Nanomaterials: Versatile Drug Carriers for Nanomedicine
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would help to change cellular ion balance. When pHLIP-liposomes target the cancer
cells, they are either fused to the plasma membrane or up-taken by endocytosis and
then merged with a lysosomal layer. Here, the gramicidin A is delivered, and pores
with a diameter of 4–5 ˚A are formed in the cell membranes of cancer cells [133].
The intracellular space is acidified due to the nanopores, thus eliminating the vital
NA+/K+ ion balance. Along with the treatment strategy to solid acidic tumors, it
also opens new opportunities to deliver various membrane proteins and peptides to
the cells widening the application of nanomedicine and biotechnology.
Yao et al. showed AuNPs (1.4 nm diameter) were coupled to pHLIP at N-terminus,
which successfully targeted cancer cells at low pH [134]. In vivo studies were done
using mice-tumor models, showing high uptake of NPs by tumors in both intratumoral and intravenous administration when compared with non-functionalized
AuNPs. The pHLIP-AuNPs provided the capability of specific targeting, increased
homogenous local concentration in a solid tumor, allowing NPs to remain inside of
a cell for several days, thus helping in radiation therapy and imaging.
Davies et al. used pHLIP luminescent europium coated nanoparticles into platelets
[135]. The AuNPs (13 nm) were co-coated with pHLIP and luminescent europium
(EuL) to give pHLIP-EuL-Au NPs. Human platelets are vulnerable to microinjection
or transfection. But with the help of this method, NPs consisting of approximately
640 lanthanides per particle were delivered. This resulted that NPs could internalize
into platelets only at low pH. This research signifies that pHLIP helps to translocate
NPs in a pH-dependent manner.
Han et al. reported the use of pHLIP in delivering pDNA to cancer cells [136].
The surface of dendrigraft poly-l-lysines (DGLs) of generation 3 with 123 amino
groups per molecules was conjugated to N-terminus of pHLIP. This electrostatically interacted between positively charged DGL head group of DGL-PEG-pHLIP
and negatively charged pDNA to create DGL-PEG-pHLIP/pDNA NPs. The in vitro
results revealed the uptake of NPs at pH 6.0. Thus, the NPs entered the cells by
absorptive endocytosis. The same effects were observed in in vivo studies. This
clearly showed the enhanced pH-controlled NPs localization by pHLIP in tumors.
pHLIP peptide could target tumors in acidic micro-environment along with the
controlled release of NPs in the intracellular spaces [137]. The researchers chose
mesoporous silica nanoparticles (especially MCN-41) to load with doxorubicin.
MSN has high homogenous porosity, biocompatibility, payload capacity, inertness,
and could quickly surface functionalized. MSN particles connected the pHLIP at Cterminus by a disulfide bond. At pH < 6.5, doxorubicin-loaded pHLIPs-MSN were
pressed into the cell membrane and translocated into cytosol. The doxorubicin was
released by cleaving the disulfide bond into the cytoplasm.
There are various challenges faced by the nano-drug delivery system and yet to
overcome. Every nano-drug platform should be assessed experimentally, which can
be found to be strenuous. Here the physical targeting of nanomedicine, especially the
pHLIP nanotechnology, alone or combined with other approaches, has been found
to have the inherent capability to address most of the difficulties and challenges with
new formulations translatable to clinical trials.
281
would help to change cellular ion balance. When pHLIP-liposomes target the cancer
cells, they are either fused to the plasma membrane or up-taken by endocytosis and
then merged with a lysosomal layer. Here, the gramicidin A is delivered, and pores
with a diameter of 4–5 ˚A are formed in the cell membranes of cancer cells [133].
The intracellular space is acidified due to the nanopores, thus eliminating the vital
NA+/K+ ion balance. Along with the treatment strategy to solid acidic tumors, it
also opens new opportunities to deliver various membrane proteins and peptides to
the cells widening the application of nanomedicine and biotechnology.
Yao et al. showed AuNPs (1.4 nm diameter) were coupled to pHLIP at N-terminus,
which successfully targeted cancer cells at low pH [134]. In vivo studies were done
using mice-tumor models, showing high uptake of NPs by tumors in both intratumoral and intravenous administration when compared with non-functionalized
AuNPs. The pHLIP-AuNPs provided the capability of specific targeting, increased
homogenous local concentration in a solid tumor, allowing NPs to remain inside of
a cell for several days, thus helping in radiation therapy and imaging.
Davies et al. used pHLIP luminescent europium coated nanoparticles into platelets
[135]. The AuNPs (13 nm) were co-coated with pHLIP and luminescent europium
(EuL) to give pHLIP-EuL-Au NPs. Human platelets are vulnerable to microinjection
or transfection. But with the help of this method, NPs consisting of approximately
640 lanthanides per particle were delivered. This resulted that NPs could internalize
into platelets only at low pH. This research signifies that pHLIP helps to translocate
NPs in a pH-dependent manner.
Han et al. reported the use of pHLIP in delivering pDNA to cancer cells [136].
The surface of dendrigraft poly-l-lysines (DGLs) of generation 3 with 123 amino
groups per molecules was conjugated to N-terminus of pHLIP. This electrostatically interacted between positively charged DGL head group of DGL-PEG-pHLIP
and negatively charged pDNA to create DGL-PEG-pHLIP/pDNA NPs. The in vitro
results revealed the uptake of NPs at pH 6.0. Thus, the NPs entered the cells by
absorptive endocytosis. The same effects were observed in in vivo studies. This
clearly showed the enhanced pH-controlled NPs localization by pHLIP in tumors.
pHLIP peptide could target tumors in acidic micro-environment along with the
controlled release of NPs in the intracellular spaces [137]. The researchers chose
mesoporous silica nanoparticles (especially MCN-41) to load with doxorubicin.
MSN has high homogenous porosity, biocompatibility, payload capacity, inertness,
and could quickly surface functionalized. MSN particles connected the pHLIP at Cterminus by a disulfide bond. At pH < 6.5, doxorubicin-loaded pHLIPs-MSN were
pressed into the cell membrane and translocated into cytosol. The doxorubicin was
released by cleaving the disulfide bond into the cytoplasm.
There are various challenges faced by the nano-drug delivery system and yet to
overcome. Every nano-drug platform should be assessed experimentally, which can
be found to be strenuous. Here the physical targeting of nanomedicine, especially the
pHLIP nanotechnology, alone or combined with other approaches, has been found
to have the inherent capability to address most of the difficulties and challenges with
new formulations translatable to clinical trials.