Path-breaking directions of nanotechnology-based chemotherapy and molecular cancer therapy

Working Paper Series

#2014-005
Path‐breaking directions of nanotechnology‐based
chemotherapy and molecular cancer therapy
Mario Coccia and Lili Wang

Maastricht Economic and social Research institute on Innovation and Technology (UNU‐MERIT)
email: info@merit.unu.edu | website: http://www.merit.unu.edu

Maastricht Graduate School of Governance (MGSoG)
email: info‐governance@maastrichtuniversity.nl | website: http://mgsog.merit.unu.edu

Keizer Karelplein 19, 6211 TC Maastricht, The Netherlands
Tel: (31) (43) 388 4400, Fax: (31) (43) 388 4499

UNU-MERIT Working Papers
ISSN 1871-9872

Maastricht Economic and social Research Institute on Innovation and Technology,
UNU-MERIT
Maastricht Graduate School of Governance
MGSoG

UNU-MERIT Working Papers intend to disseminate preliminary results of research
carried out at UNU-MERIT and MGSoG to stimulate discussion on the issues raised.

Path-breaking directions of nanotechnology-based chemotherapy
and molecular cancer therapy
Mario Cocciaa1 and Lili Wangb
a

CNR - National Research Council of Italy; b UNU-MERIT, The Netherlands

ABSTRACT: A fundamental question is how to detect likely successful anticancer treatments based on
nanotechnology. We confront this question here by analysing the trajectories of nanotechnologies applied to
path-breaking cancer treatments, which endeavour to pinpoint ground-breaking and fruitful directions in
nanomedicine. Results tend to show two main technological waves of cancer treatments by nanotechnology
applications. The early technological wave in the early 2000s was embodied in some types of chemotherapy
agents with a broad spectrum, while after 2006 the second technological wave appeared with new
nanotechnological applications in both chemotherapy agents and molecular target therapy. The present study
shows new directions of nanotechnology-based chemotherapy and molecular cancer therapy in new treatments
for breast, lung, brain and colon cancers. A main finding of this study is the recognition that, since the late 2000s,
the sharp increase of several technological trajectories of nanotechnologies and anticancer drugs seems to be
driven by high rates of mortality of some types of cancers (e.g. pancreatic and brain) in order to find more
effective anticancer therapies that increase the survival of patients. The study also shows that global research
leaders specialize in nanotechnology applications for specific cancers (e.g. Switzerland in prostate cancer, Japan
in colon cancer, China in ovarian cancer and Greece in pancreatic cancer). These ground-breaking technological
trajectories are paving new directions in biomedicine and generating a revolution in clinical practice that may
lead to more effective anticancer treatments in the not-too-distant future.
KEYWORDS: Nanotechnology, Nanoscience, Biomedicine, Nanomedicine, Target Therapy, Chemotherapy,
Cancer, Bibliometrics, Publications, Technological Trajectories.
JEL-CODES: C89; O30, C53, I10; MATHEMATICS SUBJECT CLASSIFICATION (MSC2010): 91; 92
Acknowledgments: This research was started by the authors in 2012 and was further developed in 2013 while
Mario Coccia was a visiting scholar at UNU-MERIT in Maastricht. We thank Prof. Bart Verspagen for fruitful
suggestions to this paper. Mario Coccia gratefully acknowledges the CNR – National Research Council of Italy
for financial support to this research project by the short mobility programme at UNU-MERIT. Preliminary
results have been presented at the S.NET 4th Annual Meeting of the society for the study of nanoscience and
emerging technologies (22-25 October 2012), University of Twente (The Netherlands). The usual disclaimer
applies.

* Corresponding author at: CNR - National Research Council of Italy - via Real Collegio, n. 30, 10024,
Moncalieri (Torino) – Italy, Tel.: +39 011 68 24 925; fax : +39 011 68 24 966 – email: m.coccia@ceris.cnr.it

1

1. Introduction and the problem
Interdisciplinary theoretical and experimental results related to nanoscience and
nanotechnology in the life sciences support the diagnosis, monitoring, prevention and
treatment of diseases. Nanotechnology in medicine has generated a vital technological change
and as a consequence a revolution in clinical practice. (Islam and Miyazaki, 2010; Rafols and
Meyer, 2010; Coccia, 2012a; Wolinsky et al., 2012; Madeira et al., 2013)2. No and Park
(2010), using patent citations, argue that the interaction of biotechnology and nanotechnology
may provide important signals for future patterns in nanobiomedicine (cf. Sylvester and
Bowman, 2010; Coccia, 2012). In fact, nanotechnology has a high development potential for
biomedical purposes such as the ground-breaking applications in new therapies for oncology
(cf. Lim et al., 2010; Coccia, 2012a; 2012b).
Bibliometrics is an important approach for investigating emerging fields of
nanotechnology (Arora et al., 2013). In fact, some studies, based on publications, show that
the patterns of nanotechnology research are spreading among different scientific domains and
pathways, generating new technological paradigms mainly in chemistry, medicine and
engineering research fields (cf. Coccia, 2012a; Robinson et al., 2013). As far as the
performance in nanotechnology research is concerned, Shapira and Wang (2010) show the
leadership of some countries, such as the USA and China, which are considered among the
top nanotechnology research publishing countries. This result can be due to high R&D
investments in this vital research field and incentives given to researchers to publish in Web
of Science indexed journals (Lin and Zhang, 2007; Shapira and Wang, 2009). However,
Youtie et al. (2008) claim that publication counts do not necessarily equate to publication
influence.
An interesting problem that deserves to be analysed is how to detect the path-breaking
directions of nanotechnology trajectories applied for vital anticancer treatments. In particular,
we confront this main issue by analysing:


the directions of technological trajectories of the most common anticancer drugs
(chemotherapy agents, substances, or target therapies) inserted in nanoparticle to treat
cancers more effectively;



the evolutionary pathways of types of cancer where there is a high intensive research
activity of treatments that use nanotechnology;

