cellspecific uptake properties of HA onto large carriers. Cargos delivered to CD44 over-expressing cells include anti-cancer drugs: epirubicin, 14 doxorubicin, 37,38,41,69,70,71 paclitaxel, 28,29,62,63 and mitomycin c, 14,70 as well as agents such as siRNA, 72 iron oxide magnetic particles, 73 and DNA. 74 These studies are summarized in Tables 3 and 4. Several different methods have been used to improve the distribution of doxorubicin, which has significant cardiotoxicity as a free drug.…”

Section: C Hyaluronan In a Targeted Nanocarrier Systemmentioning

confidence: 99%

“…Non-native CD44 variants may also arise from alternate splicing of cytoplasmic regions of CD44 during translation. 13 Interference with the CD44-HA interaction by either targeting drugs to CD44, 14 targeting drugs to the HA matrix 15 or interfering with HA matrix-CD44 interactions 16 are viable strategies for cancer treatments. The CD44-HA system is illustrated in Figure 2.…”

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confidence: 99%

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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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Section: B Hyaluronan Conjugates As Drug Carriersmentioning

confidence: 99%

Section: C Hyaluronan In a Targeted Nanocarrier Systemmentioning

confidence: 99%

mentioning

confidence: 99%

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

2008

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“…Therefore, anticancer drug targeting to tumor cells and tumor metastases can be accomplished by HA polymer drug conjugates via the HA receptor-mediated uptake of these drugs (Akima et al, 1996). Furthermore, anticancer drugs coupled to HA can provide advantages in drug solubilization, stabilization, localization and controlled release (Maeda et al, 1992).…”

Section: Gene Deliverymentioning

confidence: 99%

Hyaluronic Acid in Drug Delivery Systems

Jin¹,

Termsarasab²,

Kim³

2010

Journal of Pharmaceutical Investigation

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− Hyaluronic acid (HA) is a biodegradable, biocompatible, non-toxic, non-immunogenic and non-inflammatory linear polysaccharide, which has been used for various medical applications including arthritis treatment, wound healing, ocular surgery, and tissue augmentation. Because of its mucoadhesive property and safety, HA has received much attention as a tool for drug delivery system development. It has been used as a drug delivery carrier in both nonparenteral and parenteral routes. The nonparenteral application includes the ocular and nasal delivery systems. On the other hand, its use in parenteral systems has been considered important as in the case of sustained release formulation of protein drugs through subcutaneous injection. Particles and hydrogels by various methods using HA and HA derivatives as well as by conjugation with other polymer have been the focus of many studies. Furthermore, the affinity of HA to the CD44 receptor which is overexpressed in various tumor cells makes HA an important means of cancer targeted drug delivery. Current trends and development of HA as a tool for drug delivery will be outlined in this review.

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“…14,15 Some studies have reported that the use of HA as a ligand in a targeted delivery system is an effective strategy for cancer therapy. [16][17][18][19][20][21] It is also well known that the use of polyethylene glycol (PEG) reduces immunogenic response and creates a hydrophilic barrier, which enables the delivery system to circulate in the body for an extended period. [22][23][24] A previous study indicated that HA conjugated with polymer has PEG-like properties, creating a hydrophilic stealth shield and prolonging circulation time.…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan-conjugated liposomes encapsulating gemcitabine for breast cancer stem cells

Han

Shin

Kim

et al. 2016

IJN

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Investigation of potential therapeutics for targeting breast cancer stem cells (BCSCs) is important because these cells are regarded as culprit of breast cancer relapse. Accomplishing this kind of strategy requires a specific drug-delivery system using the distinct features of liposomes. Studies on targeted liposomal delivery systems have indicated the conjugation of hyaluronan (HA), a primary ligand for CD44 surface markers, as an appropriate method for targeting BCSCs. For this study, enriched BCSCs were obtained by culturing MCF-7 breast cancer cells in nonadherent conditions. The enriched BCSCs were challenged with HA-conjugated liposomes encapsulating gemcitabine (2, 2-difluoro-2-deoxycytidine, GEM). In vitro study showed that the HA-conjugated liposomes significantly enhanced the cytotoxicity, anti-migration, and anti-colony formation abilities of GEM through targeting of CD44 expressed on BCSCs. In pharmacokinetic study, area under the drug concentration vs time curve (AUC) of the immunoliposomal GEM was 3.5 times higher than that of free GEM, indicating that the HA-conjugated liposomes enhanced the stability of GEM in the bloodstream and therefore prolonged its half-life time. The antitumor effect of the immunoliposomal GEM was 3.3 times higher than that of free GEM in a xenograft mouse model, probably reflecting the unique targeting of the CD44 receptor by HA and the increased cytotoxicity and stability through the liposomal formulation. Furthermore, marginal change in body weight demonstrated that the use of liposomes considerably reduced the systemic toxicity of GEM on normal healthy cells. Taken together, this study demonstrates that HA-conjugated liposomes encapsulating GEM show promise for the therapy of breast cancer in vitro and in a xenograft model by targeting the BCSCs.

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Evaluation of antitumor activities of hyaluronate binding antitumor drugs: synthesis, characterization and antitumor activity

Cited by 71 publications

References 12 publications

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

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

Hyaluronic Acid in Drug Delivery Systems

Hyaluronan-conjugated liposomes encapsulating gemcitabine for breast cancer stem cells

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