154 Page 16 of 17
Pharm Res
(2019) 36:154
In the literature there are many examples of improved
drug delivery as a promising strategy to optimise the effective-
ness of anticancer drugs while reducing the toxicity associated
with treatment. This study is the first step towards enhancing
our knowledge about the design of selective conjugates which
can be successfully used for targeted therapy.
REFERENCES
1. Vicent MJ, Duncan R. Polymer conjugates: nanosized medicines
for treating cancer. Trends Biotechnol. 2006;24(1):39–47.
2. Hurrell T, Outhoff K. The in vitro influences of epidermal
growthfactor and heregulin-β1 on the efficacy of trastuzumab used
in Her-2positive breast adenocarcinoma. Cancer Cell Int. 2013;13:97.
3. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L,
Tubiana-Hulin M, et al. Randomized phase II trial of the efficacy
and safety of trastuzumab combined with docetaxel in patients with
human epidermal growth factor receptor 2-positive metastatic
breast cancer administered as first-line treatment: the M77001
study group. J Clin Oncol. 2005;23:4265–74.
CONCLUSION
Preclinical studies have demonstrated that HER-2 overex-
pression occurs in over 20% of breast carcinomas and is asso-
ciated with resistance to anticancer drugs such as paclitaxel
and docetaxel (28). Such studies have also reported the addi-
tive effects of synergistic interactions between trastuzumab
and taxanes (29). The present study presents the successful
synthesis and characterisation of the HER-2-targeted conju-
gates PAMAM-doc-trastuzumab and PAMAM-ptx-
trastuzumab. Analysis of the cytotoxicity, cellular uptake and
internalisation of the conjugates indicate that they represent
promising carriers for HER-2-expressing tumour-selective de-
livery. The observed selectivity is achieved not only through
the inclusion of trastuzumab, which binds and blocks HER-2,
but also through the selection of a pH-sensitive linker that
breaks in the tumour environment to allow PAMAM-drug
conjugate release. Both conjugates show potential as drug
delivery systems enhancing the therapeutic index and reduc-
ing the required dosage of anticancer drugs. In our opinion
these conjugates might be superior for in vivo application due
to their increased toxicity for HER-2-positive breast cancer
due to specific targeting to tumor cells.
4. National Comprehensive Cancer Network (NCCN): Breast Cancer
Guidelines.
5. Datko F, D'Andrea G, Dickler M, Theodoulou M, Goldfarb S,
Lake D, et al. Abstract P5-18-20: phase II study of pertuzumab,
trastuzumab, and weekly paclitaxel in patients with metastatic
HER2-overexpressing metastatic breast cancer. Cancer Res.
2012;72(24 Suppl):18–20.
6. Esfand R, Tomalia DA. Poly(amidoamine) (PAMAM) dendrimers:
from biomimicry to drug delivery and biomedical applications.
Drug Discov Today. 2001;6:427–36.
7. Teow HM, Zhou Z, Najlah M, Yusof SR, Abbott NJ, D'Emanuele
A. Delivery of paclitaxel across cellular barriers using a dendrimer-
based nanocarrier. Int J Pharm. 2013;441(1–2):701–11.
8. Khandare JJ, Jayant S, Singh A, Chandna P, Wang Y, Vorsa N,
et al. Dendrimer versus linear conjugate: influence of polymeric
architecture on the delivery and anticancer effect of paclitaxel.
Bioconjug Chem. 2006;17(6):1464–72.
9. Miyano T, Wijagkanalan W, Kawakami S, Yamashita F, Hashida
M. Anionic amino acid dendrimer-trastuzumab conjugates for spe-
cific internalization in HER2-positive cancer cells. Mol Pharm.
2010;7:1318–27.
10. Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its
role in cancer. Biochim Biophys Acta. 1994;1198(2–3):165–84.
11. Duncan R. The dawning era of polymer therapeutics. Nat Rev
Drug Discov. 2003;2:347–60.
12. Khandare J, Kolhe P, Pillai O, Kannan S, Lieh-Lai M, Kannan
RM. Synthesis, cellular transport, and activity of polyamidoamine
dendrimer-methylprednisolone conjugates. Bioconjug Chem.
2000;16(2):330–7.
13. Garea SA, Ghebaur A. FT-IR spectroscopy and thermogravimetrical
characterization of prodrugs based on different dendritic polymers
and antitumoral drug. Materiale Plastice. 2012;49:1–4.
14. Marcinkowska M, Sobierajska E, Stanczyk M, Janaszewska A,
Chworos A, Klajnert-Maculewicz B. Conjugate of PAMAM dendri-
mer, doxorubicin and monoclonal antibody-trastuzumab: The new
approach of a well-known strategy. Polymers 2018; 10 (2), art. no. 187.
15. Ciolkowski M, Petersen JF, Ficker M, Janaszewska A, Christensen
JB, Klajnert B, et al. Surface modification of PAMAM dendrimer
improves its biocompatibility. Nanomedicine. 2012;8(6):815–7.
16. Yabbarov NG, Posypanova GA, Vorontsov EA, Popova ON,
Severin ES. Targeted delivery of docetaxel/paclitaxel: drug deliv-
ery system based on PAMAM dendrimers. Biochemistry. 2013;78:
884–94.
ACKNOWLEDGMENTS AND DISCLOSURES
This work was sponsored by the National Science Centre
(Project: “Nanoparticle conjugates with the monoclonal anti-
body – a new opening in target tumor therapy” UMO-2015/
19/N/NZ3/02942).
AUTHOR CONTRIBUTIONS
The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License
mits unrestricted use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made.
17. Zhu S, Hong M, Zhang L, Tang G, Jiang Y, Pei Y. PEGylated
PAMAM dendrimer-docetaxel/paclitaxel conjugates: in vitro
evaluation and in vivo tumor accumulation. Pharm Res.
2010;27:161–74.
18. Shukla R, Thomas TP, Desai AM, Kotlyar A, Park SJ, Baker JR.
HER2 specific delivery of methotrexate by dendrimer conjugated
anti-HER2 mAb. Nanotechnology. 2008;19:295102.