2

cf. also Genet et al., 2012; Chen et al., 2013; Tierney et al., 2013, von Raesfeld et al., 2012.

2



the countries that are best performers in applications of nanotechnologies to treat
cancer and the specialization of countries to treat specific cancer by nanotechnology.
This study can provide important information concerning emerging and fruitful

directions of nanotechnology applied in ground-breaking anticancer treatments that may
generate a revolution in clinical practice to improve human health and quality of life in a nottoo-distant future.
2. Theoretical background and related works
Breakthroughs in nanotechnology are providing “a new dimension” to medicine (da
Rocha et al., 2014). Therapies integrated in nanoparticles or cooperative nanosystems are
spurring new insights to ground-breaking cancer treatments. The National Cancer Institute’s
nanotechnology strategy started in 2004 to support multidisciplinary researchers in the
applications of nanotechnology to new anticancer treatments (Hull et al., 2013). In fact, R&D
in this field has experienced an exponential growth since the early 2000s, such that “cancer
nanotherapeutics are progressing at a steady rate” (Bertrand et al., 2013). For this reason,
pharmaceutical companies have formed strategic alliances and partnerships with
biotechnology firms to improve and accelerate the drug discovery process (Coccia, 2014a). A
fundamental question in the field of the economics of innovation is how trajectories of
scientific fields evolve, expand, converge (or diverge) and break out. Bibliometrics plays a
main role to detect and map this continuous evolution (Huang et al., 2014), being associated
with powerful software to analyse diverse and large volume of data. Motoyama and Eisler
(2011, p. 1174) consider bibliometrics the “primary method of gaging progress in
nanotechnology”. As a matter of fact, social scientists, more and more, use bibliometric and
scientometric approaches to detect and analyse trajectories in the wide domain of cancer
nanotechnology research (Wang et al., 2013). These approaches play an important role to
explore the current evolutionary knowledge growth of trajectories of nanotechnology that
may support future patterns of technological innovation in emerging and cutting-edge areas
of biomedical sciences. De Bellis (2009) observes that citation analysis, a bibliometric
technique, is a prominent feature in the study of new scientific knowledge.
Thomas et al. (2011) discuss a nanoparticle ontology for cancer nanotechnology
research to represent knowledge underlying nanomaterials involved in cancer research.
Huang et al. (2010) show that there are different search strategies for nanotechnology
research such as citation analyses, core journal strategies (core is when the journal has nano
in its title), lexical queries, etc. (cf. Mogoutov and Kahane, 2007). Zitt et al. (2011) argue that
3

keywords act as main signals of scientific inquiry, while citations are more effective in
identifying research streams. Using a keyword mining approach, Wang et al. (2013) find that
the general trend of integration in the application of nanotechnology fields is converging.
Arora et al. (2013) employ structured text-mining software to profile keyword terms and
identify new nanotechnology-related keywords. This strategy shows the main role of several
emerging cited-subject categories of nanotechnology, particularly in the biomedical sciences.
Instead, Zitt and Bassecoulard (2006) employ citation networks to expand their corpus of
nanotechnology publications. Leydesdorff and Zhou (2007) present an approach based on a
core set of six nanotechnology journals and citation and network analysis to provide fruitful
results in understanding this research field.
Among all the research areas, biomedicine is one of the key scientific fields where
nanotechnologies are providing vital innovative applications in diagnostics and in
therapeutics (Cf. Hu et al., 2011; da Rocha et al., 2014; Gao et al., 2013). Coccia (2012a)
displays that the current convergence of genetics, genomics and nanotechnology is the
scientific backbones of new technological paradigms and trajectories in biomedical sciences.
This convergence of vital scientific fields is supporting innovative anticancer treatments and
a revolution in clinical practice.
There are several nanotechnologies applied in biomedicine for supporting anticancer
treatments (Chen et al., 2011; He et al. 2010; Luo et al., 2011). For instance, Nanoparticles
(NPs) can be designed to selectively target the specific tissue/organ in which there is the
cancer (Coccia, 2012b). In addition, functionalizing the surface of NPs with specific and
appropriate ligands can allow their use as drug carriers to target them selectively to the
tissue/organ affected by cancer (see Pöselt et al., 2012; Shukoor et al., 2012; Shukoor et al.,
2011). Nanoparticles can also act as carriers for drugs, which can be contained into organic
nanomicelles or porous inorganic nanoparticles that, by apt bioactive systems, can target
tumoral cells of the body (see Yao et al., 2011; Goel et al., 2010).
Quantum Dots (QDs), instead, are a specific subset of NPs (Obonyo et al., 2010;
Byers and Hitchman, 2011; Rosenthal et al., 2011). The QDs in medicine are mainly applied
as targeted drug delivery (Jain, 2012).
Carbon nanotubes are an allotropic form of carbon, having cylindrical structure and
can be used to deliver drugs against cancer cells, protecting them towards external agents
(Ezzati Nazhad Dolatabadi et al., 2011; Bareket et al., 2010). In fact, carbon nanotubes
combined with cytotoxic (antineoplastic or chemotherapy) agents are a key area of
development for biomedical sciences (Shapira et al., 2011).
4

