Editorial
(wileyonlinelibrary.com) DOI 10.1002/jctb.4689
Advances in Drug Delivery
Recent advances in drug delivery stem from innovation in
nano/microparticle design, innovative biomaterials, new drugs
(including posttranscriptional gene silencing nucleotides) and
nanoparticle targeting moieties. These drug delivery systems are
a product of innovative bio-nanomaterial design and construction,
whereby the components are assembled via various chemistries
and physicochemical interactions to create new therapeutic enti-
ties that have therapeutic and/or imaging capability. Indeed the
combination of therapeutics and imaging has given rise to thera-
nostic agents, whereby the eect of the therapy may be monitored
over time through imaging. Biomaterials have played an equally
important role in allowing the delivery of these products. The
biocompatibility, biodegradability (including the rate of degra-
dation), encapsulation eciency and porosity of the particles are
major determining factors for the choice of the most suitable
biomaterial.
A large number of biodegradable polymers have been explored
for the development of suitable drug delivery systems. These
include both synthetic and natural polymers. The most com-
monly used synthetic polymers include Polylactic acid (PLA),
Polylactic acid-co-glycolic acid (PLGA), Polycaprolactone (PCL),
Polydiaxanone (PDS), Polyanhydrides and Polyamides. In con-
trast, the natural polymers used for the development of drug
delivery systems include collagen, chitosan, polyhydroxyalka-
noates, hyaluronic acid, gelatin, alginate, dextran and starch.
These have varying material properties and degradation rates
which can be used for controlled delivery in dierent applica-
tions. In addition, the natural and synthetic polymers vary in their
degree of hydrophobicity/hydrophilicity and hence can be used
for the delivery of polar and nonpolar drugs. These polymers can
therefore be processed to form micro/nanoparticles, scaolds
and implants to release the drug in a controlled manner. Also,
these polymers can be used to develop targeted drug delivery
constructs, especially in the context of cancer therapy.
Although there have been many clinical trials utilising nano/
microparticles composed of a myriad of dierent materials, there
are less than ten approved nanomedicines for the treatment of
cancer, as reported by Sanna et al. (2014).1 The goal of seques-
tering within or attaching drugs to nanoparticles is to reduce
the bio-distribution and hence the required dosage. Additionally
nanoparticles can be targeted to the tumour site, reduce o-target
toxicity and ideally enhance the pharmacokinetics of cytotoxic
agents. Many chemotherapeutic drugs have limited water solu-
bility and partitioning within a hydrophobic core or entrapment
within hydrophobic nanoparticles is an ecient method of deliv-
ery.
The development of multiple drug resistance (MDR) in patients
remains a major obstacle in the treatment of cancer. Nanopar-
ticles may carry a payload of multiple drugs including small
molecule therapeutics and siRNA, for example. The delivery of a
cocktail of drugs at high dose to the tumour site can negate MDR
through rstly challenging tumour cells with drugs that operate
J Chem Technol Biotechnol 2015; 90: 11671168 www.soci.org
through dierent cytotoxic mechanisms, and secondly by over-
whelming drug eux from tumour cells via membrane-bound P
glycoprotein.
Currently, approved nanomedicines are all passively targeted
nanoparticles with payloads consisting of various chemothera-
peutic drugs.1 Targeted nanoparticles utilising peptides, antibody
fragments and other ligands can increase the uptake of nanopar-
ticles into tumour cells, while not altering the amount accumu-
lating at the tumour site through passive targeting. Although
the consensus is that this active targeting of nanoparticles has
advantages, there are nevertheless many obstacles to nanoparticle
delivery to tumour sites, including evading the reticuloendothe-
lial system, extravasation through fenestrated endothelium and
subsequent penetration of biological barriers that, depending on
tumour location, might include smooth muscle cells, peri-cellular
tissue, tumour stromal cells and broblasts. Furthermore, poor
lymphatic drainage of tumours manifests in a hydraulic pressure
gradient away from the tumour, further hindering nanoparticle
penetration. Notwithstanding these obstacles there are several
targeted nanomedicines in clinical trial, as reported by Sanna et al.,
(2014).1 Through optimising particle attributes including size,
shape, charge, modulus and chemistry, and by selecting appro-
priate drug combinations, it is likely that drug-laden, targeted
nanoparticles will become an ecacious therapeutic modality for
the treatment of cancer.
