ReviewNanomedicine in cancer therapy: Challenges, opportunities, and clinical applications
Graphical abstract
Introduction
For more than two decades, advances in understanding cancer biology have only slowly been translated into significant improvements in cancer care. The World Health Organization (WHO) attributed 8.2 million deaths to cancer in 2012, which constituted 13% of all deaths. Within the next two decades, new global cancer incidences are expected to increase from 14 million in 2012 to as many as 22 million. One of the main reasons is the lack of selective delivery of anti-cancer compounds to neoplastic tissue. High systemic exposure to anti-neoplastic agents frequently results in dose-limiting toxicity. Therefore, targeted delivery is of utmost importance in order to overcome current limitations in cancer therapy. Recent developments in nanotechnology are expected to improve drug delivery, thereby increasing efficacy while decreasing the side effects of anti-cancer drugs.
Nanocarriers2 have unique properties such as nanoscale size, high surface-to-volume ratio, and favorable physico-chemical characteristics. They have the potential to modulate both the pharmacokinetic and pharmacodynamic profiles of drugs, thereby enhancing their therapeutic index. Loading of drugs into nanocarriers can increase in vivo stability, extend a compound's blood circulation time, and allow for controlled drug release. Thus, nanomedicine compounds can alter the biodistribution of drugs by allowing them to accumulate preferably at the tumor site. This phenomenon is known as enhanced permeability and retention effect (EPR) (Section 2.2.1).
A wide range of nanomaterials based on organic, inorganic, lipid, protein, or glycan compounds as well as on synthetic polymers have been employed for the development of new cancer therapeutics (Fig. 3). According to the registry maintained by clinicaltrials.gov, a total of 1575 nanomedicine formulations (search terms ‘liposome’/‘nanoparticle’/‘micelle’) had been registered for clinical trials by December 2014. As many as 1381 of these are in the field of cancer therapy [1] (Fig. 1B). However, most clinical trials focus on marketed products, such as liposomal doxorubicin or albumin-bound paclitaxel. Either new indications or therapies in combination with other anti-cancer agents are investigated. Our search of the key word ‘cancer nanoparticles’ in Web of Science® yielded 57,944 publications available in December 2014 (Fig. 1A). This illustrates the huge gap between technical and clinical development. There are concerns that a delay in clinical development of new nanomedicine drugs may be detrimental to cancer patients. With this in mind, we discuss in this review the recent developments of nanomedicine therapeutics in early and late clinical trials. We cover opportunities to develop next-generation clinical nanomedicine therapeutics with advanced functionalities. In addition, we address challenges encountered during drug development and regulatory approval.
Section snippets
Rationale for the development of nanomedicine products for cancer therapy
There are convincing arguments in favor of developing nano-sized therapeutics [2].
First, nanoparticles may help to overcome problems of solubility and chemical stability of anti-cancer drugs. Poor water solubility limits the bioavailability of a compound and may hamper the development of anti-cancer agents identified during early drug screens [3]. Uptake and delivery of poorly soluble drugs may be increased by enveloping the compound in a hydrophilic nanocarrier. At the same time, this may
Nanomedicine in clinical cancer care
Various types of nanomedicine compounds have been used in clinical cancer care, including viral vectors, drug conjugates, lipid-based nanocarriers, polymer-based nanocarriers, and inorganic nanoparticles (Fig. 3) [2]. The different nanomedicine products are discussed below, with special emphasis placed on clinical trials. Most nanomedicine therapeutics are investigated in phase 1 trials in patients with solid tumors. Specific cancer indications are explored in advanced (phases 2 and 3) clinical
Challenges and current limitations
Nanomedicine is as one of the most promising and advanced approaches in the development of frontier cancer treatment. Thousands of publications suggest that nanomedicine therapeutics are effective in cancer treatment, both in vitro and in vivo (Fig. 1A). However, only very few nanocarrier-based cancer therapeutics have successfully entered clinical trials (Fig. 1B). Thus, it is important to address the challenges in developing optimized nanomedicine products for clinical use [139].
Conclusions
Nanomedicine represents one of the fastest growing research areas and is regarded as one of the most promising tools for frontier cancer treatment. Several nanomedicine platforms have been developed and many are used in clinical cancer care. The most important advantages and disadvantages of the different strategies are summarized in Table 7. This table provides an expert opinion on clinical opportunities and summarizes preferred applications for the discussed technologies. Several phase 3
Acknowledgment
The authors thank Dr. Silvia Rogers for editorial assistance and Andrea Fehrenbach for graphic support. Financial support was provided by the Swiss Centre of Applied Human Toxicology (SCAHT).
