Strategically fabricated theranostic nanocarrier delivery system is an unmet need in personalized medicine. Herein, this study reports a versatile folate receptor (FR) targeted nanoenvelope delivery system (TNEDS) fabricated with gold core silica shell followed by chitosan-folic acid conjugate surface functionalization by for precise loading of doxorubicin (Dox), resembled as Au@SiO -Dox-CS-FA. TNEDS possesses up to 90% Dox loading efficiency and internalized through endocytosis pathway leading to pH and redox-sensitive release kinetics. The superior FR-targeted cytotoxicity is evaluated by the nanocarrier in comparison with US Food and Drug Administration (FDA)-approved liposomal Dox conjugate, Lipodox. Moreover, TNEDS exhibits theranostic features through caspase-mediated apoptosis and envisages high surface plasmon resonance enabling the nanoconstruct as a promising surface enhanced Raman scattering (SERS) nanotag. Minuscule changes in the biochemical components inside cells exerted by the TNEDS along with the Dox release are evaluated explicitly in a time-dependent fashion using bimodal SERS/fluorescence nanoprobe. Finally, TNEDS displays superior antitumor response in FR-positive ascites as well as solid tumor syngraft mouse models. Therefore, this futuristic TNEDS is expected to be a potential alternative as a clinically relevant theranostic nanomedicine to effectively combat neoplasia.
Comprehensive
profiling of multiple protein targets plays a critical role in deeper
understanding of specific disease conditions associated with high
heterogeneity and complexity. Herein, we present the design and fabrication
of smart programmable nanoarchitectures, which could integrate clinically
relevant diagnostic modalities for the multiplexed detection of most
prevalent panel of disease biomarkers present in lung cancer. The
multiplex nanoprobes were prepared by attaching dual-functional Raman-active
fluorogens onto spherical gold nanoparticles through a peptide linker,
Phe-Lys-Cys (FKC), which is engineered with a cathepsin B (cathB)
enzyme cleavage site. The presence of cathB induces the scission of
FKC upon homing into the cancer cells, resulting in the release of
the initially latent fluorophores with a concomitant quenching of
the surface-enhanced Raman signal intensity, thereby realizing an
on–off switching between the fluorescence and Raman modalities.
The enzyme-triggered switchable nanoprobes were utilized for the simultaneous
detection of pathologically relevant lung cancer targets by tethering
with specific antibody units. The multiplex-targeted multicolor coded
detection capability of the antitags was successfully developed as
a valid protein screening methodology, which can address the unmet
challenges in the conventional clinical scenario for the precise and
early diagnosis of lung cancer.
We have designed and synthesized novel tetraphenylethylene (TPE) appended organic fluorogens and unfold their unique Raman fingerprinting reflected by surface-enhanced Raman scattering (SERS) upon adsorption on nanoroughened gold surface as a new insight in addition to their prevalent aggregation-induced emission (AIE) and aggregation-caused quenching (ACQ) phenomena. A series of five TPE analogues has been synthesized consisting of different electron donors such as (1) indoline with propyl (TPE-In), (2) indoline with lipoic acid (TPE-In-L), (3) indoline with Boc-protected propyl amine (TPE-In-Boc), (4) benzothaizole (TPE-B), and (5) quinaldine (TPE-Q). Interestingly, all five TPE analogues produced multiplexing Raman signal pattern, out of which TPE-In-Boc showed a significant increase in signal intensity in the fingerprint region. An efficient SERS nanoprobe has been constructed using gold nanoparticles as SERS substrate, and the TPE-In as the Raman reporter, which conjugated with a specific peptide substrate, Cys-Ser-Lys-Leu-Gln-OH, well-known for the recognition of prostate-specific antigen (PSA). The designated nanoprobe TPE-In-PSA@Au acted as SERS "ON/OFF" probe in peace with the vicinity of PSA protease, which distinctly recognizes PSA expression with a limit of detection of 0.5 ng in SERS platform. Furthermore, TPE-In-PSA@Au nanoprobe was efficiently recognized the overexpressed PSA in human LNCaP cells, which can be visualized through SERS spectral analysis and SERS mapping.
Effective treatment
of malignant melanoma requires an appropriate
combination of therapeutic intervention with long-term prognosis as
it often survives by monotherapies. Herein, we report a novel melanoma-targeted
theranostic nanoenvelope (MTTNe: ISQ@BSA-AuNC@AuNR@DAC@DR5) which
has been constructed by assembling a bovine serum albumin (BSA) stabilized
gold nanocluster on a gold nanorod (BSA-AuNC@AuNR), a three-in-one
theranostic modality, i.e., photothermal therapy (PTT), photodynamic
therapy (PDT), and chemotherapy, tethered with a surface-enhanced
Raman scattering (SERS) detection technique. The resultant MTTNe was
coloaded with the melanoma-specific FDA approved drug dacarbazine
(DAC) and a newly synthesized near-infrared (NIR) absorbing squaraine
molecule ISQ that served partly as a photosensitizer and multiplex
Raman reporter. Finally, a nanoenvelope was anchored with anti-DR5
monoclonal antibodies as a targeting motif for highly expressed melanoma-specific
death receptors in malignant cells. Significant phototherapies of
MTTNe were initiated upon an 808 nm single laser trigger which showed
a synergistic effect of photothermal hyperthermia as well as singlet
oxygen (1O2) driven photodynamic effect in the
presence of ISQ followed by on-demand thermoresponsive drug release
in the intracellular milieu. Moreover, a multiplex SERS spectral pattern
of ISQ (1345 cm–1) and DAC (1269 cm–1) has been utilized for monitoring precise drug release kinetics
and target-specific recognition on melanoma cells by Raman imaging.
Therapeutic performance of the nanoenvelope was evaluated by in vitro cytotoxicity studies in human melanoma cells (A375)
and confirmed the apoptotic phenomenon by molecular-level monitoring
of intracellular SERS fingerprints. Finally, to address the biocompatibility
of MTTNe, in vivo subacute toxicity was conducted
on BALB/c mice. Hence, the current studies mark a footstep of a facile
strategy for the treatment of melanoma by synergistic multimodal photothermal/photodynamic/chemotherapy.
Herein, we have examined distinctive structural and functional variations of cellular components during apoptotic cell death induced by a targeted theranostic nanoprobe, MMP-SQ@GNR@LAH-DOX, which acted as a SERS "on/off" probe in the presence of a MMP protease and executed synergistic photothermal chemotherapy, as reflected by the SERS fingerprinting, corresponding to the phosphodiester backbone of DNA.
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