This In Focus issue of JCTB addresses advances in drug delivery,
and covers a broad range of topics. Goodall et al. has designed
a self-assembling polymeric nanoparticle based on PNIPAM, and
shows that direct conjugation of an antibody scFv fragment(s)
results in a potentially multi-targeted nanoparticle.2 Buecheler
et al. have created a cysteine mutant protein cage based on the
E1 subunit of pyruvate decarboxylase.3 The free thiol subunit of
the E1 subunit allows conjugation of a scFv with an engineered
C-terminal cysteine through a bifunctionalised maleimide linker.
The protein cage nanoparticle has potential as a theranostic agent.
A mini-review by Goodall et al. focuses on antibody-targeted
polymeric nanoparticles, and highlights the potential of antibody
fragments as targeting agents for these nanoparticles.4 Although
liposomal-based nanoparticles have been approved for therapy,
polymeric nanoparticles are more versatile and oer some advan-
tages over liposomes. Antibodies that have been selected for tar-
geting and the various strategies for creating polymeric nanopar-
ticles are discussed along with recent strategies for preparing
biopolymer conjugates.
A review by Ardana et al. revisits gene therapy as a therapeu-
tic approach, despite the problems and pitfalls that have ham-
pered the development of gene therapy as a mainstream thera-
peutic modality.5 Gene therapy has re-emerged as an extremely
promising therapeutic approach, providing a means to regulate
gene expression in animals. However, the complexities associated
with not only delivering the gene to the tissue of interest, but
also into the correct cellular compartment, has proved a signi-
cant hurdle to translation of the technology to clinical use. The
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review article entitled Polymeric siRNA delivery vectors: knocking
2015 Society of Chemical Industry
 www.soci.org
down cancers with polymeric-based gene delivery systems high-
lights recent advances in polymeric vectors as delivery vehicles for
gene therapeutics and describes some of the approaches that are
utilised to improve therapeutic ecacy.
Molecular imaging plays a key role in understanding the eec-
tiveness of drug delivery. Puttick et al. describe recent advances
in utilising simultaneous positron emission tomography and mag-
netic resonance imaging in their manuscript entitled Imaging
tumour distribution of a polymeric drug delivery platform in vivo
by PET-MRI.6 The study describes the increased information that
can be obtained from the technique and uses an animal tumour
model as an exemplar.
A review by Blunden and Stenzel highlights the potential of
Ruthenium complexes as anti-cancer drugs. 7 Ruthenium pos-
sesses unique properties that have led to the development of
promising anticancer and antimetastatic therapeutics, for example
RAPTA-C, KP1019 and NAMI-A. Ruthenium can exhibit three oxi-
dation states under physiological conditions and is able to form
macromolecular structures with multiple ligands. These macro-
molecules are able to be encapsulated within nanoparticles for
enhancing the stability and bioavailability.
