Biomimetic pseudopolyrotaxane prodrug micelles with high drug content for intracellular drug delivery

Background: The conventional chemotherapy has some noticeable drawbacks, such as lack of specificity, the requirement of high drug-dose, adverse effects, and gradual development of multidrug resistance (MDR), that reduce the efficacy of cancer therapy. Aim: To achieve intracellular drug delivery, strategies for overcoming various biologic barriers from the system level to the organ level, to the cellular level. To win through over these challenges in chemotherapy is to be achieving high drug loading combination with low leakage at physiologic pH, minimal toxicity toward healthy cells, and tunable controlled release at the site of action is an ongoing challenge. Methods: To assist drug delivery, we have prepared PVPylated-TiO2NPs consisting of Qtn with high loading efficiency (26.6% w/w) for NDDS. Qtn-PVPylated-TiO2NPs uptake via endocytosed by cancer cells able to generate intracellular ROS, to decrease the mitochondrial membrane potential loss (Δψm) to release cytochrome- c, Bcl-2 dysregulation into the cytosol and then activating caspase-3 to induce cancer cell apoptosis. Results: These novel nanocombinations can be used to improve cancer nanotherapy by induction of apoptosis in vitro. Analysis at molecular level revealed that Qtn-PVPylated-TiO2NPs nanocombination induced Δψm-mediated apoptotic signaling pathway. Conclusion: To our knowledge, this is a novel report using Qtn-PVPylated-TiO2NPs nanocombinations to study the pH-dependent intracellular NDDS to cancer cells. This new nanoformulations of this study may further advance the use of Qtn-PVPylated-TiO2NPs based nanotherapeutic of biomaterials for various biomedical applications, especially cancer nanotherapy.

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Polyprodrug with ultra-high drug content for tumor intracellular acid-triggered degradation and drug delivery

European Polymer Journal ◽

10.1016/j.eurpolymj.2021.110820 ◽

2021 ◽

pp. 110820

Author(s):

Xinming Li ◽

Xiaomei Zhao ◽

Peng Liu

Keyword(s):

Drug Delivery ◽

High Drug ◽

Drug Content ◽

Intracellular Acid

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Doxorubicin Loaded Nanoparticle Consisting of Chitosan and Mannose Modified Graphene Oxide for Intracellular Drug Delivery and Anti-tumor Activity

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2020.13.5.13 ◽

2020 ◽

Vol 13 (5) ◽

pp. 5155-5164

Author(s):

Meena K. S. ◽

Sonia K ◽

Alamelu Bai S

Keyword(s):

Drug Delivery ◽

Graphene Oxide ◽

Drug Delivery System ◽

Delivery System ◽

In Vitro Release ◽

Cancer Drug ◽

Hemolysis Assay ◽

Functionalized Graphene Oxide ◽

Intracellular Drug Delivery ◽

Modified Graphene Oxide

In order to develop the efficiency and the specificity of anticancer drug delivery, we have designed an innovative nanocarrier. The nanocarrier system comprises of a multifunctional graphene oxide nanoparticle-based drug delivery system (GO-CS-M-DOX) as a novel platform for intracellular drug delivery of doxorubicin (DOX). Firstly, graphene oxide (GO) was synthesized by hummer’s method whose surface was functionalized by chitosan (CS) in order to obtain a more precise drug delivery, the system was then decorated with mannose (M). Further conjugation of an anti-cancer drug doxorubicin to the nanocarrier system resulted in GO-CS-M-DOX drug delivery system. The resultant conjugate was characterized for its physio-chemical properties and its biocompatibility was evaluated via hemolysis assay. The drug entrapment efficiency is as high as 90% and in vitro release studies of DOX under pH 5.3 is significantly higher than that under pH 7.4. The anticancer activity of the synthesized drug delivery system was studied by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay against MCF-7 cell line. These results stated that the pH dependent multifunctional doxorubicin- chitosan functionalized graphene oxide based nanocarrier system, could lead to a promising and potential platform for intracellular delivery and cytotoxicity activity for variety of anticancer drugs.

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Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study

Biomolecules ◽

10.3390/biom11070927 ◽

2021 ◽

Vol 11 (7) ◽

pp. 927

Author(s):

Sebas D. Pronk ◽

Erik Schooten ◽

Jurgen Heinen ◽

Esra Helfrich ◽

Sabrina Oliveira ◽

...

Keyword(s):

Drug Delivery ◽

Targeted Delivery ◽

Single Domain ◽

Drug Conjugates ◽

Intracellular Drug Delivery ◽

Internalization Rate ◽

Single Domain Antibodies ◽

Different Characteristics

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRβ, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates.

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