Dual-ligand modified liposomes provide effective local targeted delivery of lung-cancer drug by antibody and tumor lineage-homing cell-penetrating peptide

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Abstract

The abilities of a drug delivery system to target and penetrate tumor masses are key factors in determining the system’s chemotherapeutic efficacy. Here, we explored the utility of an anti-carbonic anhydrase IX (anti-CA IX) antibody and CPP33 dual-ligand modified triptolide-loaded liposomes (dl-TPL-lip) to simultaneously enhance the tumor-specific targeting and increase tumor cell penetration of TPL. In vitro, the dl-TPL-lip increased the cytotoxicity of TPL in CA IX-positive lung cancer cells, which showed tunable size (137.6 ± 0.8 nm), high-encapsulation efficiency (86.3 ± 2.6%) and sustained release. Dl-TPL-lip significantly improved the ability of liposomes to penetrate 3 D tumor spheroids and exhibited a superior inhibiting effect. Furthermore, pharmacokinetic studies in rats that received TPL liposomal formulations by endotracheal administration showed a reduced concentration of TPL (17.3%–30.6% compared to free TPL) in systemic circulation. After pulmonary administration in orthotopic lung tumor-bearing mice, dl-TPL-lip significantly enhanced TPL anti-cancer efficacy without apparent systemic toxicity. This dual-ligand modified liposomal vehicle presents a potential system for localized and targeted delivery of anti-cancer drugs to improve their efficacy.

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Recent Developments in Targeting Carbonic Anhydrase IX for Cancer Therapeutics

Paul McDonald, Jean-Yves Winum, Claudiu Supuran … (2012)

Carbonic anhydrase IX (CAIX) is a hypoxia-inducible enzyme that is overexpressed by cancer cells from many tumor types, and is a component of the pH regulatory system invoked by these cells to combat the deleterious effects of a high rate of glycolytic metabolism. CAIX functions to help produce and maintain an intracellular pH (pHi) favorable for tumor cell growth and survival, while at the same time participating in the generation of an increasingly acidic extracellular space, facilitating tumor cell invasiveness. Pharmacologic interference of CAIX catalytic activity using monoclonal antibodies or CAIX-specific small molecule inhibitors, consequently disrupting pH regulation by cancer cells, has been shown recently to impair primary tumor growth and metastasis. Many of these agents are in preclinical or clinical development and constitute a novel, targeted strategy for cancer therapy.

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Recent advances in the use of cell-penetrating peptides for medical and biological applications.

Sonali B Fonseca, Mark P Pereira, Shana O Kelley (2009)

The selective permeability of the plasma membrane prohibits most exogenous agents from gaining cellular access. Since many therapeutics and reporter molecules must be internalized for activity, crossing the plasma membrane is essential. A very effective class of transporters harnessed for this purpose are cell penetrating peptides (CPPs), a group of short cationic sequences with a remarkable capacity for membrane translocation. Since their discovery in 1988, CPPs have been employed for the delivery of a wide variety of cargo including small molecules, nucleic acids, antibodies and nanoparticles. This review describes recent advances in the use of CPPs for biological and therapeutic applications. In particular, an emphasis is placed on novel systems and insights acquired since 2006. Basic research on CPPs has recently yielded techniques that provide further information on the controversial mechanism of CPP uptake and has also resulted in the development of new model membrane systems to evaluate these mechanisms. In addition, recent use of CPPs for the development of new cellular imaging tools, biosensors, or biomolecular delivery systems have been highlighted. Lastly, novel peptide delivery vectors, designed to tackle some of the drawbacks of CPPs and enhance their versatility, will be described. This review will illustrate the diverse applications for which CPPs have been harnessed and also demonstrate the remarkable advancements these peptides have facilitated in cell biology.

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Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: from biology to clinical use.

Jaromir Pastorek, SILVIA PASTOREKOVA (2015)

The tumor microenvironment includes a complicated network of physiological gradients contributing to plasticity of tumor cells and heterogeneity of tumor tissue. Hypoxia is a key component generating intratumoral oxygen gradients, which affect the cellular expression program and lead to therapy resistance and increased metastatic propensity of weakly oxygenated cell subpopulations. One of the adaptive responses of tumor cells to hypoxia involves the increased expression and functional activation of carbonic anhydrase IX (CA IX), a cancer-related cell surface enzyme catalyzing the reversible conversion of carbon dioxide to bicarbonate ion and proton. Via its catalytic activity, CA IX participates in regulation of intracellular and extracellular pH perturbations that result from hypoxia-induced changes in cellular metabolism producing excess of acid. Through the ability to regulate pH, CA IX also facilitates cell migration and invasion. In addition, CA IX has non-catalytic function in cell adhesion and spreading. Thus, CA IX endows tumor cells with survival advantages in hypoxia/acidosis and confers an increased ability to migrate, invade and metastasize. Accordingly, CA IX is expressed in a broad range of tumors, where it is associated with prognosis and therapy outcome. Its expression pattern and functional implications in tumor biology make CA IX a promising therapeutic target, which can be hit either by immunotherapy with monoclonal antibodies or with compounds inhibiting its enzyme activity. The first strategy has already reached the clinical trials, whereas the second one is still in preclinical testing. Both strategies indicate that CA IX can become a clinically useful anticancer target, but urge further efforts toward better selection of patients for immunotherapy and deeper understanding of tumor types, clinical situations and synthetic lethality interactions with other treatment approaches.

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Author and article information

Journal

Journal ID (nlm-ta): Drug Deliv

Journal ID (iso-abbrev): Drug Deliv

Journal ID (publisher-id): IDRD

Journal ID (publisher-id): idrd20

Title: Drug Delivery

Publisher: Taylor & Francis

ISSN (Print): 1071-7544

ISSN (Electronic): 1521-0464

Publication date Collection: 2018

Publication date (Electronic): 15 January 2018

Volume: 25

Issue: 1

Pages: 256-266

Affiliations

[a ]School of Chinese Medicine, Hong Kong Baptist University , Hong Kong, China;

[b ]School of Biomedical Sciences, Chinese University of Hong Kong , Hong Kong, China;

[c ]School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong, China;

[d ]Changshu Research Institute, Hong Kong Baptist University, Changshu Economic and Technological Development (CETD) Zone , Changshu, China

Author notes

Supplemental data for this article can be accessed here .

CONTACT Zhijun Yang yzhijun@ 123456hkbu.edu.hk ;

Aiping Lu aipinglu@ 123456hkbu.edu.h School of Chinese Medicine, Hong Kong Baptist University , Hong Kong, China

Article

Publisher ID: 1425777

DOI: 10.1080/10717544.2018.1425777

PMC ID: 6058720

PubMed ID: 29334814

SO-VID: 278f72a6-43ee-416c-9199-9fce94b8e113

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 07 November 2017

Date revision received : 02 January 2018

Date accepted : 05 January 2018

Page count

Pages: 11, Words: 6367

Funding

Funded by: Hong Kong Baptist University 10.13039/501100001747

Award ID: FRG2/15-16/078

This work was supported by the University Grants Committee of Hong Kong for the General Research Fund [GRF/RGC Ref No. 12102514—HKBU: 32-14-125], and the Hong Kong Baptist University Faculty Research Grant [FRG2/15-16/078].

Dual-ligand modified liposomes provide effective local targeted delivery of lung-cancer drug by antibody and tumor lineage-homing cell-penetrating peptide

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Most cited references 35

Recent Developments in Targeting Carbonic Anhydrase IX for Cancer Therapeutics

Recent advances in the use of cell-penetrating peptides for medical and biological applications.

Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: from biology to clinical use.

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