Some edge areas of bio-nanomedical applications (closer to molecular biology) are
still at the stage of first experimental trials, such as the combination between nanoparticle and
siRNA3.
Gao et al. (2013) show that nanomedicine, based on a targeted drug delivery system,
significantly improve cancer metastasis treatments. Hence, nanotechnology-based approaches
are a promising research field for early-stage diagnosis and for advanced treatments of
cancers that have high rate of mortality (Patra and Truner, 2014; Coccia 2014; Coccia, 2013;
2012c).
GLOBOCAN (2008) shows high mortality (in terms of Age-standardized rate4), in
comparison to incidence, by cancer of the lung and bronchus (19.3), breast (12.4), colorectum
(8.2), cervix uteri (7.8), prostate (7.4), ovary (3.8), pancreas (3.7) and brain (2.5).
In general, these serious diseases can be treated with:
a) Chemotherapy agents that are cytotoxic anti-neoplastic drugs to destroy cancer cells;
b) Targeted cancer therapies that are: “drugs or other substances that block the growth and
spread of cancer by interfering with specific molecules involved in tumour growth and
progression” (National cancer institute as quoted by Coccia, 2012b, p. 276);
c) Anti-oestrogen therapy, such as tamoxifen, that blocks the effects of the hormone
oestrogen in the breast;
d) Cancer siRNA therapy (SiRNA seem to substantially better than antibodies, because they
might easily applicable to any therapeutic target including intracellular factors and even
transcription factors. The selectivity of siRNA inhibitors of gene expression might
improve targeted cancer therapeutics, but the means for systemic administration and
targeted distribution to disseminated metastatic lesions are needed; see Schiffelers et al.,
2004);
e) Chemopreventive substances, such as curcumin.
We confront the initial problems of the paper by analysing the evolution and fruitful
directions of trajectories of the nanotechnology applied to improve these different types of
treatments for above-mentioned cancers with higher rate of mortality.
3

Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of
double-stranded RNA molecules that play a variety of roles in biology.
4
Mortality: Population weighted average of the area-specific country rates applied to the 2008 area population.
Age-standardised rate (W): A rate is the number of new cases or deaths per 100 000 persons per year. An agestandardised rate is the rate that a population would have if it had a standard age structure. Standardization is
necessary when comparing several populations that differ with respect to age because age has a powerful
influence on the risk of cancer.

5

3. Method of research
We analyse evolution and direction of the most important and ground-breaking
anticancer treatments based on:


Nanotechnology with chemotherapy agents (cytotoxic anti-neoplastic drugs) such as
Paclitaxel, Cisplatin, Gemcitabine, Carboplatin, Docetaxel, Doxorubicin, etc.;



Nanotechnology with molecular cancer therapies such as herceptin, cetuximab,
lapatinib, tamoxifen (anti-oestrogen), and cancer si-RNA therapy;



Nanotechnology with chemoprevention substances such as curcumin.
Considering the high mortality of some types of cancer discussed in the previous

section, seven cancer fields - brain cancer, breast cancer, colon cancer, lung cancer, ovarian
cancer, pancreatic cancer and prostate cancer – are covered in our analysis.
The performance of this paper is based on a set of publication and citation data
collected from Scopus in the 2013. The search query was developed by the combination of
nano and each cancer field, searched from abstracts, keywords and titles. The time span
covers 13 years (2000-2012). Research records prior to 2000 were not included because of
insignificant publication numbers. To refine the data quality, we excluded publications that
appeared in less relevant sources, e.g. journals in social science, etc., but we focus on 12
important journal categories5. In total, this study covers 5,080 (nano & cancer treatment)
publications, including 1,440 cited references from nanotechnology. VantagePoint and Ucinet
software are used for accurate and deeper analysis as well as for visualizing technological
networks.
After gathering all the publication records, we classify the applications of
nanotechnology into different groups by keywords. We focus on vital types of anticancer
drugs/therapies applied by means of nanotechnology.
The nanotechnology and anticancer drug groups are: 01) nano & paclitaxel, 02) nano
& cisplatin, 03) nano & gemcitabine, 04) nano & carboplatin, 05) nano & docetaxel; 06) nano
& doxorubicin, 07) nano & herceptin (or trastuzumab), 08) nano & lapatinib, 09) nano &

5

These 12 journal categories are: 1) Medicine, 2) Biochemistry, Genetics and Molecular Biology, 3)
Pharmacology, Toxicology and Pharmaceutics, 4) Health Professions, 5) Nursing, 6) Engineering, 7) Chemistry,
8) Agricultural and Biological Sciences, 9) Immunology and Microbiology, 10) Neuroscience, 11) Chemical
Engineering, 12) Materials Science.

