Bio‐Responsive Macromolecular Drug and Small‐Molecular Drug Conjugates: Nanoparticulate Prodrugs for Tumor Microenvironment Heterogeneity Management and Therapeutic Response Enhancement

Abstract

How to break through the poor response of current drug therapy, which often resulted from tumor microenvironment heterogeneity (TMH), remains an enormous challenge in the treatment of critical diseases. In this work, a practical solution on bio‐responsive dual‐drug conjugates for overcoming TMH and improving antitumor treatment, which integrates the advantages of macromolecular drugs and small‐molecular drugs, is proposed. Nanoparticulate prodrugs based on small‐molecular drug and macromolecular drug conjugates are designed as a robust weapon for programmable multidrug delivery at tumor‐specific sites: the tumor microenvironment acid condition triggers delivery of macromolecular aptamer drugs (AX102) to manage TMH (including tumor stroma matrix, interstitial fluid pressure, vasculature network, blood perfusion, and oxygen distribution), and intracellular lysosomal acid condition activates rapid release of small‐molecular drugs (doxorubicin and dactolisib) to enhance curative effects. As compared with doxorubicin chemotherapy, the tumor growth inhibition rate is enhanced by 47.94% after multiple tumor heterogeneity management. This work verifies that the nanoparticulate prodrugs facilitate TMH management and therapeutic response enhancements, as well as elucidates synergetic mechanisms for drug resistance reversal and metastasis inhibition. It is hoped that the nanoparticulate prodrugs will be an excellent demonstration of the co‐delivery of small‐molecular drugs and macromolecular drugs.

Hyperbranched Polymeric 19F MRI Contrast Agents with Long T2 Relaxation Time Based on β-Cyclodextrin and Phosphorycholine

“…These findings indicate that CD-CF 3 -4 undergoes metabolic processes primarily through the liver and kidney, akin to polymers with similar structures, as reported in previous studies. 67,68 Additionally, the accumulation of CD-CF 3 -4 within the tumor suggests its potential for in vivo tumor imaging by using 19 F MRI techniques. The promising results of 19 F MRI in vitro and at the cellular level promote an investigation of the in vivo imaging capabilities of CD-CF 3 -4.…”

Iterative Design Reveals Molecular Domain Relationships in Supramolecular Peptide–Drug Conjugates

“…9,10 The enhanced therapeutic potential of sPDCs has been increasingly appreciated, 11,12 and exciting recent advances are sPDC formulations that codeliver both chemotherapies and immunotherapies, 13,14 sPDCs that gel in situ on contact with physiological environments, 13−15 and the potential to incorporate bioactive targeting and therapeutic functionalities, such as through integrin or collagen binding peptide sequences, 9,16 and DNA aptamers. 17 Accordingly, sPDC materials constitute a growing class of peptide-based materials being explored for applications in drug delivery. 18 A continuing challenge in these materials comes in elucidating and controlling the contributions from prodrug− prodrug interactions in the desolvated nanofiber core to the self-assembly pathway and the material properties of the hydrogels.…”

“…sPDCs typically include a small molecule prodrug as a hydrophobic block attached to a more hydrophilic and (typically) β-sheet-forming peptide to yield an amphiphilic molecular design; the prodrug motif promotes hydrophobic association of the resulting amphiphilic molecules in aqueous environments and contributes to the self-assembly of precise nanostructures . The most commonly produced nanoforms are high aspect-ratio one-dimensional nanofibers, which may further engage in physical entanglements to form hydrogels useful as localized drug delivery depots. , The enhanced therapeutic potential of sPDCs has been increasingly appreciated, , and exciting recent advances are sPDC formulations that codeliver both chemotherapies and immunotherapies, , sPDCs that gel in situ on contact with physiological environments, − and the potential to incorporate bioactive targeting and therapeutic functionalities, such as through integrin or collagen binding peptide sequences, , and DNA aptamers . Accordingly, sPDC materials constitute a growing class of peptide-based materials being explored for applications in drug delivery …”

Systemic Administration with Bacteria-Inspired Nanosystems for Targeted Oncolytic Therapy and Antitumor Immunomodulation

“…Third, enlightened by the bacterial infection microenvironment and tumor microenvironment, 30,31 we engineered a tumor acidcleavable shielding of oncolytic peptides, reducing damage to normal tissues while inventing tumor-specific oncolysis. 32,33 Fourth, inspired by bacterial cell walls, we have utilized tumortargeting RGD-functionalized oligosaccharides to mimic cell walls through electrostatic interactions, providing invisible cloaks during long-acting transportation but tumor-specific targeting. 34 Last, actuated by the limitations of oncolysisinduced immune suppression, 10 we have exploited cytoplasmlike pockets of OBNs to deliver tumor immunomodulator, reversing the immunosuppressive microenvironments.…”

“…Second, inspired by the specific d -amino acid composition of bacteria and amino acid sequences of oncolytic peptides, we have designed dendritic oncolytic peptides with homochiral tryptophan-rich residues surrounding nanorods via coordination interactions, thereby enhancing oncolytic activity based on multivalent effects and supramolecular effects. Third, enlightened by the bacterial infection microenvironment and tumor microenvironment, , we engineered a tumor acid-cleavable shielding of oncolytic peptides, reducing damage to normal tissues while inventing tumor-specific oncolysis. , Fourth, inspired by bacterial cell walls, we have utilized tumor-targeting RGD-functionalized oligosaccharides to mimic cell walls through electrostatic interactions, providing invisible cloaks during long-acting transportation but tumor-specific targeting . Last, actuated by the limitations of oncolysis-induced immune suppression, we have exploited cytoplasm-like pockets of OBNs to deliver tumor immunomodulator, reversing the immunosuppressive microenvironments.…”