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Compositions and Methods for Transport of Molecules with Enhanced Release Properties Across Biological Barriers

Stanford Reference:



An interdisciplinary team of Stanford inventors has developed drug delivery conjugates, consisting of a drug cargo and molecular transporter, designed to transport cargo (therapeutic, diagnostic, and optical agents) across biological barriers (cell membranes, skin, buccal, lung, etc.) and then controllably release the biologically active cargo only after entering the target environment. Intracellular release can be biological or abiological and can be controlled by target cell or tissue enzymes. The drug-transporter conjugates can be designed to be inactive as conjugates, but to release active drug only after cell entry and at a rate determined by design, thus avoiding bolus effects and ensuring sustained payout. The conjugates are water soluble, easily formulated and can be used for delivery of small molecules therapeutics, peptides, proteins, oligonucleotides, metals, optical probes and diagnostics. The conjugates can be targeted using a kinetic selection strategy complementary to thermodynamic selection based on monoclonal targeting. The conjugates can be used to change or enhance biodistribution, thereby minimizing or eliminating off target toxicity. They can be used to alter metabolism and, significantly, to circumvent Pgp efflux-based resistance. Known drugs suffering from side effects or resistance can thus be re-purposed as effective agents against resistant disease through transporter conjugation. The studies have been conducted in cells and animals and tested successfully ex vivo in patient primary cell samples. One type of transporter has cleared a phase I trial.

Stage of Research
The inventors have completed cellular, in vivo mouse, and ex vivo patient studies which demonstrated that their drug delivery system based on molecular transporters can effect drug-conjugate delivery, drug release, and drug turnover by an intracellular target in real time. The molecular transporters used in this strategy have passed phase I clinical trials. The delivery strategy applies to a range of therapeutic agents and serves to produce conjugates that are water soluble, easily formulated, exhibit enhanced cellular uptake, and release drugs inside a cell at sustained and controllable rates thereby avoiding bolus effects, altering cargo metabolism and biodistribution, and circumventing off target cargo effects. The technology has also been used to study other families of transporters that have potential for topical, buccal and inhalant delivery. Significantly, the research has shown that a drug which elicits resistance can be rendered effective against the resistance mechanism after it is conjugated to a transporter. The mechanism of action of the drug is not changed when delivered as a transporter conjugate but its susceptibility to resistance is. Thus known drugs that suffer from formulation, uptake, bioavailability, bolus effects and/or efflux-based resistance can be re-purposed for clinical use as drug-transporter conjugates. Bioavailability and uptake problems encountered with new drug candidates can also be fixed through transporter conjugation. The delivery strategy works for drugs or probes that are polar (e.g., siRNA), non-polar (e.g., taxol) or of intermediate polarity.

Ongoing Research
This approach has been shown to work in vivo in animal models and ex vivo in primary cells collected from patients undergoing clinical treatment for cancer. In all ex vivo cases, the conjugates outperformed current patient therapy.


  • Drug delivery and new therapeutic strategies - transporters can be used to deliver otherwise poorly soluble or poorly bioavailable drugs by allowing for formulation in water and enabling or enhancing uptake into cells.
    • Transporter conjugates of drugs can enhance or enable bioavailability of known drugs or drug candidates
    • Unlike polar drugs that cannot pass through a non-polar cell membrane and non-polar drugs that are difficult to formulate, transporter conjugates of polar (e.g., siRNA) and non-polar (e.g., taxol) drugs are easily prepared and formulated and readily enter cells
    • Transporter conjugates can be targeted to cells and tissue based on kinetic selection complementary to monoclonal antibody approaches
    • Transporter conjugates can be used to fix problems encountered with known drugs, most notably Pgp-effluxed based resistance, without the need to develop a new drug
    • Transporter conjugates have been shown in a major cancer indication to out perform the current standard of therapy in ex vivo studies with patient samples
    • Transporter conjugates can be used as “molecular patches”, rapidly entering cells but releasing a drug or cargo at a tunable rate determined by design from short to long release periods
    • Transporter conjugates are easily synthesized (typically 3-4 steps), requiring a single functional group (e.g., OH, NHR, etc.) found in the vast majority of drugs.
    • A GMP synthesis of one class of transporters has been conducted.
    • One type of transporter has passed phase I clinical trials
    • Transporter conjugates are shelf stable but can be designed to biodegrade
    • Transporters can be used to deliver small molecules, peptides, proteins, siRNA, metals and other entities into cells
    • Transporter conjugates can be used to deliver 2 or more drugs at different rates from a common carrier
    • Transporters can be used to enable or enhance uptake into skin
    • Transporter conjugates can be used to enhance uptake in stem cells
    • Transporter conjugates can be used to deliver agents across the blood-brain barrier
    • Transporter conjugates can be used to localize drug delivery
    • Transporter conjugates can be used to deliver diagnostic agents
    • Transporter conjugates can be used for imaging studies and applications
  • Tunable - conjugates can be tuned to:
    • control rate of release of free cargo (drug or probe) inside a cell, thereby avoiding bolus effects and allowing for sustained release at therapeutic levels
    • suppress metabolism of cargo
    • minimize off-target effects
    • overcome resistance
    • allows for easier drug formulation
  • Drug discovery:
    • Transporter conjugates can be used to improve “hit rates” of libraries by minimizing or eliminating uncertainties with cell permeation
    • Transporter conjugates can be used to transfect cells
    • Transporter conjugates can be used to introduce biologics and optical agents into cells for pathway analysis
    • Transporter non-covalent complexes can be used to deliver siRNA for protein suppression studies and target validation studies
    • Conjugates with a reporter cargo can be used to screen new transporter agents for cellular uptake and for uptake selectivity
    • Conjugates can be used to screen a variety of linkers
    • Conjugates can be used to provide optimal release kinetics


  • Aqueous formulation - technology allows aqueous formulation of even poorly water soluble agents at high concentration
  • Improve uptake - enables or enhances uptake into cells and tissue of wide variety of agents including small molecules, peptides, proteins, siRNA, imaging probes, quantum dots, nanoparticles, liposomes, and etc.
  • Change biodistribution - by changing the properties of the drug or probe the conjugates show different biodistributions and can be used to target cells and tissue
  • Change metabolism - by altering the properties and distribution of the attached cargo, its distribution and metabolism are changed
  • Localize delivery - such as topical, lung, buccal, or delivery to the eye.
  • Tissue targeting - tissue selective release with “attenuators” linked to the transporter by specific linkers that would be cleaved in certain environments
  • Overcome resistance - by by-passing Pgp exports pumps often over-expressed in resistant cells, the transporters can be use to overcome Pgp based resistance, often the major cause of chemotherapy failure
  • Releasable - to achieve and control activity, the linker moiety is stable under conditions of storage and administration, but releases cargo within the target environment through bioactivation
  • Rapid - transporter screening for distribution, uptake amount and selectivity of uptake can be performed in real-time in living cells and animals
  • Easy to test - transporter conjugates of known drugs or drug leads can be prepared in a few steps and tested rapidly in cells and animals
  • Control - can be used to:
    • control drug release, avoiding bolus effects
    • sustain release as an intracellular “molecular patch”
    • suppress metabolism
    • suppress side effects
    • control selective uptake
    • fix problems with existing drugs
    • fix problems with drug candidates
    • enable or enhance uptake of known or new cargos


Transporter Portfolio

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Licensing Contact

Irit Gal, Senior Licensing Associate
650-723-1586 (Business)
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Related Keywords

therapeutic: drug design   research tool: reagent   research tool: mouse model   therapeutic: drug delivery   screening: screen   



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