6

Cetuximab, 10) nano & tamoxifen, 11) nano & siRNA and 12) nano & curcumin 6 . In
particular, No. 01-No. 06 are new anticancer treatments based on chemotherapy agents
applied by nanotechnology, while target therapies applied with nanotechnology are No.07, 08,
09; anti-oestrogen therapy (Tamoxifen) applied by nanotechnology is No. 10; cancer siRNA
therapy is No. 11 and chemoprevention substance is No. 12.
Some technological fields, such as: 13) nano & EGFR (or epidermal)7, 14) nano &
HER2 (or HER-2), 15) nano & RNA, 16) nano & PLGA (poly lactic glycolic acid)8, which
also provide substantial information about ground-breaking applications of cancer treatments
via nanotechnology, are included while gathering our publication database. However, due to
the fact that they do not represent anticancer drugs, they are not illustrated in the technologyspecific analysis.
The study is conducted by the following steps:


Step 1: To examine the evolutionary growth of nanotechnology applied in cancer
research. From the perspective of target fields, the evolutionary development of
nanotechnology applied in cancer treatment field are mapped.



Step 2: From the perspective of applied nanotechnology, the vital role of
nanotechnology applied with some anticancer treatments is explored by citation
analysis.



Step 3: To link (within a network) specific nanotechnology and anticancer drugs with
a specific cancer field.
Remark: Some evolutionary trends are plotted by a Log-Linear Regression model9,
estimated by Ordinary Least Squares Method in order to approximately measure and
assess, by the coefficient of regression, the acceleration of some technological
trajectories.

6

Number 13, 14, 15 and 16 are not included in the figures in next section, because these keywords do not
concern anticancer drugs but EGFR (epidermal growth factor receptor: the protein found on the surface of
some cells and to which epidermal growth factor binds, causing the cells to divide.), HER2 (a protein involved
in normal cell growth), etc.
7
For EGFR and HER2, see previous footnote.
8
Poly(lactic-co-glycolic acid) (PLGA) is one of the most successfully developed biodegradable polymers.
Among the different polymers developed to formulate polymeric nanoparticles, PLGA has attracted
considerable attention due to its attractive properties (Danhier F. et al., 2012).
9
The estimation of a linear relationship is based on the following model: LogYi=α+βTi+ i; i=1, …, n
( i=Errors).

7

Given that not all the nanotechnologies are equally applied in all cancer treatments, we
adopt network analysis to link and detect the specific nanotechnology and anticancer
drugs/therapies to cancer field.


Step 4: To spot the top profile countries which are in the leading position in applying
new cancer treatments by nanotechnology.
Moreover if we suppose i is a certain country and j is the cancer field, the research

weight of country i in field j can be calculated by i-country’s publications in j-field divided
by all global publications in j-field. Hence, the general research weight index ( ) of i-country
is the sum of i-country’s research weight in all cancer fields. This is given by:
∑



(1)

Step 5: To examine the internal specification of each top country.

Each country may have their own concentration of research in nanotechnology applied to
treat specific types of cancer. Therefore, we use the following index to examine country’s
specialization in the seven cancer treatment areas. Specialization ratio of country i in field
j, defined as

, is the ratio of its publications in j field divided by its total publications in

all cancer fields. Specialization ratio of worldwide in j field, written as

, is the ratio of

worldwide publications in j field divided by total publication in all cancer fields
worldwide. The disparity between

and

is the specialization index of country i in

field j, which is taken as γ .
;

1, … , .
;

;

1, … , .

1, … , .

(2)
(3)
(4)

A high level of index γ indicates that the high specialization of the country i in the
specific research field j.
In particular, γ0 means high specialization in the scientific research in this type of
cancer, whereas if γ  0 means that there is lower specialization. High values γ means a

8

higher intensive research activity in the specific cancer area by application of nanotechnology
to cancer treatments.
In addition, this study intends to test the following hypothesis (HP) by a hypotheticaldeductive approach proposed by Carl Hempel:
HP: High growth of trajectories of nanotechnology applied to new anticancer treatments is
due to higher rate of mortality of some types of cancer.
In order to validate this HP, a main statistical technique applied is the nonparametric
measure of association by the coefficients of correlation Tau-b of Kendall and of Spearman
between average nanocitations and ratio mortality/incidence. This research departs from the
position that there can be no adequate knowledge where causes are unknown and analyses the
phenomena to be explained by a scientific realism.

4. Experimental results and discussions
Figure 1 shows that the number of scientific publications concerning cancer
treatments associated to nanotechnology is growing over years. The highest magnitude of
scientific output in these research fields is driven by cancers that have a high incidence rate,
such as breast, lung and colon cancer. In addition, it is interesting to note that growth rate of
scientific research by brain and pancreatic cancer is increased sharply in later years, although
they had a low activity of scientific production in early 2000. In fact, coefficient of regression
(a proxy of increase over time) by brain and pancreatic cancer trends is higher than Breast
cancer. In the long run, there shows a convergence of these trajectories over time. This
general trend can be further approved by the citation of nanotechnology in these fields (see
Figure 1A in Appendix).