References (270)
- et al.
Interactions of nanomaterials and biological systems: implications to personalized nanomedicine
Adv. Drug Deliv. Rev.
(2012) - et al.
Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress
J. Control. Release
(2012) - et al.
Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study
Lancet Oncol.
(2012) - et al.
Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma
Cancer Cell
(2012) - et al.
Nanoparticles for drug delivery: the need for precision in reporting particle size parameters
Eur. J. Pharm. Biopharm.
(2008) - et al.
Nanomedicine: developing smarter therapeutic and diagnostic modalities
Adv. Drug Deliv. Rev.
(2006) - et al.
Endocytic mechanisms for targeted drug delivery
Adv. Drug Deliv. Rev.
(2007) - et al.
Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status
Adv. Drug Deliv. Rev.
(2013) - et al.
Evaluation of pH-responsive liposomes containing amino acid-based zwitterionic lipids for improving intracellular drug delivery in vitro and in vivo
J. Control. Release
(2010) - et al.
Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: concepts and applications
Adv. Drug Deliv. Rev.
(2012)
Liposomes with detachable polymer coating: destabilization and fusion of dioleoylphosphatidylethanolamine vesicles triggered by cleavage of surface-grafted poly(ethylene glycol)
FEBS Lett.
Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions
J. Control. Release
Ultrasound triggered release of cisplatin from liposomes in murine tumors
J. Control. Release
Stimuli-responsive polymers and nanomaterials for gene delivery and imaging applications
Adv. Drug Deliv. Rev.
Multifunctional and stimuli-sensitive pharmaceutical nanocarriers
Eur. J. Pharm. Biopharm.
The targeted co-delivery of DNA and doxorubicin to tumor cells via multifunctional PEI-PEG based nanoparticles
Biomaterials
In vivo treatment of tumors using host-guest conjugated nanoparticles functionalized with doxorubicin and therapeutic gene pTRAIL
Biomaterials
Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, inducing apoptosis in proportion to accumulated drug
J. Control. Release
Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes
Int. J. Pharm.
pH-triggered intracellular release from actively targeting polymer micelles
Biomaterials
Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications
Curr. Opin. Biotechnol.
Nanotheranostics for personalized medicine
Adv. Drug Deliv. Rev.
Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial
Lancet Oncol.
Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial
Lancet Oncol.
Oncolytic viruses in cancer therapy
Cancer Lett.
Extravasation of macromolecules
Adv. Drug Deliv. Rev.
Doxil®—the first FDA-approved nano-drug: lessons learned
J. Control. Release
Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer
Ann. Oncol.
Liposomal drug delivery systems: from concept to clinical applications
Adv. Drug Deliv. Rev.
A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma
Ann. Oncol.
Immunoconjugates and long circulating systems: origins, current state of the art and future directions
Adv. Drug Deliv. Rev.
Active targeting schemes for nanoparticle systems in cancer therapeutics
Adv. Drug Deliv. Rev.
Immunoliposomes bearing polyethyleneglycol-coupled Fab' fragment show prolonged circulation time and high extravasation into targeted solid tumors in vivo
FEBS Lett.
A service of the U.S. National Institutes of Health
Nanomedicine(s) under the microscope
Mol. Pharm.
Strategies to address low drug solubility in discovery and development
Pharmacol. Rev.
Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery
Proc. Natl. Acad. Sci. U. S. A.
Drug penetration in solid tumours
Nat. Rev. Cancer
Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery
J. Am. Chem. Soc.
Therapeutic nanoparticles to combat cancer drug resistance
Curr. Drug Metab.
By-passing of P-glycoprotein using immunoliposomes
J. Drug Target.
Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes
Clin. Cancer Res.
Immunoliposomal delivery of doxorubicin can overcome multidrug resistance mechanisms in EGFR-overexpressing tumor cells
J. Drug Target.
Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors
Cancer Res.
Treatment of large solid tumors in mice with daunomycin-loaded sterically stabilized liposomes
Drug Deliv.
Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment
Proc. Natl. Acad. Sci. U. S. A.
Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology
Cancer Res.
Combining two strategies to improve perfusion and drug delivery in solid tumors
Proc. Natl. Acad. Sci. U. S. A.
The theranostic path to personalized nanomedicine
Clin. Transl. Imaging Rev. Nucl. Med. Mol. Imaging
Delivering nanomedicine to solid tumors
Nat. Rev. Clin. Oncol.
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Both authors contributed equally to this work.