The review by Roy et al. describes the use of a particular group
of natural polymers, Polyhydroxyalkanoates (PHAs), in the devel-
opment of drug delivery systems.8 The PHAs are a family of
polymers produced by bacteria under nutrient limiting con-
ditions with properties that can be varied depending on the
monomer composition of the PHA. Hence, depending on the
requirement of the specic drug delivery, the biocompatibil-
ity, degradation rate and hence the pharmacokinetics of drug
release can be tailored by using a particular PHA within the
family. The review describes both passive and targeted drug
delivery systems using PHAs. Within the biodegradable implants,
P(3HB-co-4HB) and P(3HB-co-3HV) rods loaded with antibiotics,
P(3HB-co-3HV) orthopaedic discs, P(3HB)/P(4HB) based glau-
coma drainage implants and P(3HB)/P(3HO) blend based stents
have been described. Tablets based on PHAs were found not
to be used extensively, possibly due to the cost factor. Micro-
sphere/nanosphere formulations using a wide range of PHAs
were described including P(3HB), P(3HB-co-3HV), P(3HB-co-4HB),
amphiphilic copolymers such as P(3HB-co-3HHx)-b-PEG and PHA
based blends and composites. Finally, targeted drug delivery
using folate mediated delivery and polyhydroxyalkanoate bind-
ing proteins were described, including interesting theranostic
applications. This review conrmed that polyhydroxyalkanaotes
were promising future materials for the development of a range
of unique targeted and non-targeted drug delivery systems.
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wileyonlinelibrary.com/jctb 2015 Society of Chemical Industry
Editorial
The investigations presented in this In Focus Advances in Drug
Delivery issue (28) are examples of innovations and advances
in drug delivery, and are a snapshot of the extensive and diverse
approaches to research occurring globally in drug delivery. We are
hopeful that more of these innovations will be translated from the
clinic to medical practice in the not too distant future, paving a
way forward for more eective and tolerable cancer therapies. We
wish to thank the contributing authors to this In Focus Advances
in Drug Delivery issue. We would also like to thank the Executive
Editors and Editorial Sta of JCTB, for their invaluable assistance
and advice in compiling and publishing this issue.
Guest Editors
Stephen Mahler, Australian Institute for Bioengineering and
Nanotechnology (AIBN), University of Queensland (UQ), Brisbane,
QLD 4072, Australia.
Ipsita Roy
Department of Life Sciences, Faculty of Science and Technology,
University of Westminster, London W1W 6UW, United Kingdom.
REFERENCES
1 Sanna V, Pala N, Sechi M, Targeted therapy using nanotechnology:
Focus on cancer. Int Nanomedicine 9:467483 (2014).
2 Goodall S, Howard CB, Jones ML, Munro T, Jia Z, Monteiro M et al., An
EGFR Targeting Immunomicelle Self Assembled using a Thermore-
sponsive Polymer. J Chem Technol Biotechnol 90:1222-1229 (2015).
3 Buecheler JW, Howard CB, de Bakker CJ, Goodall S, Jones ML, Win T et al.,
Development of a protein nanoparticle platform for targeting EGFR
expressing cancer cells. J Chem Technol Biotechnol 90:1230-1236
(2015).
4 Goodall S, Jones ML, Mahler S, Monoclonal Antibody-Targeted Poly-
meric Nanoparticles for Cancer Therapy Future Prospects. J Chem
Technol Biotechnol 90:1169-1176 (2015).
5 Ardana A, Whittaker AK, McMillan NAJ, Thurecht KJ, Polymeric siRNA
delivery vectors: knocking down cancers with polymeric based gene
delivery systems. J Chem Technol Biotechnol 90:1196-1208 (2015).
6 Puttick S, Boase NRB, Blakey I, Thurecht KJ, Imaging tumour distribution
of a polymeric drug delivery platform in vivo by PET-MRI. J Chem
Technol Biotechnol 90:1237-1244 (2015).
7 Blunden BM, Stenzel MH, Incorporating ruthenium into advanced drug
delivery carriers an innovative generation of chemotherapeutics. J
Chem Technol Biotechnol 90:1177-1195 (2015).
8 Nigmatullin R, Thomas P, Lukasiewicz B, Puthussery H, Roy I, Polyhydrox-
yalkanoates, a family of natural polymers, and their applications in
drug delivery. J Chem Technol Biotechnol 90:1209-1221 (2015).
J Chem Technol Biotechnol 2015; 90: 11671168