9

Figure 1: Publications of cancer treatments by nanotechnology in different typology of
cancer (2000-2012)
6,5
6,0
y = 0.2023t + 3.8017
R² = 0.966(Breast)

LN Pubblications (t)

5,5
5,0

y = 0.2758t + 1.4181
R² = 0.916 (Pancreatic)

4,5
4,0
3,5
3,0

y = 0.4181xt‐ 0.0793
R² = 0.874 (Brain)

2,5
2,0
2002

2003

2004

2005

breast‐cancer
colon‐cancer
brain‐cancer
Linear (brain‐cancer)

2006

2007

2008

lung‐cancer
ovarian‐cancer
Linear (breast‐cancer)

2009

2010

2011

2012

prostate‐cancer
pancreatic‐cancer
Linear (pancreatic‐cancer)

Note: The logarithm of publications is taken to better present the values. This figure also shows
the estimate relationships by ordinary least square (and R square) to indicate approximate rate
of growth of some trends.
Source: Authors’ own calculation.

To take the size of different research fields into account, we calculate the average of
nano citation intensity concerning nano applications in the studied seven cancer fields. In
particular, Table 1 shows that nanotechnology applications have the highest citation intensity
in brain cancer. Following brain cancer, pancreatic cancer is the second field where
nanotechnology has been intensively applied to new anticancer treatments, with average
nanocitation intensity at 11.9%. Albeit the total research output of nanotechnology in breast
cancer, colon cancer and prostate cancer, as showed in Figure 1, is rather high, the citation
intensity of nanotechnology in these three cancer fields is relatively low (see the last three
rows of the first column in Table 1).

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Table 1: Intensity of nano citation (standardized) and mortality ratio in cancer field
Field

Brain-cancer
Pancreatic-cancer
Ovarian-cancer
Lung-cancer
Breast-cancer
Colon-cancer
Prostate-cancer

Average of nano citation
intensity in cancer field
(average of 2009‐2012)

RaMI=Ratio of
Mortality/incidence

19.3%
11.9%
8.7%
8.3%
8.1%
6.8%
6.8%

0.714
0.949
0.603
0.843
0.319
0.477
0.265

Coefficients of Correlation between average nanocitations and ratio τ
are: Tau-b of Kendall= +0.59; Spearman =+0.76 (sig. 0.05)
Note: 1) The percentage of nano citation is standardized. Namely, the citation intensity is
calculated by the citation of nano in that year divided by the total publications of that
cancer field in all previous years. 2) Due to the lack of citation data for some small research
fields in early years, the average is taken between 2009 and 2012.

In order to test the HP, Table 1 shows the combination of factors of the mortality and
incidence rate of different cancer fields. It is interesting to observe that cancer fields in which
the ratio of mortality to incidence (Called RaMI) is high, all have high nano citation density,
and vice versa. In fact, coefficients of correlation between average nanocitations and ratio
RaMI are: Tau-b of Kendall= +0.59; Spearman =+0.76 (sig. 0.05). This result suggests that
cancer fields, where incidence is low while mortality is high, although the total joint research
output with nanotechnology is relatively low, the intensity of nanotechnology applications to
ground-breaking anticancer treatments is very high. This reveals that nanotechnology plays a
crucial role in these specific cancers (with high mortality rate) because it might support new
technological avenues to find effective therapies in order to increase the survival of patients.
This result validates the HP and is confirmed by Figure 2, where the high intensive citations
of nanotechnology research are exactly in brain and pancreatic cancer (cf. also the Figure 1A).

11

Figure 2: Citation intensity of nanotechnology in cancer fields per different typology of
cancer (2009-2012)

LN[(CitationsT/SumPubb j)*100]; j=1,..,t‐1

4,0
3,5
3,0

brain‐cancer
pancreatic‐cancer

2,5

lung‐cancer
colon‐cancer

2,0

breast‐cancer
ovarian‐cancer

1,5

prostate‐cancer

1,0
0,5
2009

2010

2011

2012

Note: The logarithm of publications is taken to better present the values.

Figure 3 shows the trajectories of main anticancer drugs applied by nanotechnology.
This figure displays interesting findings. First of all, the scientific research of chemotherapy
agents applied through nanotechnologies is started in 2002-2003 (i.e. No.01 - No.06),
whereas the new molecular target therapies leveraged with nanotechnologies are started later,
2007 or thereabouts (i.e. No.07 - No.12).
As a matter of fact, since 2002 the highest intensity of scientific research in new
anticancer treatments is based on well-known chemotherapy agent paclitaxel (discovered in
USA during 1960s) and doxorubicin (discovered in Italy over 1950s) with nanotechnology.
The high growth of these anticancer drugs can be due to broad spectrum of applications to
treat different cancer: Doxorubicin is commonly used to treat some leukemias and Hodgkin's
lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft
tissue sarcoma, multiple myeloma, and others. Instead, paclitaxel albumin-stabilized
nanoparticle formulation is a form of paclitaxel contained in nanoparticles (very tiny particles
of protein). This form seems to work better than other forms of paclitaxel and has fewer side
effects. National Cancer Institute (2013) states that paclitaxel albumin-stabilized nanoparticle
formulation is approved to be used alone or with other drugs to treat:

12

•

Breast cancer that has recurred (come back) or metastasized (spread to other parts of the
body).

•

Non-small cell lung cancer that is locally advanced or has metastasized and cannot be
treated with surgery or radiation therapy. It is used with carboplatin.
Pancreatic cancer that has metastasized. It is used with gemcitabine hydrochloride.

