Tumor-Targeted Hyaluronan Nanoliposomes Increase the Antitumor Activity of Liposomal Doxorubicin in Syngeneic and Human Xenograft Mouse Tumor Models

Peer, Dan; Margalit, Rimona

doi:10.1593/neo.03460

Cited by 193 publications

(167 citation statements)

References 33 publications

(29 reference statements)

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“…This type of active targeting has been used previously to increase cellular uptake of doxorubicin-loaded liposomes ($20-fold; ref. 40). However, this work is different from most prior studies, in that the other studies used high molecular weight hyaluronic acid (>75 kDa) as the drug carrier (28,(41)(42)(43).…”

Section: Discussionmentioning

confidence: 88%

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Mittapalli

Liu

Adkins

et al. 2013

Molecular Cancer Therapeutics

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Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate ($5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G 2 -M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC 50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer.

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Section: Discussionmentioning

confidence: 88%

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Mittapalli

Liu

Adkins

et al. 2013

Molecular Cancer Therapeutics

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“…56,57) Huang and coworkers demonstrated that a PEGylated liposome-polycation-dNA nanoparticle (LPD) modified with anisamide on top of PEG efficiently delivered siRNA to lung carcinomas with high expression levels of sigma receptors, which resulted in luciferase gene silencing in metastatic tumors compared with nontargeted PEGylated LPd. 58,59) Antibodies have been widely investigated as ligands for the tumor targeting of liposomes due to their high specificity and affinity for target molecules.…”

Section: -28)mentioning

confidence: 99%

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

Hatakeyama

Akita

Harashima

2013

Biological & Pharmaceutical Bulletin

415

276

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Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the "PEG dilemma" must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described.

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“…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%

“…Liposomes (nanosized phospholipid vesicles) bearing oligosaccharide HA conjugated to a phosphatidylethanolamine lipid have been used as a targeted drug carrier for doxorubicin. 37,38,41,69,70 Two different approaches to attach HA to liposomes were developed. 41,75 In the earliest report, HMW-HA was coupled via the glucuronic carboxylate to phosphatidylethanolamine in pre-formed liposomes.…”

mentioning

confidence: 99%

“…The HMW-HA liposomes were originally proposed as a bioadhesive formulation 75 and then subsequently used to target cytotoxic drugs to tumors. 69,70 Peer and co-workers encapsulated doxorubicin or mitomycin HMW-HA liposomes were very successful at decreasing tumor burden in several different tumor models. HA coated liposomes carrying either doxorubicin or mitomycin c also showed an increased circulation time over traditional, non-targeted liposomes 69, 70 with a half-life slightly less than that of PEGylated "stealth" liposomes.…”

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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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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Tumor-Targeted Hyaluronan Nanoliposomes Increase the Antitumor Activity of Liposomal Doxorubicin in Syngeneic and Human Xenograft Mouse Tumor Models

Cited by 193 publications

References 33 publications

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

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

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