Figure 3: Main nanotechnology streams associated to drugs to treat the cancers
(2000-2012)
1,20
1,00
SQRT (Cit/Publications)

•

0,80
0,60
0,40
0,20
0,00
2002

2003

2004

2005

2006

2007

2008

2009

01_nano & paclitaxel

06_nano & doxorubicin

07_nano & herceptin (or trastuzumab)

08_nano & lapatinib

09_nano & Cetuximab

10_nano & tamoxifen

11_nano & SiRNA

2012

04_nano & carboplatin

05_nano & docetaxel

2011

02_nano & cisplatin

03_nano & gemcitabine

2010

12_nano & curcumin

Note: 1) Chemotherapy agents applied with nanotechnologies are No. 01-No.06, while molecular
target therapies and other anticancer treatments are No.07-No.12.
2) No.13-No.16 are not included in this figure because they do not concern anticancer drugs but
EGFR, HER2, etc.
3) Square root is applied to better represent the values.

13

Paclitaxel albumin-stabilized nanoparticle formulation is also being studied in the
treatment of other types of cancer. Growing trends are also by other chemotherapy agents
applied by nanotechnology, such as docetaxel, gemcitabine and cisplatin.
Instead, since 2007 there is the development of new molecular target therapy, a new
technological paradigm to treat the cancer based on small molecule and protein drugs, that
has generating a revolution in clinical practice (Coccia, 2012b). Figure 3 shows growing
trends of the association between target/anti-oestrogen therapy and nanotechnology are by
cetuximab and tamoxifen. Cetuximab is a monoclonal antibody10 that is approved to treat
some patients with squamous cell carcinoma of the head and neck or colorectal cancer.
Tamoxifen is a type of anti-oestrogen, a drug used to treat certain types of breast cancer and
to prevent breast cancer. It blocks the effects of the hormone oestrogen in the breast.
Tamoxifen is also being studied in the treatment of other types of cancer. Herceptin
(Trastuzumab) is one of the first target therapies applied by nanotechnology to cancer
treatments; in particular, it is approved to treat certain types of breast cancer as well as some
types of gastric or gastroesophageal junction adenocarcinoma. Herceptin and nanotechnology
trend achieved a peak in 2009, though now there is a declining trend of the technological
trajectory. The trend of curcumin treatment by nanotechnology is growing. This substance
has a current high interest in chemoprevention, in particular for serious gastrointestinal
diseases such as colorectal cancer (cf. Hull and Logan, 2011 and other articles in the issue of
Best Practice & Research Clinical Gastroenterology, vol. 24 and 25).

10

“A type of protein made in the laboratory that can bind to substances in the body, including cancer cells. There
are many kinds of monoclonal antibodies. A monoclonal antibody is made so that it binds to only one
substance. Monoclonal antibodies are being used to treat some types of cancer. They can be used alone or to
carry drugs, toxins, or radioactive substances directly to cancer cells” (National Cancer Institute, 2013).

14

In short, Figure 3 shows two main technological waves concerning the application of
anticancer treatments by nanotechnology:
1. The early technological wave is in the early 2000s and based on some types of
chemotherapy agents with a broad spectrum of applications to different cancers;
2. The second technological wave appeared after 2006, with new nanotechnological
applications in both chemotherapy agents and molecular target therapy (e.g. lapatinib
for breast and other solid tumours and cetuximab for head, neck and colorectal
cancer).
Figure 4 and 5 show, by a network analysis, the field of action of chemotherapy agents or
molecular target therapy that use nanotechnology to treat cancer.
In particular, Figure 4 shows that there are two clusters based on the association of
chemotherapy agents and nanotechnology: general (No. 01 & 06) and specific ones (No.02,
03, 04 & 05).
Figure 4: Network of main nanotechnology-based chemotherapy agents applied in different
types of cancer.

15


The first cluster is doxorubicin and paclitaxel applied by nanotechnology (see the high
number and larger thickness of arrows): these chemotherapy agents have a broad-spectrum of
action (based on high number of citations) on different types of cancers. As a matter of fact,
doxorubicin has a strong connection with brain cancer, whereas paclitaxel has a strong
association meanly with brain, ovarian, breast and lung cancer.
The second cluster is given by other nanotechnology-based chemotherapy agents,
which have a reduced spectrum of applications, more focused on specific cancers, such as:
gemcitabine for pancreatic and brain cancer (the nanotechnology based gemcitabine agents
also plays a main role to treat metastases of brain cancer), cisplatin for ovarian cancer,
docetaxel for brain and ovarian cancer. Figure 4 also shows that breast and lung cancer have
a large volume of research records in this field concerning new treatments with
nanotechnology (larger square), whereas nanotechnology associated to doxorubicin and
paclitaxel is those more frequently cited.
Figure 5, instead, shows similar results for nanotechnology based on molecular target
therapies and other anticancer substances (considering the number and thickness of arrows).
Similarly to the previous results, Figure 5 presents also two groups of anticancer treatments
based on nanotechnology, i.e. widely applied general molecular target therapy/substance with
nanotechnology and specifically applied one. The curcumin substance for chemoprevention
and cancer siRNA therapy applied by nanotechnology have a broad spectrum of applications
on several types of cancer (curcumin has a strong connection mainly with brain, colon and
prostate cancer-based on high citations-; siRNA with pancreatic cancer; cf. Yang et al., 2012).
Herceptin via nanotechnology is applied mainly on breast cancer, cetuximab on brain cancer
and lapatinib11 for breast and pancreatic cancer. Figure 5 also shows an interesting connection
between tamoxifen via nanotechnology and brain cancer. Tamoxifen is most often used to
treat or prevent breast cancer, however it has also been tried for other cancers, including brain
tumours, however tamoxifen trial to treat brain cancer show that the effectiveness of this
anticancer treatment has high uncertainty. As well as, an interesting connection is between
lapatinib via nanotechnology and pancreatic cancer. In fact, based on in vitro results,
lapatinib may provide clinical benefit in EGFR12 positive pancreatic ductal adenocarcinoma
(Walsh et al., 2013).
11
12

Lapatinib is approved for the treatment of certain types of advanced or metastatic breast cancer.
Epidermal growth factor receptor, cf. Coccia (2012b)

16

As far as nanotechnology-based on molecular target therapy is concerned, breast,
brain, lung and colon cancer have a larger volume of research records in these fields (larger
square).
Figure 5: Network of main molecular target therapies applied by nanotechnologies for
ground-breaking treatments in different types of cancers.


To explore the sources of the scientific research on ground-breaking applications of
anticancer drugs via nanotechnology, we spot the top 15 performer countries in Figure 6.
These high performer countries are mainly (in decreasing order with standardized value):
USA, China, Italy, Japan, India, Germany and UK. These are also the countries with a high
intensity of scientific research of anticancer drugs by nanotechnology in all specific types of
cancer. However, Motoyama and Eisler (2013) argue that when academic publications are
divided by number of researcher, the USA is not the leader but lags behind the Germany and
the United Kingdom.

17

Figure 6: Top 15 high performer countries in nanotechnology applied for cancer treatments

SQRT(Teta i)

(2000-2012)

1,800
1,600
1,400
1,200
1,000
0,800
0,600
0,400
0,200
0,000

Note: Square root is applied to better represent the values.

Figure 6 makes a total comparison across countries, whereas Figure 7 shows the inner
specialization of the countries in new anticancer drug applications by nanotechnology in
specific type of cancer. Field specialization index γ (Eq. 4) indicates the specialization ratio
of the country i in the specific research field j. For instance, Singapore and Italy have a higher
inner specialization in breast cancer (treated by nanotechnology-based anticancer drugs) in
comparison to other types of cancer, Switzerland and Greece in prostate cancer, Israel and
Taiwan in lung cancer, Japan and Israel in colon cancer, China and Switzerland in ovarian
cancer, Greece and Japan in pancreatic cancer and for brain cancer, high inner specialization
is within Switzerland and India. Detailed values for all countries and cancer research fields
can be found in Table 1A in the Appendix.

18

Figure 7: Inner specialization of countries (with high value γ) in nanotechnology applications
to treat specific cancer

Note: See detailed calculation equations in Section Method of Research.

5. Lessons learned and concluding observations
Chemotherapy has non-specific effects in the body on normal tissues, causes toxicity,
reduces the quality of life of patients, weakens the immune system and can damage in
irreversible way the recovery power of patients. Instead, according to Gao et al. (2013):
“nanotechnology-based chemotherapies seem to have an ability to specifically and safely
reach tumor foci with enhanced efficacy and low toxicity”. In particular, nanotechnology
tends to support the discovery and clinical development of novel therapies for oncology
focused on chemotherapy agents, small molecule and protein drugs (target therapy).
Nanotechnology is contributing to create differentiated products and enhance clinical practice
for new anticancer treatments (cf. Bertrand et al., 2013). This ground-breaking pattern of
nanotechnology in medicine is enhanced by the mechanism of “‘learning via diffusion’ ….
The increased adoption of a technology paves the way for improvement in its characteristics”
19

(Sahal as quoted by Coccia, 2014).
The present paper analyses the new trajectories of ground-breaking cancer treatments
based on nanotechnology. Using publication and citation data, covering seven cancer fields
and several types of anticancer treatments via nanotechnologies, our study shows here that
some emerging directions of nanoscience and nanotechnology in oncology are growing
rapidly over time.
Some main findings of this study are:


Technological waves. The first main finding, over the studied 13 years, is represented
by two main technological waves concerning the application of anticancer treatments
by nanotechnology (Fig. 3). The early technological wave is in the early 2000s and
based on some types of chemotherapy agents with a broad spectrum of applications to
different cancers (e.g. doxorubicin and paclitaxel), while after 2006, the second
technological wave appeared with narrow applications of molecular target therapy by
nanotechnology (such as cetuximab, lapatinib, etc.). These nanotechnology waves in
medicine are opening new and effective treatments for breast, lung, brain and colon
cancers.



High rate of mortality as driver. The second main finding is the recognition that, since
the late 2000s, the sharp increase of several technological trajectories of
nanotechnology-based anticancer drugs seems to be driven by high rates of mortality of
some types of cancers (e.g. pancreatic and brain) in order to find more effective
therapies that increase the survival of patients. Hence, most importantly,
nanotechnology opens a new era for anticancer treatments where mortality of some
types of cancer is high and traditional drugs /approaches are not effective enough. In
fact, in brain cancer and pancreatic-cancer (where mortality rate is high in comparison
to the incidence, see Tab. 1), although the total research output is low, nanotechnologybased anticancer treatments seem to play an increasingly important role to find groundbreaking therapies that have high effectiveness and low adverse effects.



General and specific nanotechnology-based chemotherapy. The third result is given by
network analysis, which seems to show that there are both general and specific
nanotechnology-based chemotherapy: the first one is based on doxorubicin and
paclitaxel applied by nanotechnology mainly to treat brain, ovarian, breast and lung
cancer; the second one is based on gemcitabine for pancreatic and brain cancer,
20

cisplatin for ovarian cancer, docetaxel for brain and ovarian cancer.


Likely new directions of path-breaking nanotechnology-based molecular cancer
therapy. These new directions, detected by network analysis, seem to be tamoxifen via
nanotechnology to treat brain cancer and lapatinib via nanotechnology to treat
pancreatic cancer.



Specialization of countries. Another result is that some countries show an inner
specialization in nanotechnology-based treatments for specific types of cancer, such as
Singapore and Italy for breast cancer, Switzerland and Greece for prostate cancer, Israel
and Taiwan for lung cancer, Japan and Israel for colon cancer, China13 and Switzerland
for ovarian cancer, Greece and Japan for pancreatic cancer and Switzerland and India
for brain cancer.
These results show vital patterns of nanoscience and nanotechnology in oncology. The

technological trajectories detected may be the foundation for a continuous progress of
nanotechnology in biomedicine, supported by a high intensity of scientific and technological
production growth that accumulates technical knowledge and spurs ground-breaking and
efficient anticancer treatments.
Hence, new nanotechnological avenues are paving a pervasive diffusion in biomedical
sciences and generating a revolution in clinical practice to treat (and we hope to cure) cancers
in order to lead to longer, better and healthier living of societies in a not-too-distant future
(Mangematin and Walsh, 2012).
However, emerging trajectories of nanoscience and nanotechnology are also
problematic in medicine because they have several and unpredictable directions, in particular
when we know that in the life science systems other things are often not equal and can
change in the presence of turbulent and fast-running technological change.

13

Cf. Motoyama et al. (2014).

21

Appendix
Figure 1A: Citations of nanotechnology in cancer treatments per different typology of cancer
(2000-2012)
5,0
4,5
4,0
LN(Citation t)

3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
2002

2003

2004

2005

2006

2007

2008

2009

brain‐cancer

breast‐cancer

colon‐cancer

ovarian‐cancer

pancreatic‐cancer

prostate‐cancer

Note: The logarithm of publications is taken to better present the values.

22

2010

2011

lung‐cancer

2012

Table 1A: Specialization of countries in specific cancer based on new applications of
anticancer drugs via ground-breaking nanotechnology (2000-2012)
COUNTRY
Australia
Canada
China
France
Germany
Greece
India
Iran
Israel
Italy
Japan
Netherlands
Singapore
South Korea
Spain
Sweden
Switzerland
Taiwan
United Kingdom
United States

breast‐
cancer
‐0.174
‐0.021
‐0.003
0.045
0.028
‐0.113
‐0.028
‐0.064
‐0.069
0.093
‐0.004
0.070
0.134
0.050
‐0.002
‐0.073
‐0.027
‐0.072
‐0.008
‐0.012

prostate‐
cancer
‐0.050
0.024
‐0.041
‐0.005
0.019
0.070
‐0.053
‐0.017
0.035
0.003
‐0.028
‐0.029
‐0.110
0.065
‐0.065
0.060
0.112
‐0.065
‐0.040
0.032

lung‐
cancer
‐0.057
‐0.016
0.038
‐0.028
‐0.018
‐0.055
0.025
0.072
0.148
0.000
0.025
‐0.091
0.028
0.079
‐0.104
‐0.042
0.042
0.108
‐0.025
0.007

colon‐
cancer
0.046
‐0.030
0.011
‐0.006
‐0.019
‐0.011
‐0.029
0.042
0.125
‐0.006
0.145
‐0.025
0.122
0.048
0.017
0.035
0.112
0.106
0.024
‐0.009

ovarian‐
cancer

pancreatic‐
cancer

‐0.022
0.040
0.065
‐0.060
‐0.023
‐0.022
‐0.058
0.012
‐0.060
‐0.030
‐0.002
‐0.062
0.027
0.006
‐0.064
0.043
0.048
‐0.021
‐0.029
0.020

brain‐
cancer

‐0.035
‐0.010
0.014
0.012
‐0.012
0.164
0.027
0.016
‐0.002
0.009
0.069
0.030
0.035
‐0.017
0.006
‐0.033
‐0.033
‐0.036
‐0.015
0.013

‐0.026
‐0.001
‐0.023
‐0.014
0.023
‐0.042
0.044
‐0.031
‐0.042
0.015
0.016
‐0.028
0.027
0.006
0.003
‐0.042
0.073
‐0.035
‐0.007
0.004

Note: if i is the country and j is the research field (e.g. Breast cancer), the location of the countries in the map is
given by the index γ that indicates the high specialization of the country i in the specific research field j
;
;

;
1, … , .

In Bold the countries with the highest value γ; moreover, if the index γ0 means high specialization in the
scientific research in this type of cancer, whereas if γ  0 means that there is lower specialization. High values γ
means a higher intensive research activity in the specific cancer area.

23

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